According to the WHO, breast cancer is the most common cancer in women worldwide. Identification of underlying mechanisms in breast cancer progression is the main concerns of researches. The mechanical forces within the tumor microenvironment, in addition to biochemical stimuli such as different growth factors and cytokines, activate signaling cascades, resulting in various changes in cancer cell physiology. Cancer cell proliferation, invasiveness, migration, and, even, resistance to cancer therapeutic agents are changed due to activation of mechanotransduction signaling. The mechanotransduction signaling is frequently dysregulated in breast cancer, indicating its important role in cancer cell features. So far, a variety of experimental investigations have been conducted to determine the main regulators of the mechanotransduction signaling. Currently, the role of miRNAs has been well-defined in the cancer process through advances in molecular-based approaches. miRNAs are small groups of RNAs (∼22 nucleotides) that contribute to various biological events in cells. The central role of miRNAs in the regulation of various mediators involved in the mechanotransduction signaling has been well clarified over the last decade. Unbalanced expression of miRNAs is associated with different pathologic conditions. Overexpression and downregulation of certain miRNAs were found to be along with dysregulation of mechanotransduction signaling effectors. This study aimed to critically review the role of miRNAs in the regulation of mediators involved in the mechanosensing pathways and clarify how the cross-talk between miRNAs and their targets affect the cell behavior and physiology of breast cancer cells.

Breast cancer remains one of the most prevalent cancers among women in the world. According to the WHO report in 2018, 627,000 deaths have been reported from breast cancer, accounting for approximately 15% of all cancer-related deaths among women (1). The etiology of breast cancer is a complex phenomenon in which many genetic and epigenetic factors are involved (2, 3). As a tumor grows, its genetic and epigenetic features alter as a result of microenvironment changes and, even, therapeutic pressure. Moreover, changes in the genetic and epigenetic features of cancer cells mutually have an impact on the cancer microenvironment (4–7). The cancer microenvironment is composed of many players such as extracellular matrix (ECM), stromal cells, and tissue-specific cells. ECM, as a main niche for normal and tumor cells, plays an important role in cell hemostasis (8). Collagens are a major component of ECM. However, other compartments, including hyaluronan and proteoglycans, participate in ECM formation (9, 10). It is well-documented that the physical properties of ECM, including stiffness and topologic features, profoundly affect cancer stem cell behaviors (11). In the breast tumor microenvironment, overexpression of various ECM components increases the stiffness of tumor niche, which alter the biological behaviors of cancer cells (12). Breast cancer cells cultured on a stiff substrate showed an increased expression of breast cancer stem cell markers through activation of the ILK/PI3K/Akt pathway (12). It is also reported that the adhesion of breast cancer stem cells to ECM components, such as hyaluronic acid through CD44, increases the expression of genes involved in cancer stem cell development and drug resistance, including NANOG/SOX2 and Multi Drug Resistance 1, respectively (13). Topologic features of ECM also alter the migration of cancer cells so that breast cancer cell invasion is facilitated when the collagen fibers radially align relative to tumors (14). These data showed that ECM must be considered as an important environmental factor that can affect the biological behaviors of breast cancer cells (Fig. 1.) In addition to ECM, tumor cells encounter with different mechanical forces that alter their biological behavior. In recent years, various studies have been carried out to find the effect of different mechanical stresses on the various characteristics of cancer cells such as proliferation, invasiveness, and metastasis (15–17). It is well documented that the mechanical signals possess a pivotal role in the cancer progression, in which many oncogene signaling pathways interact with those activated by mechanical forces (18). Therefore, the cytoskeleton contractility of tumor cells by activation of mechanotransduction pathways in response to the physical stimuli profoundly affect cell attachment, cellular shape, cell proliferation, and migration through various players such as miRNAs (18).

Figure 1.

ECM overexpression within the tumor microenvironment occurs as a result of imbalance between ECM synthesis and production of ECM-remodeling enzymes. Moreover, the ECM composition of tumor environment differs from normal tissue due toa higher cross-linking rate, posttranslational modifications, and changes in the proportion of matrix compartments. Changes in ECM physical properties activate various mechanotransduction cell signaling pathways, eventually altering cell behaviors including cell proliferation, cell invasiveness, cell drug resistance as well as angiogenesis.

Figure 1.

ECM overexpression within the tumor microenvironment occurs as a result of imbalance between ECM synthesis and production of ECM-remodeling enzymes. Moreover, the ECM composition of tumor environment differs from normal tissue due toa higher cross-linking rate, posttranslational modifications, and changes in the proportion of matrix compartments. Changes in ECM physical properties activate various mechanotransduction cell signaling pathways, eventually altering cell behaviors including cell proliferation, cell invasiveness, cell drug resistance as well as angiogenesis.

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miRNAs are a part of the noncoding RNA family, which play a key regulatory role in gene expression (19, 20). Currently, the relationship between dysregulation of miRNAs and different pathogenic conditions, especially cancer, has been well established so that the evaluation of miRNA expression has been introduced as a promising approach for cancer detection (21–24). The miRInform Pancreas test is a well-known example of using miRNAs as a biomarker for cancer diagnosis (25). With advances in molecular techniques, the role of miRNAs in the regulation of a wide range of genes has been well documented (26–28). The interaction between the mechanotransduction signaling and miRNA expression has been an interesting topic for researchers to find the underlying mechanisms involved in cancer cell behaviors in their microenvironment. The aim of this study was to review the literature to clarify the interaction between miRNA dysregulation and the mechanotransduction signaling in breast cancer cells.

The role of mechanotransduction in various biological events, such as proliferation and migration, has been well investigated (29–31). In response to the ECM rigidity and stiffness, the focal adhesion (FA) complexes and junction-related proteins trigger a series of interactions that eventually convert extracellular mechanical forces into an intracellular response (32). Mechanical forces can also directly activate the ion channels and induce actomyosin contractility (33). Integrins are oligomerized following the mechanical signals generated by the interaction between cells and ECM. The oligomerized integrins are then activated and form a complex with talin proteins, leading to increased intermolecular interactions (34). The focal complexes are formed following the initial interaction between integrins and adhesion plaque proteins. Eventually, the focal complexes are assembled and matured into the FA structures (34). Taking together, interaction between integrins, actomyosin fibers, and signaling mediators increases the proliferation and invasion of cancer cells. (Fig. 2.) In addition to the FA structures, the presence of adherens junctions plays a critical role in the transmission of intercellular mechanical signals through various mediators such as cadherins and catenins (35).

Figure 2.

The interaction between FA complex and cell nucleus. In the cytoplasmic side, the complex of Talin, Paxilin, and Vinculin forms an initial anchor to accumulate proteins involved in focal adhesion. The actin polymerization occurs at the focal adhesion complex site and, then, the polymerized fibers are stabilized and branched through proteins such as α-actin and Arp2/3 complex. Binding of actin filaments to a protein complex located in the nucleus membrane is responsible for the transmission of physical forces to the cell nucleus, leading to changes in the structure of nuclear lamina and gene expression.

Figure 2.

The interaction between FA complex and cell nucleus. In the cytoplasmic side, the complex of Talin, Paxilin, and Vinculin forms an initial anchor to accumulate proteins involved in focal adhesion. The actin polymerization occurs at the focal adhesion complex site and, then, the polymerized fibers are stabilized and branched through proteins such as α-actin and Arp2/3 complex. Binding of actin filaments to a protein complex located in the nucleus membrane is responsible for the transmission of physical forces to the cell nucleus, leading to changes in the structure of nuclear lamina and gene expression.

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Interestingly, there is a cross-talk between mechanotransduction and cytokine-induced signaling pathways, leading to modulation of cell behaviors within a tissue (36). Wendt and colleagues reported that treatment of MDA-MB-231 breast cancer cells with TGFβ significantly increases the expression of the proline-rich tyrosine kinase 2 (Pyk2) gene (37). Pyk2, as a member of the FAK family, participates in actin reorganization (38). Wendt and colleagues showed that TGFβ promotes the expression of Pyk2 through activation of Src and Smad4 signaling pathways, leading to epithelial-to-mesenchymal transition (EMT)-mediated cancer cell invasion (37). It is a clear example of how interactions between mechanical and chemical signals can increase the invasion of cancer cells. Changes in proliferation and progression of cancer cells can also occur due to interaction between mechanotransduction mediators and oncogenes (39). Qin and colleagues showed that MDA-MB-231 breast cancer cells under low shear stress exhibit an increased cell proliferation through activation of the MAPK/ERK/YAP signaling (39).

Angiogenesis is a critical stage in cancer progression. In the cancer microenvironment, vessels have a nonconventional morphology and arrangement with more permeability than normal vasculature (40). There are various reasons that justify this phenomenon. As the tumor size increases, the need for the entrance of nutrients is responded by creating new vessels within the tumor microenvironment (41). Because of various mechanical forces in the tumor area, endothelial cells acquire an unusual structure that forms vascular with specific properties such as the high opening in the wall and loose cell–cell junction (41). In general, mechanical forces in the tumor microenvironment can be categorized into two major groups, including solid and fluid stresses (42). In the solid stresses, mechanical forces stem from a combination of various components of the tumor microenvironment, including ECM, cancer cells, and tissue cells (42). As a tumor progresses, the composition and concentration of ECM alter and differ from the ECM contents in the normal tissue (43). It is well documented that the amount and stiffness of ECM in tumors are remarkably higher than that in normal tissue. The composition and concentration of ECM alter during tumor progression, which directly influences the formation of the capillary network by endothelial cells (44–46). It has been reported that endothelial cells on a highly cross-linked stiff matrix exhibit higher cell growth, new vessel branching, and invasiveness compared with those cultured on viscoelastic matrix (47). Treatment of tumors with β-aminopropionitrile, which reduces the stiffness of the tumor, could remarkably decrease angiogenesis and new vessel branching within the tumor microenvironment. In addition to the ECM, a continuing increase in the number of cancer and stromal cells within the tumor microenvironment causes excessive mechanical stress to the endothelial cells, which alters their morphology and gene expression (48).

In the fluid stresses, transmitted mechanical forces into the newly formed vessels are produced by the flow of blood into the tumor microenvironment. The presence of leaky vasculature, as well as ineffective intratumoral lymph vessels, remarkably increases the interstitial fluid pressure, so that its amount has been reported about 4 to 60 mm Hg in various solid tumors (49, 50). Flow stresses, especially shear flow and basal-to-apical stresses, have an important role in activating signaling cascades in endothelial cells, which changes their morphology, resulting in the alteration of vascular networks (51, 52). It is reported that the transmission of basal-to-apical flow stress to endothelial cells gives an invasive character to these cells through activating the FA kinase pathway as well as alteration in the cell–cell junctions (53). As a result of such stresses, tumor endothelial cells exhibit a range of distinct characteristics, including constant activation of survival, angiogenic, and activating signaling pathways (54). These findings highlighted the importance of physical forces in tissue homeostasis so that abnormal changes in mechanical forces within cell microenvironment alter their characteristics and may lead them to form tumors.

The presence of linker structures, including the LINC complex, on the nuclear envelope enables the physical connection between the nucleus and cytoskeleton (55). Furthermore, the intranuclear network of structural proteins, known as nuclear lamina, facilitates the transduction of mechanical forces into the nucleus, resulting in a sense of physical forces by the nucleus. It was reported that proteins forming nuclear lamina, mainly lamins, serve also as a mechanosensor, which regulates the function of transcription factors (56). Despite the extensive efforts to understand the way that the nucleus senses mechanical forces, little is known regarding the mechanisms underlying how these mechanical signals induce changes in gene expression. However, various studies suggested different mechanisms in this context, as discussed below.

It was reported that the import of transcriptional factors into the nucleus is controlled during mechanical pressure to the cell and nucleus (ref. 57; Fig. 3.) For example, the entrance of myocardin-related transcription factors (MRTF) into the nucleus is dependent on G-actin concentration and cell polarization. This transcription cofactor is inactive when binding to G-actin in the cytoplasm. As cell polarization increases, the actin polymerization into the F-actin fibers is elevated, resulting in dissociation of MRTF and G-actin (57). Upon it release, MRTF enters the nucleus and binds to the serum response factor, leading to the expression of genes involved in the regulation of actin dynamics. Moreover, following diminished polymerization of actin fibers, the import of the p65 transcription factor into the nucleus increases, while MRTF is exported to the cytoplasm (57). It was shown that the mechanical forces could alter the import and export of transcriptional factors into the nucleus.

Figure 3.

The suggested mechanisms for how mechanical forces affect gene expression. Until now, some mechanisms have been suggested to describe the effect of physical forces on gene expression. It was found that mechanical forces increase the entrance of different transcriptional factors into the nucleus. Moreover, the interaction between LNIK complexes and cytoplasmic actin fibers transmits the mechanical forces to the nuclear lamina network, which alter the 3D organization of chromatins and gene expression. In addition, mechanical stresses may affect the spatial arrangement of genes, facilitating the juxtaposition of cis elements and gene promotors. TF, Transcription factor.

Figure 3.

The suggested mechanisms for how mechanical forces affect gene expression. Until now, some mechanisms have been suggested to describe the effect of physical forces on gene expression. It was found that mechanical forces increase the entrance of different transcriptional factors into the nucleus. Moreover, the interaction between LNIK complexes and cytoplasmic actin fibers transmits the mechanical forces to the nuclear lamina network, which alter the 3D organization of chromatins and gene expression. In addition, mechanical stresses may affect the spatial arrangement of genes, facilitating the juxtaposition of cis elements and gene promotors. TF, Transcription factor.

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It is suggested that the morphology and organization of the nucleus have a great impact on gene expression. As mentioned before, there is a connection between the nucleus and cytoskeleton, so that any alteration in actomyosin structure changes the 3D organization of the nucleus (58). One clear example is the upregulation of dihydrofolate reductase transgene through applying local forces to the cell surface (59). In a study, Tajik and colleagues evaluated the effect of shear stress applied by the three-dimensional magnetic twisting cytometry technique on the expression of the GFP-tagged DHFR transgene. They reported that applying shear stress to cells results in chromatin stretching in the direction of applied stress that upregulates the expression of DHFR. It was found that the amount of upregulation of DHFR is proportional to the amount of chromatin stretching (59).

The spatial arrangement of genes seems to be very critical in the regulation of gene expression. Once cells are stimulated with cytokines, the formation of chromatin loops brings together the cis element and promoters of the cytokine-related genes. Moreover, chromatin remodeling has a great impact on master regulation of a cluster of genes such as the Hox gene cluster (60). These changes in the chromatin structure have been also observed following physical stress to cells where the polarized fibroblasts exhibit a localized functional gene cluster within the intermingling regions of the chromatins (58). However, there appear to be other mechanisms for the effect of mechanical forces on gene expression. Future studies in this area will help clarify the role of mechanical forces in the regulation of gene expression.

miRNAs, as a main member of noncoding RNAs, are found in a wide range of organisms (61). This type of regulatory molecules has an important role in gene regulation, whose unbalanced expression leads to different diseases, especially cancer (62). The first reports on the role of miRNAs in breast cancer dates back to 2005. Since then, a variety of studies have been conducted each year to further clarify the role of these molecules in breast cancer (63).

RNA polymerase II, although responsible for miRNA transcription, was demonstrated to play a role in transcription of a group of miRNAs has been discovered (64). miRNAs are encoded in different parts of the genome, including the intron of protein-coding genes as well as the intron and exon of noncoding RNAs (65). miRNA synthesis is a multistep process in which various enzymes are involved. At the first step, miRNA precursors are transcribed by RNA polymerase, leading to formation of a pri-miRNA with a stem-loop structure. Then, various modifications, such as capping, polyadenylation, and splicing, are introduced to the pri-miRNAs (66). In the next step, the stem-loop structure of pri-miRNA serves as an identifying mark for Drosha complex, resulting in the separation of a hairpin loop with ∼70 nt (pre-miRNA) by this enzyme (67). The Drosha microprocessor complex consists of Drosha, an RNA-binding protein called DGCR8, and various cofactors (67). Downregulation of Drosha was observed in triple-negative breast cancer and patients with breast cancer with the higher tumor volume and histologic grade. Moreover, overexpression of DGCR8 was found in breast cancer samples with characteristics including Ki67+/ ER+ as well as invasive ductal breast carcinoma (68).

Following processing of pri-miRNAs to pre-miRNAs by the Drosha microprocessor complex, pre-miRNAs are exported to the cytoplasm through binding to a transporter complex composed of exportin-5 (XPO5) and Ran-GTP (69). Overexpression of the aforementioned transporter complex is along with an invasive phenotype in breast cancer (70, 71).

At the final step, pre-miRNA in the cytoplasm binds to the RISC complex, which is converted to a duplex miRNA with ∼22 nt length. This double-strand miRNA is separated and forms guide and messenger strands (72). The interaction between Ago proteins and guide strand miRNA forms a complex for recognition and cleavage of target mRNA. In addition to the direct role of miRNA in mRNA degradation, these molecules regulate the expression of their targets in the translational level (72). Changes in the expression of the RISC complex were frequently observed in breast cancer. For example, the expression level of the Ago2 protein was significantly lower in highly invasive breast cancer as compared with nonneoplastic ones (73). Based on the above, any dysregulation in the expression of mediators involved in miRNA processing influences the synthesis of miRNAs, which disrupts the expression balance of their target. Accordingly, an overwhelming majority of studies confirmed the difference between miRNA patterns of breast cancer samples and normal breast tissue, highlighting the importance of these regulator molecules in the balance of physiologic events in normal cells (69, 71, 74–77).

According to the important effect of mechanical forces in the progression of breast cancer, in the following, we discussed the role of miRNAs in the regulation of mechanotransduction mediators in breast cancer (Table 1). Even though the mechanotransduction signaling is a complex subject, including the interaction between a wide varieties of mediators, we attempted to separately review the cross-interaction between miRNAs and different stages of mechanotransduction pathways.

Table 1.

miRNAs involved in the mechanotransduction cell signaling in breast cancer.

miRNATarget protein/proteinsExpression status in breast cancer cellsEffectTarget siteRef
miR-551a/miR-7 FAK Downregulation Inhibitory effect on proliferation, invasion, and migration 3′UTR 86, 87 
miR-362-3p/miR-329 P130Cas Downregulation Inhibitory effect on proliferation, invasion, and migration 3′UTR 94 
miR-10b Syndecan-1 Upregulation Induction of invasiveness and migration, induction of filopodium formation, down-regulation of E-cadherin 3′UTR 97 
miR-142-3p WASL/integrin-αV Downregulation Inhibitory effect on cell invasion, decreased cell size and membrane protrusion structures 3′UTR 99 
miR-30c TWF1/VIM Downregulation Decreased EMT, decreased FA formation, increased sensitivity to paclitaxel and doxorubicin 3′UTR 106 
miR-149 GIT1 Downregulation Inhibitory effect on cell invasion and migration, decreased FA formation 3′UTR 111 
miR-584 PHACTR1 Downregulation Inhibitory effect on cell invasion and migration, decreased FA formation 3′UTR 119 
miR-200c FHOD1/PPM1F Downregulation Inhibitory effect on cell invasion and migration 3′UTR 128 
miR-204 BDNF Loss of loci Decreased invasion, decreased lung metastasis in the mouse model 3′UTR 140 
miR-145 JAM-A/Fascin Downregulation Decreased cell invasion and filopodium formation, increased cortical actin distribution 3′UTR 143 
miR-490-3p RhoA Downregulation Inhibitory effect on cell invasion and proliferation, arresting cells in the G1 phase, decreased tumor growth in the mouse model 3′UTR 151 
miR-146a RhoA Downregulation Inhibitory effect on cell invasion and migration 3′UTR 152 
miR-135b LATS2 Upregulation Increased proliferation, migration, and colony formation 3′UTR 166 
miRNA-125a LIFR Upregulation Increased stem cell pool, increased non-malignant breast epithelial stem cells toward malignant cells 3′UTR 168 
miRNA-136-5p/miRNA-1285-5p HERC4 Downregulation Inhibitory effect on the cell proliferation, survival, and migration, decreased tumor growth in the nude mouse model 3′UTR 167 
miRNATarget protein/proteinsExpression status in breast cancer cellsEffectTarget siteRef
miR-551a/miR-7 FAK Downregulation Inhibitory effect on proliferation, invasion, and migration 3′UTR 86, 87 
miR-362-3p/miR-329 P130Cas Downregulation Inhibitory effect on proliferation, invasion, and migration 3′UTR 94 
miR-10b Syndecan-1 Upregulation Induction of invasiveness and migration, induction of filopodium formation, down-regulation of E-cadherin 3′UTR 97 
miR-142-3p WASL/integrin-αV Downregulation Inhibitory effect on cell invasion, decreased cell size and membrane protrusion structures 3′UTR 99 
miR-30c TWF1/VIM Downregulation Decreased EMT, decreased FA formation, increased sensitivity to paclitaxel and doxorubicin 3′UTR 106 
miR-149 GIT1 Downregulation Inhibitory effect on cell invasion and migration, decreased FA formation 3′UTR 111 
miR-584 PHACTR1 Downregulation Inhibitory effect on cell invasion and migration, decreased FA formation 3′UTR 119 
miR-200c FHOD1/PPM1F Downregulation Inhibitory effect on cell invasion and migration 3′UTR 128 
miR-204 BDNF Loss of loci Decreased invasion, decreased lung metastasis in the mouse model 3′UTR 140 
miR-145 JAM-A/Fascin Downregulation Decreased cell invasion and filopodium formation, increased cortical actin distribution 3′UTR 143 
miR-490-3p RhoA Downregulation Inhibitory effect on cell invasion and proliferation, arresting cells in the G1 phase, decreased tumor growth in the mouse model 3′UTR 151 
miR-146a RhoA Downregulation Inhibitory effect on cell invasion and migration 3′UTR 152 
miR-135b LATS2 Upregulation Increased proliferation, migration, and colony formation 3′UTR 166 
miRNA-125a LIFR Upregulation Increased stem cell pool, increased non-malignant breast epithelial stem cells toward malignant cells 3′UTR 168 
miRNA-136-5p/miRNA-1285-5p HERC4 Downregulation Inhibitory effect on the cell proliferation, survival, and migration, decreased tumor growth in the nude mouse model 3′UTR 167 

Abbreviations: BDNF, brain-derived neurotrophic factor; FA, focal adhesion; FAK, focal adhesion kinase; FHOD1, formin homology domain protein 1; GIT1, G protein-coupled receptor kinase-interacting protein; JAM-A, junctional adhesion molecule-A; LATS2, large tumor suppressor kinase 2; LIFR: LIF receptor subunit alpha; PHACTR1, phosphatase and actin regulator 1′; PPM1F, protein phosphatase Mg2+/Mn2+ dependent 1F; RhoA, Ras homolog gene family member A; TWF1, twinfilin actin-binding protein 1; VIM, vimentin; and WASL, WASP like actin nucleation promoting factor.

The role of miRNAs in the regulation of mediators involved in the mechanotransduction signaling is important to understand how changes in mechanotransduction mediators through miRNAs affect proliferation, invasiveness, and migration of breast cancer cells (Fig. 4.) In the following sections, we discussed the role of miRNAs in the regulation of different mechanotransduction mediators.

Figure 4.

The effect of physical forces on the expression of mechanotransduction mediators. Breast tissue cells in the tumor microenvironment exhibit a dysregulated miRNA expression pattern, which affects the expression of various mediators in the mechanotransduction signaling. Changes in the expression of mechanotransduction signaling effectors profoundly influence cell behaviors, including cell proliferation, invasiveness, and metastasis.

Figure 4.

The effect of physical forces on the expression of mechanotransduction mediators. Breast tissue cells in the tumor microenvironment exhibit a dysregulated miRNA expression pattern, which affects the expression of various mediators in the mechanotransduction signaling. Changes in the expression of mechanotransduction signaling effectors profoundly influence cell behaviors, including cell proliferation, invasiveness, and metastasis.

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miRNAs and FA signaling

FA structures are composed of the interaction between the actin cytoskeleton and transmembrane integrins that are in contact with the ECM components. Integrins with heterodimer units form a transmembrane receptor, mediating the first contact between the cytoskeleton and ECM in the cell microenvironment (78). In the cytoplasmic side, actin-binding proteins, such as talin, vinculin, and paxillin as well as other mediators including signaling effectors, such as GTPases, capping proteins, actin-binding proteins (ABP), phosphatases, phospholipases, and FAKs, enforce the interaction of integrins with actin cytoskeleton, resulting in further polymerization of actin fibers (79, 80). FAK, a 125-kDa nonreceptor protein tyrosine kinase, is one of the key elements in FA complexes. This protein is phosphorylated as a downstream substrate for activated v-Src in response to integrin–ECM interaction (81, 82). As a tumor grows, FAK exhibits two main functions, including promoting tumor cell adhesion and providing an antiapoptosis signal (83). The correlation between overexpression/activation of FAK and tumorigenesis, invasion, and metastasis in various cancer types has been described (84). Overexpression of FAK in the benign and invasive breast cancers is along with preinvasive and aggressive phenotypes, respectively (85). Reports showed that there is an inverse relationship between FAK and miR-551a expression in breast cancer cells. The real-time expression analysis exhibited decreased expression of miR-551a in tumor samples as compared with the normal tissue around the tumor site. In this light, forced expression of miR-551a in MDA-MB-231 and ZR75 cancer cell lines led to decreased expression of FAK, which was dependent on miR-551a concentrations (86). Further analyses using miR-551a antagomirs exhibited an elevated expression of FAK in the aforementioned cell lines. In general, forced overexpression of miR-551a in the MDA-MB-231 cells led to a decrease in cell proliferation as well as colony-forming ability (86). An in vivo study demonstrated that nude mice receiving miR-551a-transfected MDA-MB-231 exhibit lower tumor values as compared with those receiving empty vector–transfected cells. The miR-551a expression was reported to be mainly promoted by c-Fos, so that the expression of this transcription factor, similar to miR-551a, is remarkably lower in the breast tumor samples as compared with breast normal tissues (86).

miR-7 is another miRNA involved in FAK regulation in breast cancer cells. A study on the FAK protein level revealed a significant difference in various breast cancer cell lines (87). The FAK protein level was found to be related directly to the degree of invasiveness of various breast cancer cell lines. Results obtained from that study showed that the amount of FAK in HBL-100, as a nonmalignant human mammary epithelial cell, was lower than those in breast cancer cell lines with moderate invasiveness (MDA-MB-468, MDA-MB-453, and MCF-7), while the highest amount of the FAK protein was observed in MDA-MB-435s, BT-549, and MDA-MB-231 cells that exhibited a highly invasive phenotype (87). However, the expression of miR-7 indicated an inverse pattern as compared with FAK, such that the noninvasive and moderately invasive cell lines showed a higher expression rate of miR-7 than highly invasive breast cancer cells. As a result of forced miR-7 overexpression in the MDA-MB-435s and MDA-MB-231 cells, EMT was significantly decreased (87). EMT is a phenomenon in which morphologic changes in epithelial cells cause them to find a structure similar to mesenchymal cells, which is a vital precondition for various developmental processes of cancer cells such as metastasis (88). Transient overexpression of miR-7 in MDA-MB-435 and MDA-MB-231 cells changed their spindle fibroblast-like morphology to a typical epithelial cobblestone-like shape. Moreover, the transient overexpression of miR-7 in the mentioned cells led to decreased expression of SNAIL, VIM, fibronectin and N-cadherin, and elevated expression of E-cadherin (87). Furthermore, overexpression of miR-7 was accompanied by tumor growth and metastasis suppression in vivo. However, the expression pattern of FAK and miR-7 is not the same in all breast cell lines (87). For example, T47D, which is categorized as a breast cancer cell with moderate invasiveness, shows low expression of FAK and miR-7. This finding suggests that there may be other pathways involved in the regulation of FAK and miR-7 in these cells (87).

P130Cas is one of the important regulators in the mechanotransduction signaling. This protein has interaction with various mediators such as tyrosine kinases, guanine nucleotide exchange factors (GEF), and other adaptor molecules. FAK and Scr proteins are the key regulators of p130Cas by phosphorylation of this protein (89–91). p130Cas overexpression in breast cancer is accompanied by resistance to tamoxifen and low survival rates (92, 93). miR-362-3p and miR-329 expression was found to be downregulated in breast cancer. The P130Cas protein is the target for the abovementioned miRNAs, whose expression increases in breast cancer as a result of downregulation of miR-362-3p and miR-329 (94). Forced expression of miRNAs 362-3p and 329 in MCF-7 cells exhibited that the expression rate of P130Cas significantly decreases in the transfected cells. DNA methylation is suggested as a possible mechanism responsible for downregulation of the abovementioned miRNAs. It seems that MeCP2, as a CpG island–binding protein, plays a role in DNA methylation of miR-362-3p and miR-329 promoters (94).

Syndecan-1 is a transmembrane proteoglycan that has a different role in cancer development, serving as a coreceptor for various growth factors and cytokines as well as modulating integrin function (95). Overexpression of miR-10b downregulates syndecan-1 expression in breast tumor cells (96). Overexpression of this oncomiR led to appearance of a preinvasive phenotype in breast cancer cell lines with a nonmetastatic phenotype. Syndecan-1–depleted MDA-MB-231 cells exhibited upregulation in genes involved in motility and invasiveness such as COX-2, actin γ 2, vinculin, cadherin-11, MYL9, ATF-2, transgelin-1, and RhoA/C (97). Moreover, a tight adherence of syndecan-1–depleted MDA-MB-231 cells to ECM components, including fibronectin and laminin, resulted in further activation of FAK and RhoGTPases and an acquired invasive phenotype in these cells (97).

The formation of membrane protrusions is the critical step in cell motility and FA complex formation (98). miR-142-3p decreases membrane protrusions and invasiveness in various breast cancer cells through direct targeting of 3′ UTR of WASL and integrin-αV (99). These two proteins actively participate in metastasis (100, 101). Schwickert and colleagues studied the role of miR-142-3p in the prevention of breast cancer cell invasiveness. They reported that forced overexpression of this oncomiR in various cell lines, including MCF-7, MDA-MB-468, and MDA-MB-231, effectively decreases the expression level of WASL and integrin-αV (99). In addition, transfected cells showed a lower expression rete of the genes involved in cytoskeleton motility and regulation such as RAC1 and CFL2. According to the Matrigel invasion assay and confocal immunofluorescence microscopy results, miR-142-3p–overexpressing cell lines were shown to have remarkably lower invasiveness, protrusion formation, and cell size as compared with the control (99).

The relationship between EMT and breast cancer chemoresistance has been well confirmed in literature (102, 103). In the early stages of breast tumor formation, EMT plays an undeniable role in resistance to endocrine therapy and chemotherapies (104). EMT is regulated by various mediators in the cancer cells such as twinfilin 1 (TWF1), which is known as an actin-binding protein. This protein has two ADF-H domains that prevent the actin polymerization through interaction with the capping protein and sequestration of G-actins (105). miR-30c was found to be a key element in the downregulation of TWF1. Transient overexpression of this oncomiR in MDA-MB-231 cells not only decreased the F-actin formation and EMT, but also increased the sensitivity to paclitaxel and doxorubicin at low doses (106). Furthermore, vinculin staining showed a significant decrease in the FA formation in the transfected cells. An attempt to find the transcription factor responsible for miR-30c expression led to introduction of GATA3, whose overexpression in the GATA3-deficient MDA-MB-231 increases the expression level of miR-30c (106).

The GIT1 protein is one of the key regulators of FA formation and cell migration (107, 108). This protein has a complex structure, containing various domains and effector sites (109). In the cell migration phase, this protein is colocalized with FAK and paxillin within the FA points and interacts with a verity of mediators such as GEFs, PAK complex, Rac1/Cdc42, and PIX, which consequently promote the protrusion structures (110). The examination of primary breast tumors and, even, lymph node metastases revealed a higher expression level of GIT1 compared with the surrounded normal tissues (111). Furthermore, the expression rate of miR-149 was found to be remarkably lower in the tumor samples. There is an inverse relationship between miR-149 and GIT1 expression in breast tumor cells. Increased expression of GIT1 and downregulation of miR-149 have been reported in the advanced stages of breast cancer (111). In vitro analysis showed that miR-149 directly targets the 3′UTR of GIT1. Forced overexpression of miR-149 in IV2-1, IV2-2, and Hs578T led to the suppression of cell migration and invasion. As a result of GIT1 downregulation, the FAK-mediated downstream signaling are impaired due to decreased FAK autophosphorylation at Y397, FAK phosphorylation at Y861, and paxillin phosphorylation at Y118. Moreover, GIT1 downregulation is along with increased lysosomal degradation of α5β1 integrin complexes, which negatively influences the FA complex formation (111). It explains how GIT1 downregulation interferes with the FAK–Src signaling. However, it seems that decreased phosphorylation of paxillin is not only due to the inefficient FAK–Src signaling. Paxillin instability also occurred as a result of increased proteasomal degradation as well as loss of contact with GIT1, which were observed in GIT1-downregulated IV2 cells. This highlights the important role of GIT1 as a stabilizer for α5β1 integrins and other mediators such as paxillin, which profoundly affect the formation of FA complexes (111).

Until now, various adaptor proteins have been identified to be involved in the FA complex. Our knowledge regarding how FA complexes are formed is increasing. It is obvious that further investigations will be necessary to detect the unknown mediators and miRNAs in this context.

miRNAs and the cytoskeleton

Cooperation of the actomyosin network and proteins involved in FA complexes create micromotor devices, which are a prerequisite for the mechanotransduction signaling. The actin cytoskeleton network is an interconnected and complex structure which is composed of a dynamic interaction between different components, such as G-actin, F-actin, and actin-binding mediators (112). Formation of such structures is a primary step in various biological events in tumor cells, especially metastasis. A deep understanding of the metastasis process is achievable by a detailed study on the mechanisms involved in cell motility and invasion in response to microenvironment stimuli. Cell movement controllers in normal cells severely constrain cell motility and migration within the tissue. In cancers, metastasis will occur as due to dysregulation of controller elements, such as miRNAs (113).

Vimentin (VIM) is one of the main cytoskeleton structural proteins that participates in the formation of intermediate filaments (114). This protein involves metastasis, invasion, as well as EMT in cancer cells (115). Results obtained from an in vitro study revealed that transfection of the vector containing miR-30c in the breast cancer cell line (MDA-MB-231) directly targets the 3′ UTR of VIM (105). As a result, downregulation of VIM led to a remarkable decrease in cell invasion of miR-30c–transfected MDA-MB-231 cells. The contribution of VIM in cell invasion was further confirmed by knocking down using siRNAs, where the VIM knocked down MDA-MB-231 showed a higher mesenchymal-to-epithelial transition (MET) phenotype compared with the control (105).

The TGFβ signaling has a double-edged sword role in breast cancer progression. TGFβ has an antitumor function at the early stages, inhibiting tumor initiation and progression, while serving as a prometastatic agent at advanced stages (116, 117). Indirectly, TGFβ induces metastasis in breast cancer through upregulation of protein phosphatase and actin regulator 1 (PHACTR1), which is known as an actin-binding protein. PHACTR1 is a member of the actin-binding protein family with RPEL repeats (118). This protein was found to regulate the actin polymerization/depolymerization dynamic so that knocking down of PHACTR1 results in disorganization of actin filaments. TGFβ, via the smad signaling, decreases miR-584 expression that directly targets 3′UTR of PHACTR1 (119). Study on different breast cancer cell lines revealed that overexpression and downregulation of PHACTR1 and miR-584, respectively, are observed only in invasive basal-like breast tumor cells including SUM159PT, MDA-MB-231, and SCP2. In the TGFβ-stimulated SCP2 cells, forced overexpression of miR-584 resulted in a decrease in PHACTR1 expression and TGFβ-dependent cell migration (119). Confocal microscopic analysis of the cells transfected by miR-584 exhibited an accumulation of stress fiber in these cells. Despite the formation of stress fibers in the transfected cells, these cells were unable to form filopodia, suggesting that downregulation of PHACTR1 stops the actin treadmilling cycle (119).

The miR-200 family is essential for epithelial cells to represent an epithelial phenotype. To occur EMT in most epithelial cells, expression of these oncomirs must be stopped, indicating the important role of the miR-200 family in cancer development (120–122). The morphologic changes in EMT force the immobile epithelial cells toward mesenchymal characteristics with an intrinsic proinvasive property (123). Downregulation of these oncomirs has been confirmed in the metastatic stages of cancer development compared with early one (124, 125). It is confirmed that lower expression rates of miR-200 correlate with poor prognosis in various human epithelial malignancies (121, 126, 127). FHOD1 and PPM1F proteins are a downstream target of miR-200c. These proteins, as downstream mediators of the RhoA signaling, facilitate the formation of bundled actin stress fibers (128, 129). FHOD1 promotes expression of myosin light chain (MLC2) through nuclear accumulation of MRTF-A, known as a SRF coactivator, (128, 130). On the other hand, PPM1F elevates the phosphorylation rate of MLC2 in an MLC2 expression–independent manner. PPM1F was reported to increase phosphorylation of myosin light chain phosphatase (MYPT) through inhibition of PAK at its inhibitory site (131). However, Jurmeister and colleagues reported that miR-200c overexpression in MDA-MB-231 results in increased MYPT phosphorylation at Thr696 or Thr853 sites, while the PPM1F silencing had no impact on phosphorylation of any sites on this protein. Their results showed a decrease in cell migration and invasion following forced overexpression of miR-200c in the MDA-MB-231 cells (128). Another study also confirmed the inhibitory effect of miR-200 in cell invasion and migration. In that study, overexpression of miR-200 (miR-200a and miR-200b) in breast cancer cells was along with the change in actin rearrangement (132). In fact, miR-200 overexpression changed stress fibers to cortical actin, resulting in decreased invasion and cell migration. miR-200 also inhibited the invadopodia formation and stabilized FA complexes. miR-200 was proposed to target activators of the Rho family, including ARHGEF3 and NET1, and some targets in downstream of the Rho signaling, such as ROCK2, MYH9, MYH10, MPRIP, MYPT1, and MYLK (132).

Chromosome loss occurs frequently in various cancer types, resulting in loss of functions of some essential genes involved in cell physiology and regulation (133). Different studies confirmed the loss of chromosomal loci containing miR-204 in a verity of cancer types (134, 135). The role of miR-204 as a tumor growth/metastasis suppressor is mainly related to the suppression of genes involved in tumorigenesis such as brain-derived neurotrophic factor (BDNF). This protein is known as a nerve growth factor that activates tropomyosin-related kinase B (TrkB; refs. 136, 137). In tumor cells, the BDNF/TrkB signaling involves in different steps of tumorigenesis, including metastasis, differentiation, and proliferation (138). Upregulation of BDNF/TrkB in breast cancer correlates with poor prognosis (139). Loss of miR-204 loci in breast tumor cells promotes overexpression of BDNF/TrkB and activation of the AKT/mTOR/Rac1 pathway that reorganize the actin network, leading to cancer cell migration and invasion. Study on a mouse model revealed that systemic injection of MDA-MB-231 cells in the animals severely caused lung metastasis, while those group receiving systemic administration of miR-204 showed a remarkable decrease in tumor growth and metastasis (140).

miR-145 was reported to be downregulated in both breast cancer cell lines and clinical tumor samples compared with normal breast tissue around the tumor site (63, 141, 142). In normal breast tissue, miR-145 is exclusively expressed in myoepithelial and basal cells of mammary ducts and lobules, while its expression is diminished or suppressed during tumor progression. miR-145 exerts its antimetastatic effect on normal cells through direct targeting of JAM-A and fascin proteins (143). JAM-A, as a membrane protein, plays an active role in cell–cell junction as well as cell motility regulation (144). Indeed, the PDZ-domain protein mediates the interaction between the cytoplasmic domain of JAM-A and actin cytoskeleton that influences cytoskeletal rearrangements (145). Fascin contributes to cell migration through transforming lamellipodial structures into filopodia by bundling actin filaments. Obviously, overexpression of this protein promotes cancer cell migration (143). The luciferase activation assay revealed that miR-145 directly targets 3′ UTR of JAM-A and fascin, leading to downregulation of these proteins. Transfection of the vector containing miR-145 in MDA-MB-468, MDA-MB-231, SK-BR-3, and MCF-7 cell lines revealed decrease expression of JAM-A, fascin, podocalyxin, and Serpin E1, and increased expression of MYL9, gamma-actin, and transgelin. Moreover, forced overexpression of this oncomiR in MDA-MB-231 cells remarkably reduced cell invasion and filopodia formation, but increased cortical actin distribution (143).

In a study, in silico analysis was used to identify the cross-interaction between various miRNAs and their targets by a network-based approach; findings from that study demonstrated that miRNAs, including miR-612, miR-940, and miR-661, are involved in cytoskeleton regulation of breast cancer cells (146). This claim was tested using the impact of these miRNAs on cytoskeleton changes in a RPE1 cell model. Overexpression of miR-612 and miR-940 inhibited myosin II phosphorylation and consequently led to decreased cell invasion in RPE1 cells. In contrary, cell invasion and myosin II phosphorylation increased following forced overexpression of miR-661 in RPE1 cells (146).

Cytoskeleton dynamics play a pivotal role in different aspects of cell biology. The regulation of mediators involved in cytoskeleton dynamics by miRNAs is important so that changes in the expression of miRNAs affect the normal cytoskeleton dynamics of normal breast cells. Further studies will increase our knowledge regarding the role of miRNAs in cytoskeleton rearrangement, representing a promising window for future therapeutic strategies based on the recovery of cytoskeleton rearrangement in breast cancer cells.

miRNAs and Rho-family GTPases

The Rho-GTPases family includes different small G proteins with GTPases activity that has an active role in various biological events such as cell motility. This protein family consists of more than 50 members with some shared features, including binding to hydrolyze guanine nucleotides, having a molecular weight ranging from 18 to 28 kDa, and possessing polyisoprenylation regions at their C-terminal (147). Several studies showed that any abnormal alterations in the activity of these mediators lead to pathologic conditions, especially cancers. Rho GTPases, as main regulators of cytoskeleton rearrangements, control cell morphology, growth, and adhesion, so that overactivation of these proteins is observed in malignancies (148). Therefore, understanding of mechanisms involved in Rho GTPases dysregulation in cancers would help us find possible therapeutic weapons against cancers.

RhoA is a well-known member of Rho GTPases, activating through various stimuli, including extracellular signals as well as growth factors and hormones such as insulin, PDFG, and EGF. Its activation is along with different morphological changes toward lamellipodia formation through polymerizing actin filaments and nascent focal complex formation (149). In the cell adhesion and spreading stage, inhibition of RhoA-GTP and concurrent activation of Rac1 and Cdc42 lead to suppressed actomyosin contractility and increased actin-mediated protrusions (150). So far, few miRNAs have been reported to possess a regulatory effect on RhoA expression in breast cancer. For example, miR-490-3p is found to directly target the 3′UTR of RhoA mRNA. The expression level of miR-490-3p is significantly lower in breast tumor samples as compared with surrounding normal tissue. Transient overexpression of miR-490-3p in McF-7 and T47D cells confirmed that overexpression of this oncomiR decreases the migration and invasion ability of these cells through downregulation of RhoA, MMP-9, P70S6K, and Bcl-XL proteins (151). In addition to cell migration, miR-490-3p could reduce cell proliferation through arresting the transfected cell in the G1 phase. Cell proliferation–inhibitory effects of miR-490-3p are attributed to downregulation of P70S6K protein that serves as a downstream mediator of the PI3K/AKT pathway. An in vivo study revealed that subcutaneous injection of MCF-7 cells transfected by miR-490-3p mimic in mice causes formation of smaller tumors with lower RhoA expression as compared with the control (151).

RhoA expression is also influenced by miR-146a through direct targeting of its 3′UTR. The inverse correlation between RhoA and miR-146a expression in breast tumor cells was further confirmed through the transfection of the miR-146a vector in MDA-MB-231, where the forced overexpression of this oncomiR significantly reduced the RhoA expression in both gene and protein levels. As a result of upregulation of miR-146a in MDA-MB-231, these cells lost their motility and invasion ability, suggesting the suppressor effect of miR-146a in breast cancer metastasis through the RhoA-dependent pathway (152).

Although the positive role of RhoA in the metastatic feature of breast tumor cells have been well confirmed, there is a study showing that direct targeting of this protein by miR-155 promotes TGFβ-induced EMT (153). In that study, Kong and colleagues found that the expression level of miR-155 in invasive breast tumor cells was remarkably higher than noninvasive one as well as normal breast cells. They reported that forced overexpression of miR-155 in the NMuMG cell line leads to a significant decrease in cell invasion and migration. According to their results, TGFβ/Smad directly upregulates miR-155 in the breast cancer cell (153).

Given that different members of GTPase family may participate in the mechanotransduction signaling, future studies are required to recognize other players and their related miRNA regulators in this context.

miRNA and the Hippo signaling

In recent years, the role of the Hippo signaling in cell behaviors has been investigated in various studies (154–156). The Hippo signaling pathway is responsible for controlling the nuclear accumulation of the YAP/TAZ effector that controls different biological events in cells such as organ size, survival, and proliferation. The mechanical stimuli, in addition to biochemical signals, influence the activation of the Hippo signaling pathway. The Hippo signaling pathway mediators mainly include YAP/TAZ, tumor suppressor 1/2 (LATS1/2), Mps One Binder kinase activator (MOB1), mammalian Ste20-like kinases 1/2 (MST1/2), and SAV1 (157, 158). In brief, the activation of LATS1/2 by MST1/2 occurs through phosphorylation at Thr1079/Thr1041 sites of LATS1/2. Indeed, the SAV1–MST1/2 complex phosphorylates the MOB1 protein, which enhances its binding ability to LATS1/2, resulting in phosphorylation and activation of LATS1/2. Finally, the activated LATS1/2 mediates YAP/TAZ phosphorylation, resulting in cytoplasmic accumulation and inactivation of the YAP/TAZ complex through phosphorylation of YAP at Ser127 and binding to sequester protein 14-3-3 (159). Studies on the function of the Hippo signaling in different cancer types have shown its important role in tumorigenesis. For example, in tumor microenvironment, YAP/TAZ activation enhances the ECM production by cancer-associated fibroblasts, leading to maintenance of cancer stem cells and their resistance to different cancer therapeutic approaches such as chemotherapy (160), radiotherapy (161), and various molecular targeted therapies (162). In general, overexpression of YAP/TAZ has been observed in various cancer types. A variety of studies indicated that the overactivation and expression of YAP/TAZ are associated with proliferation, invasion, and metastasis of breast cancer cells (163).

The role of miRNA in the regulation of the Hippo signaling is highly prominent, so that miRNA dysregulation was frequently found to be correlated with downregulation or upregulation of Hippo signaling mediators. In various cancer types, LATS2 expression is downregulated by different miRNAs (164, 165). In breast cancer, miR-135b is responsible for direct 3′ UTR targeting of LATS2. Study on miR-135b expression exhibited that this miRNA is remarkably upregulated in breast tumor samples and cell lines as compared with normal tissue around the tumor and nonmalignant breast epithelial cells (166). Transient transfection of MDA-MB-231 and MCF-7 cells with miR-135b mimics showed that the proliferation, migration, and colony formation of these cells were remarkably higher than those transfected with the miR-135b inhibitor as well as the negative control (166). The cell-cycle assay also confirmed that miR-135b–transfected cells showed a higher percentage of cell arrest in S and G2–M phases in comparison with the control and miR-135b inhibitor groups. According to results from the Western blot analysis, increased protein expression of LATS2 in the MDA-MB-231 and MCF-7 cells transfected with the miR-135b inhibitor leads to downregulation of CDK2 and p-YAP (166).

More recently, the role of a miRNA-HERC4 pathway has been confirmed in downregulation of LATS1 in breast cancer cells. Investigation on the expression levels of miRNA-136-5p and miRNA-1285-5p in different cancer cell lines, including MCF-7, BT474, and MDA-MB-231, showed that the expression of these two miRNAs are significantly lower in cancer cells as compared with the normal breast cell line (MCF-10A; ref. 167). miRNA-136-5p and miRNA-1285-5p directly target the 3′UTR of E3 ligase HERC4 that plays a critical role in ubiquitination and destabilization of LATS1 in cells. As a result of downregulation of the aforementioned miRNAs in breast cancer cells, the expression of HERC4 increases, leading to a decrease in LATS1 expression (167).

TAZ is indirectly regulated by miRNA-125a through downregulation of leukemia inhibitory factor receptor (LIFR), which is an upstream regulator of the Hippo signaling (168). Stem cells obtained from MCF-7, primary breast cancer cells, and MCF12A (nonmalignant) cells, interestingly showed a different miRNA-125a expression pattern. In this regard, the miRNA-125a expression level was found to be significantly higher in stem cells obtained from breast cancer cells (MCF-7 and primary breast cancer cells) than those derived from the nonmalignant MCF12A cell line (168). Further analysis showed a lower LIFR protein level in stem cells derived from MCF-7 and primary breast cancer cells when compared with MCF12A stem cells, indicating a reverse correlation between miRNA-125a and LIFR expression in breast cancer stem cells. Direct targeting of LIFR at the 3′UTR site by miRNA-125a was confirmed through the luciferase reporter assay (168). As an upstream regulator of the Hippo signaling, LIFR controls the stem cell pool dynamics. It was reported that forced overexpression of miRNA-125a in MCF12A cells significantly increases the percentage of stem cells after 24 hours (168). In contrast, transfection of MCF-7 with miRNA-125a antagomir caused a significant decrease in stem cell pool after the aforementioned time point. Phosphorylation analysis of key regulators in the Hippo signaling pathway exhibited an increase in the phosphorylation of LATS1 and TAZ in MCF-7 stem cells transfected by miRNA-125a. miRNA-125a was suggested to activate the JAK2–STAT3 signaling by inhibiting of phosphorylation of Hippo signaling mediators, promoting the nonmalignant breast epithelial stem cells toward malignant cells (ref. 168; Fig. 5).

Figure 5.

The interaction between miRNAs and effectors involved in the mechanotransduction cell signaling in breast cancer. Various miRNAs control the expression of different effectors in the mechanotransduction signaling pathways including focal adhesion complex mediators, cytoskeleton binding proteins, and integrin proteins. Furthermore, miRNAs effectively control the expression of mediators in some mechanotransduction signaling pathways, including YAP/TAZ signaling. ECM stiffness also directly controls the expression of miRNAs in normal breast tissue cells. In response to ECM stiffness, the expression of some miRNAs, including miR-18a and miR-203, changes that influences the cell behaviors. However, the exact mechanism by which the mechanical clues changes the expression of miRNAs remains unknown. WASL, WASP Like Actin Nucleation Promoting Factor; FAK, Focal adhesion kinase; GIT1, G protein-coupled receptor kinase-interacting protein; P130Cas, P130 Crk-associated substrate; RhoA, Ras homolog gene family member A; FHOD1, Formin Homology Domain Protein 1; PPM1F, Protein phosphatase, Mg2+/Mn2+–dependent 1F; BDNF, brain-derived neurotrophic factor; TWF1, Twinfilin actin binding protein 1; VIM, Vimentin; PHACTR1, phosphatase and actin regulator 1; LIFR, LIF Receptor Subunit Alpha; LATS1, Large Tumor Suppressor Kinase 1; LATS2, Large Tumor Suppressor Kinase 2; HERC4, HECT and RLD domain containing E3 ubiquitin ligase 4; JAM-A, junctional Adhesion Molecule-A; HOXA9: Homeobox protein Hox-A9; ROBO1, Roundabout Guidance Receptor 1.

Figure 5.

The interaction between miRNAs and effectors involved in the mechanotransduction cell signaling in breast cancer. Various miRNAs control the expression of different effectors in the mechanotransduction signaling pathways including focal adhesion complex mediators, cytoskeleton binding proteins, and integrin proteins. Furthermore, miRNAs effectively control the expression of mediators in some mechanotransduction signaling pathways, including YAP/TAZ signaling. ECM stiffness also directly controls the expression of miRNAs in normal breast tissue cells. In response to ECM stiffness, the expression of some miRNAs, including miR-18a and miR-203, changes that influences the cell behaviors. However, the exact mechanism by which the mechanical clues changes the expression of miRNAs remains unknown. WASL, WASP Like Actin Nucleation Promoting Factor; FAK, Focal adhesion kinase; GIT1, G protein-coupled receptor kinase-interacting protein; P130Cas, P130 Crk-associated substrate; RhoA, Ras homolog gene family member A; FHOD1, Formin Homology Domain Protein 1; PPM1F, Protein phosphatase, Mg2+/Mn2+–dependent 1F; BDNF, brain-derived neurotrophic factor; TWF1, Twinfilin actin binding protein 1; VIM, Vimentin; PHACTR1, phosphatase and actin regulator 1; LIFR, LIF Receptor Subunit Alpha; LATS1, Large Tumor Suppressor Kinase 1; LATS2, Large Tumor Suppressor Kinase 2; HERC4, HECT and RLD domain containing E3 ubiquitin ligase 4; JAM-A, junctional Adhesion Molecule-A; HOXA9: Homeobox protein Hox-A9; ROBO1, Roundabout Guidance Receptor 1.

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In miRNA biogenesis, mature miRNAs are produced from pre-miRNA hairpins by Dicer enzyme (169). Chaulk and colleagues conducted a study to find the role of YAP/TAZ in total miRNA biogenesis in the MCF-10A cell line. According to their results, low cell density of MCF-10A causes nuclear accumulation of YAP/TAZ and increased biogenesis of miRNAs. In contrary, high cell density of MCF-10A impairs miRNA biogenesis through Let-7–dependent reduction in Dicer levels. YAP/TAZ nuclear accumulation significantly suppresses the Let-7 mature miRNA through LIN28, as a main regulator of this protein (170, 171). The tumor suppressor role of Let-7 has been well proved in various studies (172–174).

Despite widespread efforts in recent years to further understand the Hippo signaling pathway, there are still many questions about how this pathway interacts with other cell signaling pathways. miRNA dysregulation may indirectly affect the Hippo signaling through other signaling pathways in breast cancer cells. However, more investigations will be helpful in this area.

ECM features and miRNA expression

The relationship between ECM stiffness and breast cancer progression has been investigated in recent years. The ECM stiffness was reported to directly alter the miRNA expression in breast epithelial cells (175). MCF-10A cells cultured on a stiff polyacrylamide-based membrane exhibited an increased expression of miR-18a compared with those grown on a soft membrane. miR-18a decreases the expression of PTEN and HOXA9 genes, leading to induction of invasion and metastasis through over-activation of the IP3/AKT signaling (175).

It is critical for cells to regulate the expression of mechanotransduction mediators to prevent their overactivation that disrupts cellular homeostasis (176). One of the example in the context is regulation of the ROBO1 protein by miR-203. This protein is the key effector in the SLIT2/ROBO1 signaling in which the interaction between ROBO1 and SLIT2 results in activation of adaptor proteins such as different members of the Rho GTPase family due to interaction with the cytoplasmic side of ROBO1 proteins (177). Le and colleagues reported that ECM stiffness directly affects the expression of miR-203 so that the normal murine mammary gland cells (NMuMG) cultured on a high-density collagen gel exhibited lower expression of miR-203 and higher expression of ROBO1 compared with those grown on a low-density gel. They reported that miR-203 directly targets the 3′UTR of ROBO1 and downregulates its expression in response to physical features of ECM (178).

Despite the fact that mechanical cues have an important role in gene regulation mediated by miRNAs in cancer and normal breast cells, there are many unknown aspects due to the lack of comprehensive studies in this area. In future, targeted investigations will help clarify the mechanisms underlying how mechanical signals regulate the expression of miRNAs in breast cancer cells.

In the past decades due to increased environmental risk factors, aging society and the complex lifestyle in modern society significantly increased the rate of breast cancers. Therefore, research councils and other funding bodies, including pharmaceuticals and other biomedical industries, invested billions of dollars in early diagnosis and effective treatment of breast cancer. To design a novel diagnostic tool and effective treatment, the scientific research focus has been on understanding the underlying mechanisms in breast cancer development. The role of physical stimuli is major factors in the development of tumors, in this context, so that cell stress signals within the tumor microenvironment affect the different phases of cancer development such as proliferation, invasion, and metastasis. Therefore, understanding the key regulators that control the mechanotransduction signaling will help provide a comprehensive road map in cancer therapy. miRNAs are probably to be the missing piece of the puzzle that serves as the master regulators of mechanotransduction signaling pathways. Recent advances in molecular technologies have made it possible to analyze the concurrent expression of many miRNAs and their possible targets in the cancer cells. Until now, the relationship between the dysregulation of miRNAs and changes in expression of proteins involved in the cell signaling pathway has been clarified in different studies. However, some fundamental questions regarding how transcription factors affect the expression of miRNAs in response to the mechanical stresses remain unknown. Moreover, focusing on the role of mechanical forces in epigenetic modifications of miRNA genes in breast cancer cells that alter their expressions will increase our knowledge in this context. It is obvious that recognition of different mediators involved in the regulation of miRNAs in response to physical forces will enable us to design effective therapeutic strategies to restore the expression of miRNAs to the normal state in breast cancer cells.

No potential conflicts of interest were disclosed.

1.
Abdollahpour-Alitappeh
M
,
Lotfinia
M
,
Bagheri
N
,
Sineh Sepehr
K
,
Habibi-Anbouhi
M
,
Kobarfard
F
, et al
Trastuzumab-monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2-positive human breast cancer
.
J Cell Physiol
2019
;
234
:
2693
704
.
2.
Dumitrescu
RG
. 
Interplay between genetic and epigenetic changes in breast cancer subtypes
.
Methods Mol Biol
2018
;
1856
:
19
34
.
3.
Hemmati
M
,
Najafi
F
,
Shirkoohi
R
,
Moghimi
HR
,
Zarebkohan
A
,
Kazemi B
. 
Synthesis of a novel PEGDGA-coated hPAMAM complex as an efficient and biocompatible gene delivery vector: an in vitro and in vivo study
.
Drug Deliv
2016
;
23
:
2956
69
.
4.
Pidsley
R
,
Lawrence
MG
,
Zotenko
E
,
Niranjan
B
,
Statham
A
,
Song
J
, et al
Enduring epigenetic landmarks define the cancer microenvironment
.
Genome Res
2018
;
28
:
625
38
.
5.
Poli
V
,
Fagnocchi
L
,
Zippo
A
. 
Tumorigenic cell reprogramming and cancer plasticity: interplay between signaling, microenvironment, and epigenetics
.
Stem Cells Int
2018
;
2018
:
4598195
.
6.
Sahmani
M
,
Vatanmakanian
M
,
Goudarzi
M
,
Mobarra
N
,
Azad
M
. 
Microchips and their significance in isolation of circulating tumor cells and monitoring of cancers
.
Asian Pac J Cancer Prev
2016
;
17
:
879
94
.
7.
Rahmani
T
,
Azad
M
,
Chahardouli
B
,
Nasiri
H
,
Vatanmakanian
M
,
Kaviani
S
, et al
Patterns of DNMT1 promoter methylation in patients with acute lymphoblastic leukemia
.
Int J Hematol Oncol Stem Cell Res
2017
;
11
:
172
.
8.
Insua-Rodríguez
J
,
Oskarsson
T
. 
The extracellular matrix in breast cancer
.
Adv Drug Deliv Rev
2016
;
97
:
41
55
.
9.
Jabłońska-Trypuć
A
,
Matejczyk
M
,
Rosochacki
S
. 
Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs
.
J Enzyme Inhib Med Chem
2016
;
31
:
177
83
.
10.
Viola
M
,
Karousou
E
,
DAngelo
ML
,
Moretto
P
,
Caon
I
,
De Luca
G
, et al
Extracellular matrix in atherosclerosis: hyaluronan and proteoglycans insights
.
Curr Med Chem
2016
;
23
:
2958
71
.
11.
Wullkopf
L
,
West
AKV
,
Leijnse
N
,
Cox
TR
,
Madsen
CD
,
Oddershede
LB
, et al
Cancer cells' ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential
.
Mol Biol Cell
2018
;
29
:
2378
85
.
12.
Pang
MF
,
Siedlik
MJ
,
Han
S
,
Stallings-Mann
M
,
Radisky
DC
,
Nelson
CM
. 
Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells
.
Cancer Res
2016
;
76
:
5277
87
.
13.
Bourguignon
LY
,
Spevak
CC
,
Wong
G
,
Xia
W
,
Gilad
E
. 
Hyaluronan-CD44 interaction with protein kinase Cε promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells
.
J Biol Chem
2009
;
284
:
26533
46
.
14.
Han
W
,
Chen
S
,
Yuan
W
,
Fan
Q
,
Tian
J
,
Wang
X
, et al
Oriented collagen fibers direct tumor cell intravasation
.
Proc Natl Acad Sci U S A
2016
;
113
:
11208
13
.
15.
Walker
C
,
Mojares
E
,
del Río Hernández
A
. 
Role of extracellular matrix in development and cancer progression
.
Int J Mol Sci
2018
;
19
:
3028
.
16.
Northcott
JM
,
Dean
IS
,
Mouw
JK
,
Weaver
VM
. 
Feeling stress: the mechanics of cancer progression and aggression
.
Front Cell Dev Biol
2018
;
6
:
17
.
17.
Matsuda
A
,
Miyashita
M
,
Matsumoto
S
,
Sakurazawa
N
,
Kawano
Y
,
Yamahatsu
K
, et al
Colonic stent-induced mechanical compression may suppress cancer cell proliferation in malignant large bowel obstruction
.
Surg Endosc
2019
;
33
:
1290
7
.
18.
Yu
H
,
Mouw
JK
,
Weaver
VM
. 
Forcing form and function: biomechanical regulation of tumor evolution
.
Trends Cell Biol
2011
;
21
:
47
56
.
19.
Loh
HY
,
Norman
BP
,
Lai
KS
,
Rahman
NMANA
,
Alitheen
NBM
,
Osman
MA
. 
The regulatory role of microRNAs in breast cancer
.
Int J Mol Sci
2019
;
20
:
4940
.
20.
Najminejad
H
,
Kalantar
SM
,
Abdollahpour-Alitappeh
M
,
Karimi
MH
,
Seifalian
AM
,
Gholipourmalekabadi
M
, et al
Emerging roles of exosomal miRNAs in breast cancer drug resistance
.
IUBMB Life
2019
;
71
:
1672
84
.
21.
Tayebi
B
,
Abrishami
F
,
Alizadeh
S
,
Minayi
N
,
Mohammadian
M
,
Soleimani
M
, et al
Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression
.
Artif Cells Nanomed Biotechnol
2017
;
45
:
146
56
.
22.
Sheervalilou
R
,
Ansarin
K
,
Fekri Aval
S
,
Shirvaliloo
S
,
Pilehvar‐soltanahmadi
Y
,
Mohammadian
M
, et al
An update on sputum micro RNA s in lung cancer diagnosis
.
Diagn Cytopathol
2016
;
44
:
442
9
.
23.
Javadian
M
,
Gharibi
T
,
Shekari
N
,
Abdollahpour‐Alitappeh
M
,
Mohammadi
A
,
Hossieni
A
, et al
The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis
.
J Cell Physiol
2019
;
234
:
5399
412
.
24.
Hosseinahli
N
,
Aghapour
M
,
Duijf
PH
,
Baradaran
B
. 
Treating cancer with microRNA replacement therapy: a literature review
.
J Cell Physiol
2018
;
233
:
5574
88
.
25.
Szafranska-Schwarzbach
AE
,
Adai
AT
,
Lee
LS
,
Conwell
DL
,
Andruss
BF
. 
Development of a miRNA-based diagnostic assay for pancreatic ductal adenocarcinoma
.
Expert Rev Mol Diagn
2011
;
11
:
249
57
.
26.
Sharma
S
,
Eghbali
M
. 
Influence of sex differences on microRNA gene regulation in disease
.
Biol Sex Differ
2014
;
5
:
3
.
27.
Palanichamy
JK
,
Rao
DS
. 
miRNA dysregulation in cancer: towards a mechanistic understanding
.
Front Genet
2014
;
5
:
54
.
28.
Brümmer
A
,
Hausser
J
. 
MicroRNA binding sites in the coding region of mRNAs: extending the repertoire of post‐transcriptional gene regulation
.
Bioessays
2014
;
36
:
617
26
.
29.
Tschumperlin
DJ
,
Ligresti
G
,
Hilscher
MB
,
Shah
VH
. 
Mechanosensing and fibrosis
.
J Clin Invest
2018
;
128
:
74
84
.
30.
Puleo
JI
,
Parker
SS
,
Roman
MR
,
Watson
AW
,
Eliato
KR
,
Peng
L
, et al
Mechanosensing during directed cell migration requires dynamic actin polymerization at focal adhesions
.
J Cell Biol
2019
;
218
:
4215
35
.
31.
Moreo
P
,
García-Aznar
JM
,
Doblaré
M
. 
Modeling mechanosensing and its effect on the migration and proliferation of adherent cells
.
Acta Biomater
2008
;
4
:
613
21
.
32.
Nonomura
K
,
Lukacs
V
,
Sweet
DT
,
Goddard
LM
,
Kanie
A
,
Whitwam
T
, et al
Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation
.
Proc Natl Acad Sci U S A
2018
;
115
:
12817
22
.
33.
Wang
F
,
Knutson
K
,
Alcaino
C
,
Linden
DR
,
Gibbons
SJ
,
Kashyap
P
, et al
Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces
.
J Physiol
2017
;
595
:
79
91
.
34.
Butcher
DT
,
Alliston
T
,
Weaver
VM
. 
A tense situation: forcing tumour progression
.
Nat Rev Cancer
2009
;
9
:
108
.
35.
Mui
KL
,
Chen
CS
,
Assoian
RK
. 
The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces
.
J Cell Sci
2016
;
129
:
1093
100
.
36.
Humphrey
JD
,
Schwartz
MA
,
Tellides
G
,
Milewicz
DM
. 
Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections
.
Circ Res
2015
;
116
:
1448
61
.
37.
Wendt
MK
,
Schiemann
BJ
,
Parvani
JG
,
Lee
Y-H
,
Kang
Y
,
Schiemann
WP
. 
TGF-β stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer
.
Oncogene
2013
;
32
:
2005
15
.
38.
Muz
B
,
Buggio
M
,
Azab
F
,
De La Puente
P
,
Fiala
M
,
Padval
MV
, et al
PYK2/FAK inhibitors reverse hypoxia-induced drug resistance in multiple myeloma
.
Haematologica
2019
;
104
:
e310
.
39.
Qin
X
,
Li
J
,
Sun
J
,
Liu
L
,
Chen
D
,
Liu
Y
. 
Low shear stress induces ERK nuclear localization and YAP activation to control the proliferation of breast cancer cells
.
Biochem Biophys Res Commun
2019
;
510
:
219
23
.
40.
Marmé
D
. 
Tumor angiogenesis: a key target for cancer therapy
.
Oncol Res Treat
2018
;
41
:
164
.
41.
Carmeliet
P
,
Jain
RK
. 
Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases
.
Nat Rev Drug Discov
2011
;
10
:
417
.
42.
Jain
RK
,
Martin
JD
,
Stylianopoulos
T
. 
The role of mechanical forces in tumor growth and therapy
.
Annu Rev Biomed Eng
2014
;
16
:
321
46
.
43.
Venning
FA
,
Wullkopf
L
,
Erler
JT
. 
Targeting ECM disrupts cancer progression
.
Front Oncol
2015
;
5
:
224
.
44.
Rao
RR
,
Peterson
AW
,
Ceccarelli
J
,
Putnam
AJ
,
Stegemann
JP
. 
Matrix composition regulates three-dimensional network formation by endothelial cells and mesenchymal stem cells in collagen/fibrin materials
.
Angiogenesis
2012
;
15
:
253
64
.
45.
Davis
GE
,
Senger
DR
. 
Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization
.
Circ Res
2005
;
97
:
1093
107
.
46.
Ghajar
CM
,
Chen
X
,
Harris
JW
,
Suresh
V
,
Hughes
CC
,
Jeon
NL
, et al
The effect of matrix density on the regulation of 3-D capillary morphogenesis
.
Biophys J
2008
;
94
:
1930
41
.
47.
Bordeleau
F
,
Mason
BN
,
Lollis
EM
,
Mazzola
M
,
Zanotelli
MR
,
Somasegar
S
, et al
Matrix stiffening promotes a tumor vasculature phenotype
.
Proc Natl Acad Sci U S A
2017
;
114
:
492
7
.
48.
Croix
BS
,
Rago
C
,
Velculescu
V
,
Traverso
G
,
Romans
KE
,
Montgomery
E
, et al
Genes expressed in human tumor endothelium
.
Science
2000
;
289
:
1197
202
.
49.
Chauhan
VP
,
Boucher
Y
,
Ferrone
CR
,
Roberge
S
,
Martin
JD
,
Stylianopoulos
T
, et al
Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure
.
Cancer Cell
2014
;
26
:
14
5
.
50.
Goel
S
,
Duda
DG
,
Xu
L
,
Munn
LL
,
Boucher
Y
,
Fukumura
D
, et al
Normalization of the vasculature for treatment of cancer and other diseases
.
Physiol Rev
2011
;
91
:
1071
121
.
51.
Yoshino
D
,
Sakamoto
N
,
Sato
M
. 
Fluid shear stress combined with shear stress spatial gradients regulates vascular endothelial morphology
.
Integr Biol
2017
;
9
:
584
94
.
52.
Helmlinger
G
,
Geiger
R
,
Schreck
S
,
Nerem
R
. 
Effects of pulsatile flow on cultured vascular endothelial cell morphology
.
J Biomech Eng
1991
;
113
:
123
31
.
53.
Vickerman
V
,
Kamm
RD
. 
Mechanism of a flow-gated angiogenesis switch: early signaling events at cell–matrix and cell–cell junctions
.
Integr Biol
2012
;
4
:
863
74
.
54.
Ghosh
K
,
Thodeti
CK
,
Dudley
AC
,
Mammoto
A
,
Klagsbrun
M
,
Ingber
DE
. 
Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro
.
Proc Natl Acad Sci U S A
2008
;
105
:
11305
10
.
55.
Bouzid
T
,
Kim
E
,
Riehl
BD
,
Esfahani
AM
,
Rosenbohm
J
,
Yang
R
, et al
The LINC complex, mechanotransduction, and mesenchymal stem cell function and fate
.
J Biol Eng
2019
;
13
:
68
.
56.
Schreiner
SM
,
Koo
PK
,
Zhao
Y
,
Mochrie
SG
,
King
MC
. 
The tethering of chromatin to the nuclear envelope supports nuclear mechanics
.
Nat Commun
2015
;
6
:
7159
.
57.
Mitra
A
,
Venkatachalapathy
S
,
Ratna
P
,
Wang
Y
,
Jokhun
DS
,
Shivashankar
G
. 
Cell geometry dictates TNFα-induced genome response
.
Proc Natl Acad Sci U S A
2017
;
114
:
E3882
E91
.
58.
Wang
Y
,
Nagarajan
M
,
Uhler
C
,
Shivashankar
G
. 
Orientation and repositioning of chromosomes correlate with cell geometry–dependent gene expression
.
Mol Biol Cell
2017
;
28
:
1997
2009
.
59.
Tajik
A
,
Zhang
Y
,
Wei
F
,
Sun
J
,
Jia
Q
,
Zhou
W
, et al
Transcription upregulation via force-induced direct stretching of chromatin
.
Nat Mater
2016
;
15
:
1287
.
60.
Montavon
T
,
Duboule
D
. 
Chromatin organization and global regulation of Hox gene clusters
.
Philos Trans R Soc B Biol Sci
2013
;
368
:
20120367
.
61.
O'Brien
J
,
Hayder
H
,
Zayed
Y
,
Peng
C
. 
Overview of microRNA biogenesis, mechanisms of actions, and circulation
.
Front Endocrinol
2018
;
9
:
402
.
62.
Peng
Y
,
Croce
CM
. 
The role of MicroRNAs in human cancer
.
Signal Transduct Targeted Ther
2016
;
1
:
15004
.
63.
Iorio
MV
,
Ferracin
M
,
Liu
C-G
,
Veronese
A
,
Spizzo
R
,
Sabbioni
S
, et al
MicroRNA gene expression deregulation in human breast cancer
.
Cancer Res
2005
;
65
:
7065
70
.
64.
Schanen
BC
,
Li
X
. 
Transcriptional regulation of mammalian miRNA genes
.
Genomics
2011
;
97
:
1
6
.
65.
Kim
VN
,
Nam
J-W
. 
Genomics of microRNA
.
Trends Genet
2006
;
22
:
165
73
.
66.
Cai
X
,
Hagedorn
CH
,
Cullen
BR
. 
Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs
.
RNA
2004
;
10
:
1957
66
.
67.
Lee
D
,
Shin
C
. 
Emerging roles of DROSHA beyond primary microRNA processing
.
RNA Biol
2018
;
15
:
186
93
.
68.
Fardmanesh
H
,
Shekari
M
,
Movafagh
A
,
Shargh
SA
,
Zonouzi
AAP
,
Shakerizadeh
S
, et al
Upregulation of the double-stranded RNA binding protein DGCR8 in invasive ductal breast carcinoma
.
Gene
2016
;
581
:
146
51
.
69.
Wu
K
,
He
J
,
Pu
W
,
Peng
Y
. 
The role of exportin-5 in microRNA biogenesis and cancer
.
Genomics Proteomics Bioinformatics
2018
;
16
:
120
6
.
70.
Vaidyanathan
S
,
Thangavelu
PU
,
Duijf
PH
. 
Overexpression of Ran GTPase components regulating nuclear export, but not mitotic spindle assembly, marks chromosome instability and poor prognosis in breast cancer
.
Target Oncol
2016
;
11
:
677
86
.
71.
Sheng
C
,
Qiu
J
,
Wang
Y
,
He
Z
,
Wang
H
,
Wang
Q
, et al
Knockdown of Ran GTPase expression inhibits the proliferation and migration of breast cancer cells
.
Mol Med Rep
2018
;
18
:
157
68
.
72.
Cai
Y
,
Yu
X
,
Hu
S
,
Yu
J
. 
A brief review on the mechanisms of miRNA regulation
.
Genomics Proteomics Bioinformatics
2009
;
7
:
147
54
.
73.
Kwon
SY
,
Lee
JH
,
Kim
B
,
Park
JW
,
Kwon
TK
,
Kang
SH
, et al
Complexity in regulation of microRNA machinery components in invasive breast carcinoma
.
Pathol Oncol Res
2014
;
20
:
697
705
.
74.
Leaderer
D
,
Hoffman
AE
,
Zheng
T
,
Fu
A
,
Weidhaas
J
,
Paranjape
T
, et al
Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis
.
Int J Mol Epidemiol Genet
2011
;
2
:
9
.
75.
Shao
Y
,
Shen
Y
,
Zhao
L
,
Guo
X
,
Niu
C
,
Liu
F
. 
Association of microRNA biosynthesis genes XPO5 and RAN polymorphisms with cancer susceptibility: Bayesian hierarchical meta-analysis
.
J Cancer
2020
;
11
:
2181
91
.
76.
Wang
L
,
Wang
J
. 
MicroRNA-mediated breast cancer metastasis: from primary site to distant organs
.
Oncogene
2012
;
31
:
2499
511
.
77.
Li
P
,
Dong
J
,
Zhou
X
,
Sun
W
,
Huang
H
,
Chen
T
, et al
Expression patterns of microRNA-329 and its clinical performance in diagnosis and prognosis of breast cancer
.
Onco Targets Ther
2017
;
10
:
5711
8
.
78.
Hynes
RO
. 
Integrins: bidirectional, allosteric signaling machines
.
Cell
2002
;
110
:
673
87
.
79.
Kuo
JC
. 
Mechanotransduction at focal adhesions: integrating cytoskeletal mechanics in migrating cells
.
J Cell Mol Med
2013
;
17
:
704
12
.
80.
Ambriz
X
,
de Lanerolle
P
,
Ambrosio
J
. 
The mechanobiology of the actin cytoskeleton in stem cells during differentiation and interaction with biomaterials
.
Stem Cells Int
2018
;
2018
:
2891957
.
81.
Marlowe
T
,
Dementiev
A
,
Figel
S
,
Rivera
A
,
Flavin
M
,
Cance
W
. 
High resolution crystal structure of the FAK FERM domain reveals new insights on the Druggability of tyrosine 397 and the Src SH3 binding site
.
BMC Mol Cell Biol
2019
;
20
:
10
.
82.
Gayrard
C
,
Bernaudin
C
,
Déjardin
T
,
Seiler
C
,
Borghi
N
. 
Src-and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity
.
J Cell Biol
2018
;
217
:
1063
77
.
83.
Sonoda
Y
,
Matsumoto
Y
,
Funakoshi
M
,
Yamamoto
D
,
Hanks
SK
,
Kasahara
T
. 
Anti-apoptotic role of focal adhesion kinase (FAK) Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60
.
J Biol Chem
2000
;
275
:
16309
15
.
84.
van Nimwegen
MJ
,
Verkoeijen
S
,
van Buren
L
,
Burg
D
,
van de Water
B
. 
Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation
.
Cancer Res
2005
;
65
:
4698
706
.
85.
Lark
AL
,
Livasy
CA
,
Dressler
L
,
Moore
DT
,
Millikan
RC
,
Geradts
J
, et al
High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype
.
Mod Pathol
2005
;
18
:
1289
.
86.
Arivazhagan
L
,
Venkatraman
G
,
Rayala
SK
. 
Increased expression of MicroRNA 551a by c-Fos reduces focal adhesion kinase levels and blocks tumorigenesis
.
Mol Cell Biol
2019
;
39
:
e00577
18
.
87.
Kong
X
,
Li
G
,
Yuan
Y
,
He
Y
,
Wu
X
,
Zhang
W
, et al
MicroRNA-7 inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via targeting FAK expression
.
PLoS One
2012
;
7
:
e41523
.
88.
Zhang
Y
,
Weinberg
RA
. 
Epithelial-to-mesenchymal transition in cancer: complexity and opportunities
.
Front Med
2018
;
12
:
361
73
.
89.
Geiger
B
. 
A role for p130Cas in mechanotransduction
.
Cell
2006
;
127
:
879
81
.
90.
Matsui
H
,
Harada
I
,
Sawada
Y
. 
Src, p130Cas, and mechanotransduction in cancer cells
.
Genes Cancer
2012
;
3
:
394
401
.
91.
Hoffman
BD
,
Grashoff
C
,
Schwartz
MA
. 
Dynamic molecular processes mediate cellular mechanotransduction
.
Nature
2011
;
475
:
316
.
92.
Zhang
C
,
Miller
DJ
,
Guibao
CD
,
Donato
DM
,
Hanks
SK
,
Zheng
JJ
. 
Structural and functional insights into the interaction between the Cas family scaffolding protein p130Cas and the focal adhesion-associated protein paxillin
.
J Biol Chem
2017
;
292
:
18281
9
.
93.
Ta
HQ
,
Thomas
KS
,
Schrecengost
RS
,
Bouton
AH
. 
A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells
.
Cancer Res
2008
;
68
:
8796
804
.
94.
Kang
H
,
Kim
C
,
Lee
H
,
Rho
J
,
Seo
J
,
Nam
JW
, et al
Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer
.
Cell Death Differ
2016
;
23
:
484
.
95.
Yip
GW
,
Smollich
M
,
Götte
M
. 
Therapeutic value of glycosaminoglycans in cancer
.
Mol Cancer Ther
2006
;
5
:
2139
48
.
96.
Hannafon
BN
,
Sebastiani
P
,
de las Morenas
A
,
Lu
J
,
Rosenberg
CL
. 
Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer
.
Breast Cancer Res
2011
;
13
:
R24
.
97.
Ibrahim
SA
,
Yip
GW
,
Stock
C
,
Pan
JW
,
Neubauer
C
,
Poeter
M
, et al
Targeting of syndecan‐1 by microRNA miR‐10b promotes breast cancer cell motility and invasiveness via a Rho‐GTPase‐and E‐cadherin‐dependent mechanism
.
Int J Cancer
2012
;
131
:
E884
96
.
98.
Katoh
K
. 
FAK-dependent cell motility and cell elongation
.
Cells
2020
;
9
:
192
.
99.
Schwickert
A
,
Weghake
E
,
Brüggemann
K
,
Engbers
A
,
Brinkmann
BF
,
Kemper
B
, et al
microRNA miR-142-3p inhibits breast cancer cell invasiveness by synchronous targeting of WASL, integrin alpha V, and additional cytoskeletal elements
.
PLoS One
2015
;
10
:
e0143993
.
100.
Sanchez
AM
,
Flamini
MI
,
Baldacci
C
,
Goglia
L
,
Genazzani
AR
,
Simoncini
T
. 
Estrogen receptor-α promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP
.
Mol Endocrinol
2010
;
24
:
2114
25
.
101.
Wu
YJ
,
Pagel
MA
,
Muldoon
LL
,
Fu
R
,
Neuwelt
EA
. 
High αv integrin level of cancer cells is associated with development of brain metastasis in athymic rats
.
Anticancer Res
2017
;
37
:
4029
40
.
102.
Shibue
T
,
Weinberg
RA
. 
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
.
Nat Rev Clin Oncol
2017
;
14
:
611
.
103.
Du
B
,
Shim
J
. 
Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer
.
Molecules
2016
;
21
:
965
.
104.
Creighton
CJ
,
Li
X
,
Landis
M
,
Dixon
JM
,
Neumeister
VM
,
Sjolund
A
, et al
Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features
.
Proc Natl Acad Sci U S A
2009
;
106
:
13820
5
.
105.
Bockhorn
J
,
Yee
K
,
Chang
YF
,
Prat
A
,
Huo
D
,
Nwachukwu
C
, et al
MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion
.
Breast Cancer Res Treat
2013
;
137
:
373
82
.
106.
Bockhorn
J
,
Dalton
R
,
Nwachukwu
C
,
Huang
S
,
Prat
A
,
Yee
K
, et al
MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
.
Nat Commun
2013
;
4
:
1393
.
107.
Ren
K
,
Tang
J
,
Jiang
X
,
Sun
H
,
Nong
L
,
Shen
N
, et al
Periodic mechanical stress stimulates GIT1-dependent mitogenic signals in rat chondrocytes through ERK1/2 activity
.
Cell Physiol Biochem
2018
;
50
:
1015
28
.
108.
Zhang
Z
,
Polu Hu
JX
,
Wang
S
. 
Inhibiting GIT1 reduces the growth, invasion, and angiogenesis of osteosarcoma
.
Cancer Manag Res
2018
;
10
:
6445
.
109.
Schlenker
O
,
Rittinger
K
. 
Structures of dimeric GIT1 and trimeric β-PIX and implications for GIT–PIX complex assembly
.
J Mol Biol
2009
;
386
:
280
9
.
110.
Ren
Y
,
Yu
L
,
Fan
J
,
Rui
Z
,
Hua
Z
,
Zhang
Z
, et al
Phosphorylation of GIT1 tyrosine 321 is required for association with FAK at focal adhesions and for PDGF-activated migration of osteoblasts
.
Mol Cell Biochem
2012
;
365
:
109
18
.
111.
Chan
S
,
Huang
W
,
Chang
J
,
Chang
K
,
Kuo
W
,
Wang
M
, et al
MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis
.
Oncogene
2014
;
33
:
4496
.
112.
Harris
AR
,
Jreij
P
,
Fletcher
DA
. 
Mechanotransduction by the actin cytoskeleton: converting mechanical stimuli into biochemical signals
.
Annu Rev Biophys
2018
;
47
:
617
31
.
113.
Yamaguchi
H
,
Condeelis
J
. 
Regulation of the actin cytoskeleton in cancer cell migration and invasion
.
Biochim Biophys Acta
2007
;
1773
:
642
52
.
114.
Shen
Y
,
Shayegan
M
,
Moncho
A
,
Li
H
,
Wu
H
,
Shi
W
, et al
Microrheology of microtubule-actin-vimentin composite cytoskeletal networks
.
Biophysical J
2019
;
118
:
440
.
115.
Richardson
AM
,
Havel
LS
,
Koyen
AE
,
Konen
JM
,
Shupe
J
,
Wiles
W
, et al
Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell–cancer-associated fibroblast interactions during collective invasion
.
Clin Cancer Res
2018
;
24
:
420
32
.
116.
Pardali
K
,
Moustakas
A
. 
Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer
.
Biochim Biophys Acta
2007
;
1775
:
21
62
.
117.
Humbert
L
,
Neel
J
,
Lebrun
J
. 
Targeting TGF-beta signaling in human cancer therapy
.
Trends Cell Mol Biol
2010
;
5
:
69
107
.
118.
Allen
PB
,
Greenfield
AT
,
Svenningsson
P
,
Haspeslagh
DC
,
Greengard
P
. 
Phactrs 1–4: a family of protein phosphatase 1 and actin regulatory proteins
.
Proc Natl Acad Sci U S A
2004
;
101
:
7187
92
.
119.
Fils-Aimé
N
,
Dai
M
,
Guo
J
,
El-Mousawi
M
,
Kahramangil
B
,
Neel
JC
, et al
MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-β mediates the migration and actin dynamics of breast cancer cells
.
J Biol Chem
2013
;
288
:
11807
23
.
120.
Korpal
M
,
Lee
ES
,
Hu
G
,
Kang
Y
. 
The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2
.
J Biol Chem
2008
;
283
:
14910
4
.
121.
Arunkumar
G
,
Rao
DM
,
Kuha
A
,
Manikandan
M
,
Prasanna Srinivasa Rao
H
,
Subbiah
S
, et al
Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma
.
Oncol Lett
2018
;
15
:
649
57
.
122.
O'Brien
SJ
,
Carter
JV
,
Burton
JF
,
Oxford
BG
,
Schmidt
MN
,
Hallion
JC
, et al
The role of the miR‐200 family in epithelial–mesenchymal transition in colorectal cancer: a systematic review
.
Int J Cancer
2018
;
142
:
2501
11
.
123.
Brabletz
T
,
Kalluri
R
,
Nieto
MA
,
Weinberg
RA
. 
EMT in cancer
.
Nat Rev Cancer
2018
;
18
:
128
.
124.
Gibbons
DL
,
Lin
W
,
Creighton
CJ
,
Rizvi
ZH
,
Gregory
PA
,
Goodall
GJ
, et al
Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression
.
Genes Dev
2009
;
23
:
2140
51
.
125.
Olson
P
,
Lu
J
,
Zhang
H
,
Shai
A
,
Chun
MG
,
Wang
Y
, et al
MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer
.
Genes Dev
2009
;
23
:
2152
65
.
126.
Shu
C
,
Yan
D
,
Mo
Y
,
Gu
J
,
Shah
N
,
He
J
. 
Long noncoding RNA lncARSR promotes epithelial ovarian cancer cell proliferation and invasion by association with HuR and miR-200 family
.
Am J Cancer Res
2018
;
8
:
981
.
127.
Luo
C
,
Pu
J
,
Liu
F
,
Long
X
,
Wang
C
,
Wei
H
, et al
MicroRNA-200c expression is decreased in hepatocellular carcinoma and associated with poor prognosis
.
Clin Res Hepatol Gastroenterol
2019
;
43
:
715
21
.
128.
Jurmeister
S
,
Baumann
M
,
Balwierz
A
,
Keklikoglou
I
,
Ward
A
,
Uhlmann
S
, et al
MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F
.
Mol Cell Biol
2012
;
32
:
633
51
.
129.
Schönichen
A
,
Mannherz
HG
,
Behrmann
E
,
Mazur
AJ
,
Kühn
S
,
Silván
U
, et al
FHOD1 is a combined actin filament capping and bundling factor that selectively associates with actin arcs and stress fibers
.
J Cell Sci
2013
;
126
:
1891
901
.
130.
Staus
DP
,
Blaker
AL
,
Medlin
MD
,
Taylor
JM
,
Mack
CP
. 
Formin homology domain–containing protein 1 regulates smooth muscle cell phenotype
.
Arterioscler Thromb Vasc Biol
2011
;
31
:
360
7
.
131.
Koh
CG
,
Tan
EJ
,
Manser
E
,
Lim
L
. 
The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family
.
Curr Biol
2002
;
12
:
317
21
.
132.
Bracken
CP
,
Li
X
,
Wright
JA
,
Lawrence
DM
,
Pillman
KA
,
Salmanidis
M
, et al
Genome‐wide identification of miR‐200 targets reveals a regulatory network controlling cell invasion
.
EMBO J
2014
;
33
:
2040
56
.
133.
Simonetti
G
,
Bruno
S
,
Padella
A
,
Tenti
E
,
Martinelli
G
. 
Aneuploidy: cancer strength or vulnerability?
Int J Cancer
2019
;
144
:
8
25
.
134.
Sümbül
AT
,
Göğebakan
B
,
Ergün
S
,
Yengil
E
,
Batmacı
CY
,
Tonyalı
Ö
, et al
miR-204-5p expression in colorectal cancer: an autophagy-associated gene
.
Tumor Biol
2014
;
35
:
12713
9
.
135.
Lee
Y
,
Yang
X
,
Huang
Y
,
Fan
H
,
Zhang
Q
,
Wu
Y
, et al
Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis
.
PLoS Comput Biol
2010
;
6
:
e1000730
.
136.
Slutsky
AB
,
Etnier
JL
. 
Caloric restriction, physical activity, and cognitive performance: a review of evidence and a discussion of the potential mediators of BDNF and TrkB
.
Int J Sport Exerc Psychol
2019
;
17
:
89
105
.
137.
Contreras-Zárate
MJ
,
Day
NL
,
Ormond
DR
,
Borges
VF
,
Tobet
S
,
Gril
B
, et al
Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases
.
Oncogene
2019
;
38
:
4685
99
.
138.
Au
CW
,
Siu
MK
,
Liao
X
,
Wong
ES
,
Ngan
HY
,
Tam
KF
, et al
Tyrosine kinase B receptor and BDNF expression in ovarian cancers–Effect on cell migration, angiogenesis and clinical outcome
.
Cancer Lett
2009
;
281
:
151
61
.
139.
Anderson
G
. 
Breast cancer: occluded role of mitochondria N-acetylserotonin/melatonin ratio in co-ordinating pathophysiology
.
Biochem Pharmacol
2019
;
168
:
259
68
.
140.
Imam
JS
,
Plyler
JR
,
Bansal
H
,
Prajapati
S
,
Bansal
S
,
Rebeles
J
, et al
Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization
.
PLoS One
2012
;
7
:
e52397
.
141.
Sempere
LF
,
Christensen
M
,
Silahtaroglu
A
,
Bak
M
,
Heath
CV
,
Schwartz
G
, et al
Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer
.
Cancer Res
2007
;
67
:
11612
20
.
142.
Wang
S
,
Bian
C
,
Yang
Z
,
Bo
Y
,
Li
J
,
Zeng
L
, et al
miR-145 inhibits breast cancer cell growth through RTKN
.
Int J Oncol
2009
;
34
:
1461
6
.
143.
Götte
M
,
Mohr
C
,
Koo
C
,
Stock
C
,
Vaske
A
,
Viola
M
, et al
miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness
.
Oncogene
2010
;
29
:
6569
.
144.
Garcia
MA
,
Nelson
WJ
,
Chavez
N
. 
Cell–cell junctions organize structural and signaling networks
.
Cold Spring Harb Perspect Biol
2018
;
10
:
a029181
.
145.
Severson
EA
,
Jiang
L
,
Ivanov
AI
,
Mandell
KJ
,
Nusrat
A
,
Parkos
CA
. 
Cis-dimerization mediates function of junctional adhesion molecule A
.
Mol Biol Cell
2008
;
19
:
1862
72
.
146.
Bhajun
R
,
Guyon
L
,
Pitaval
A
,
Sulpice
E
,
Combe
S
,
Obeid
P
, et al
A statistically inferred microRNA network identifies breast cancer target miR-940 as an actin cytoskeleton regulator
.
Sci Rep
2015
;
5
:
8336
.
147.
Royer
C
,
Lu
X
. 
Epithelial cell polarity: a major gatekeeper against cancer?
Cell Death Differ
2011
;
18
:
1470
.
148.
Porter
AP
,
Papaioannou
A
,
Malliri
A
. 
Deregulation of Rho GTPases in cancer
.
Small GTPases
2016
;
7
:
123
38
.
149.
Martin
E
,
Ouellette
MH
,
Jenna
S
. 
Rac1/RhoA antagonism defines cell-to-cell heterogeneity during epidermal morphogenesis in nematodes
.
J Cell Biol
2016
;
215
:
483
98
.
150.
Huveneers
S
,
Danen
EH
. 
Adhesion signaling–crosstalk between integrins, Src and Rho
.
J Cell Sci
2009
;
122
:
1059
69
.
151.
Zhao
L
,
Zheng
XY
. 
MicroRNA-490 inhibits tumorigenesis and progression in breast cancer
.
Onco Targets Ther
2016
;
9
:
4505
.
152.
Liu
Q
,
Wang
W
,
Yang
X
,
Zhao
D
,
Li
F
,
Wang
H
. 
MicroRNA-146a inhibits cell migration and invasion by targeting RhoA in breast cancer
.
Oncol Rep
2016
;
36
:
189
96
.
153.
Kong
W
,
Yang
H
,
He
L
,
Zhao
JJ
,
Coppola
D
,
Dalton
WS
, et al
MicroRNA-155 is regulated by the transforming growth factor β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA
.
Mol Cell Biol
2008
;
28
:
6773
84
.
154.
Mo
JS
,
Park
HW
,
Guan
KL
. 
The Hippo signaling pathway in stem cell biology and cancer
.
EMBO Rep
2014
;
15
:
642
56
.
155.
Pan
D
. 
Hippo signaling in organ size control
.
Genes Dev
2007
;
21
:
886
97
.
156.
Misra
JR
,
Irvine
KD
. 
The Hippo signaling network and its biological functions
.
Annu Rev Genet
2018
;
52
:
65
87
.
157.
Piccolo
S
,
Dupont
S
,
Cordenonsi
M
. 
The biology of YAP/TAZ: hippo signaling and beyond
.
Physiol Rev
2014
;
94
:
1287
312
.
158.
Meng
Z
,
Moroishi
T
,
Guan
KL
. 
Mechanisms of Hippo pathway regulation
.
Genes Dev
2016
;
30
:
1
17
.
159.
Hao
Y
,
Chun
A
,
Cheung
K
,
Rashidi
B
,
Yang
X
. 
Tumor suppressor LATS1 is a negative regulator of oncogene YAP
.
J Biol Chem
2008
;
283
:
5496
509
.
160.
Zhao
Y
,
Yang
X
. 
The H ippo pathway in chemotherapeutic drug resistance
.
Int J Cancer
2015
;
137
:
2767
73
.
161.
Zhang
L
,
Cheng
F
,
Wei
Y
,
Zhang
L
,
Guo
D
,
Wang
B
, et al
Inhibition of TAZ contributes radiation-induced senescence and growth arrest in glioma cells
.
Oncogene
2019
;
38
:
2788
99
.
162.
Nguyen
CD
,
Yi
C
. 
YAP/TAZ signaling and resistance to cancer therapy
.
Trends Cancer
2019
;
5
:
283
96
.
163.
Oku
Y
,
Nishiya
N
,
Shito
T
,
Yamamoto
R
,
Yamamoto
Y
,
Oyama
C
, et al
Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers
.
FEBS Open Bio
2015
;
5
:
542
9
.
164.
Zheng
YB
,
Xiao
K
,
Xiao
GC
,
Tong
SL
,
Ding
Y
,
Wang
QS
, et al
MicroRNA-103 promotes tumor growth and metastasis in colorectal cancer by directly targeting LATS2
.
Oncol Lett
2016
;
12
:
2194
200
.
165.
Li
Y
,
Sun
D
,
Gao
J
,
Shi
Z
,
Chi
P
,
Meng
Y
, et al
MicroRNA‐373 promotes the development of endometrial cancer by targeting LATS2 and activating the Wnt/β‐Catenin pathway
.
J Cell Biochem
2019
;
120
:
8611
8
.
166.
Hua
K
,
Jin
J
,
Zhao
J
,
Song
J
,
Song
H
,
Li
D
, et al
miR-135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2
.
Int J Oncol
2016
;
48
:
1997
2006
.
167.
Xu
Y
,
Ji
K
,
Wu
M
,
Hao
B
,
Yao
KT
,
Xu
Y
. 
A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1
.
Protein Cell
2019
;
10
:
595
605
.
168.
Nandy
SB
,
Arumugam
A
,
Subramani
R
,
Pedroza
D
,
Hernandez
K
,
Saltzstein
E
, et al
MicroRNA-125a influences breast cancer stem cells by targeting leukemia inhibitory factor receptor which regulates the Hippo signaling pathway
.
Oncotarget
2015
;
6
:
17366
.
169.
Suzuki
HI
,
Arase
M
,
Matsuyama
H
,
Choi
YL
,
Ueno
T
,
Mano
H
, et al
MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation
.
Mol Cell
2011
;
44
:
424
36
.
170.
Chaulk
SG
,
Lattanzi
VJ
,
Hiemer
SE
,
Fahlman
RP
,
Varelas
X
. 
The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let-7
.
J Biol Chem
2014
;
289
:
1886
91
.
171.
Shyh-Chang
N
,
Daley
GQ
. 
Lin28: primal regulator of growth and metabolism in stem cells
.
Cell Stem Cell
2013
;
12
:
395
406
.
172.
Huisken
A
,
Hojo
N
,
Wang
H
,
Chirshev
E
,
Glackin
C
,
Ioffe
Y
, et al
Abstract A73: mechanism of tumor suppressor miRNA let-7 downregulation in ovarian cancer: the epithelial-mesenchymal transition factor Snail is associated with stemness and represses let-7
.
AACR Annual Meeting 2018; April 14–18
, 
2018
;
Chicago, IL
.
173.
Cai
X
,
Wang
X
,
Cao
C
,
Gao
Y
,
Zhang
S
,
Yang
Z
, et al
HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g
.
Cancer Lett
2018
;
415
:
11
9
.
174.
Biamonte
F
,
Santamaria
G
,
Sacco
A
,
Perrone
FM
,
Di Cello
A
,
Battaglia
AM
, et al
MicroRNA let-7g acts as tumor suppressor and predictive biomarker for chemoresistance in human epithelial ovarian cancer
.
Sci Rep
2019
;
9
:
5668
.
175.
Mouw
JK
,
Yui
Y
,
Damiano
L
,
Bainer
RO
,
Lakins
JN
,
Acerbi
I
, et al
Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression
.
Nat Med
2014
;
20
:
360
.
176.
Jaalouk
DE
,
Lammerding
J
. 
Mechanotransduction gone awry
.
Nat Rev Mol Cell Biol
2009
;
10
:
63
73
.
177.
Ballard
MS
,
Hinck
L
. 
A roundabout way to cancer
.
Adv Cancer Res
2012
;
114
:
187
235
.
178.
Le
LT
,
Cazares
O
,
Mouw
JK
,
Chatterjee
S
,
Macias
H
,
Moran
A
, et al
Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness
.
J Cell Biol
2016
;
212
:
707
19
.