Introduction. microRNAs (miRNAs) are a family of small non-coding RNAs that post-transcriptionally regulate gene expression mainly by decreasing mRNA levels of target genes. Recently, numerous studies have shown the important roles of miRNAs in regulating various cellular physiological and pathological pathways including cell differentiation, proliferation and even tumorigenesis. A large number of miRNAs are indicated to be involved in multiple pathways that are critical for lung cancer, which is the leading cause of adult cancer deaths. Intriguingly, some miRNAs sensitize lung cancer to microtubule-targeting agents, such as paclitaxel. All of these highlight the potential application of miRNA-targeted oligos as next-generation therapeutic agents.
Aims and Methods. We aim to identify novel functional miRNAs in lung cancer. Using a high-throughput screening platform containing a library of chemically synthesized miRNAs, we systematically identify miRNAs that reduce lung cancer cell survival or sensitize cancer cells to paclitaxel. The top candidate miRNAs are validated and their mechanisms are further investigated.
Results and Conclusions. We show that miR-195 significantly inhibits the viability of lung cancer cells in vitro, and that transfection of miR-195 into cancer cells results in G1 phase arrest and decreased cell invasion. Intriguingly, miR-195 does not show strong inhibitory effects on viability of immortalized human bronchial epithelial cells (HBECs). Analysis of miRNA expression data from The Cancer Genome Atlas (http://cancergenome.nih.gov) indicates lower expression of miR-195 in lung cancer tumors compared to normal tissues. Merging expression with clinical annotation shows that higher expression of miR-195 in lung cancer patients is associated with longer survival. These results indicate that miR-195 is a tumor suppressor miRNA and that miR-195 may be an important factor in determining lung cancer progression and prognosis. This observation is consistent with previous studies that have shown a tumor suppressor function of miR-195 in breast cancer, bladder cancer and hepatocellular carcinoma. Overall, the inhibitory effects on lung cancer cell growth and the correlation between expression and survival indicate the involvement of miR-195 in critical pathways for lung cancer. We have identified additional miRNAs that sensitize lung cancer cells to paclitaxel, and which define a potential regulatory pathway modulating paclitaxel sensitivity. Future studies are needed to identify the targets of these miRNAs, elucidate their mechanisms of action, and clarify how they are regulated in lung cancer cells.
Citation Format: Xiaojie Yu, Zhenze Zhao, Xiuye Ma, Liqin Du, Alexander Pertsemlidis. A high-throughput screen identifies microRNAs regulating lung cancer cell survival and response to paclitaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3545. doi:10.1158/1538-7445.AM2014-3545