MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs and negatively regulate gene expression through base pairing of 3' UTRs of the target genes. Over the past decade, much of important evidences have been obtained to clarify that miRNAs are unusual expressed in human malignancies and could act as OncomiRs or Tumor suppressive miRs.

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. Especially, metastatic recurrences after esophagectomy for ESCC bears unfortunately prognosis and little exists for treatment strategy. Clarification of molecular indicators of the origin cellular deregulation in ESCC have been important objective for cancer research in ESCC.

Recently, increasing number of studies have demonstrated the involvement of miRNAs in cancer metastasis. Especially, many studies have shown that microRNAs could target genes playing a role in epithelia-mesenchymal-transition (EMT), a cellular transformation process that allows cancer cells to acquire motility and invasiveness. EMT is considered an essential step driving the early phase of cancer metastasis.

We search for miRNAs in ESCC using the miRNA expression signatures and gain-of-function analysis. It is revealed that 3 miRNAs (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion. These miRNAs, which have conserved sequences in the 3' UTR of FSCN1, inhibited FSCN1 expression. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.

FSCN1 is actin bundling protein, which is concerned with cancer invadopodia ,which is the phenomenon regarding cancer cell invasion into surrounding tissue. We focused on MMP14 and examined the gene expression of MMP14 in ESCC tissues and patient survival. FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also

evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. The relationship between the expressions of miR-133 and MMP14 is strongly negative correlation. miR-145 and miR-133 play a chief role in cancer invasion and metastasis, which control invadopodia associated proteins.

The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.

Citation Format: Masayuki Kano, Hisahiro Matsubara, Takahashi Masahiko. miRNAs regulated cancer metastasis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B31.