Abstract 1063: miR-195 represses the tumorigenesis of non-small cell lung cancer and synergizes with microtubule targeting agents

Abstract

Abstract MicroRNAs (miRNAs) play important roles in nearly all cellular physiological and pathological pathways. Dysregulated miRNAs have been shown to contribute to tumorigenesis of many cancers, including lung cancer. The let-7 miRNA family, among the first miRNAs discovered, suppresses the growth of non-small cell lung cancer (NSCLC). Other miRNAs have been shown to regulate the response of cancer cells to anticancer agents, such as the microtubule-targeting agent (MTA) paclitaxel. These findings highlight the potential application of miRNAs as the next generation of therapeutic agents, either alone or in combination with chemotherapy. A high throughput screen was performed in NSCLC cells. miRNAs that both inhibited NSCLC cell growth and sensitized NSCLC cells to paclitaxel were validated by short- and long-term assays for cell viability. The targets of miRNAs were identified by expression profiling following miRNA transfection, validated by luciferase reporter assay, and confirmed by functional assays. We show that miR-195 causes G1 phase arrest of NSCLC cells by targeting CCND3, and leads to apoptosis and reduction of cell migration and invasion by targeting BIRC5. Conversely, the inhibition of cell growth by miR-195 is compromised by overexpressing CCND3 or BIRC5; the inhibition of cell migration and invasion by miR-195 is abrogated by overexpressing BIRC5. We also show that miR-195 synergizes with MTAs paclitaxel and eribulin to inhibit the growth of NSCLC cells by regulating CHEK1. Analysis of miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) shows that miR-195 expression is negatively correlated with BIRC5 and CHEK1 but not CCND3. Clinical data from TCGA show that miR-195 is significantly down-regulated in lung tumors compared to adjacent normal tissues and that its down-regulation in lung cancer patients is associated with worse survival. The TCGA data also show that BIRC5 and CHEK1 are significantly up-regulated in lung tumors and that their up-regulation is associated with worse survival. CCND3, however, is slightly downregulated in lung tumors and its expression is not correlated with patient survival. Intriguingly, we also show that miR-195 up-regulates the oncogene MYC, inhibition of which sensitizes NSCLC cells to miR-195. We show that Myc, reported to transcriptionally repress let-7c, also represses miR-195, and further identify a feedback loop between let-7c and miR-195 in which each inhibits the other. We identify miR-195 as a tumor suppressor and chemotherapy sensitizer in NSCLC mediated by its repression of CCND3, BIRC5 and CHEK1. We also uncover a feedback network between miR-195, Myc and let-7c. The ability of miR-195 and Myc to regulate each other indicates a mechanism by which NSCLC cells can become more sensitive to miR-195. The mutual inhibition between miR-195 and let-7c suggests an interesting regulatory loop between cancer-related miRNAs that deserves further study. Citation Format: Xiaojie Yu, Zhenze Zhao, Xiuye Ma, Liqin Du, Alexander Pertsemlidis. miR-195 represses the tumorigenesis of non-small cell lung cancer and synergizes with microtubule targeting agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1063.