Abstract 5444: Therapeutic potential of miR-195 in non-small cell lung cancer
Authors: Xiaojie Yu, Xiuye Ma, Yiqiang Zhang, Zhenze Zhao, Liqin Du, Alexander Pertsemlidis
Journal: Cancer Research (2017)

Abstract Introduction: MicroRNAs (miRNAs) play important roles in nearly all cellular physiological and pathological pathways. Dysregulated miRNAs have been shown to contribute to the tumorigenesis of most cancers, including lung cancer. We aim to modulate miRNA activity as a potential therapeutic avenue either alone or in combination with other drugs. Methods: A high throughput screen with a library of 1,239 miRNA mimics was performed in NSCLC cells to identify miRNAs that both inhibit cancer cell growth and sensitize cells to microtubule-targeting agents (MTAs). The functions of candidate miRNA(s) were validated both in vitro and in vivo. Results: miR-195 causes G1 phase arrest by targeting CCND3. miR-195 induces apoptosis and senescence and represses migration and invasion of NSCLC cells by targeting BIRC5. Conversely, over-expression of CCND3 compromises the inhibition of cell growth by miR-195; over-expression of BIRC5 abrogates the inhibition of cell growth, migration and invasion by miR-195. miR-195 also synergizes with MTAs paclitaxel and eribulin to inhibit the growth of NSCLC cells by regulating CHEK1. Lung tumors with miR-195 over-expression grow significantly slower and respond better to eribulin treatment than tumors in control animals. Induction of miR-195 expression after tumor initiation slows tumor growth and that combination of doxycycline with eribulin shows stronger inhibition on tumor growth than eribulin. In addition, miR-195 inhibits lung tumor metastasis. Analysis of miRNA and gene expression profiles from TCGA shows that miR-195 expression is negatively correlated with that of BIRC5 and CHEK1. 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. TCGA data also show that BIRC5 and CHEK1 are significantly up-regulated in lung tumors compared to adjacent normal tissues and that their up-regulation is associated with worse survival. Conclusions: We report the identification of miR-195 as a tumor suppressor and chemotherapy sensitizer in NSCLC mediated by its repression of CCND3, BIRC5 and CHEK1. Mouse xenografts with miR-195 over-expression or induced miR-195 expression indicate that tumors with high miR-195 expression are more sensitive to drug treatment and that induction of miR-195 in tumors represses tumor growth and sensitizes tumors to eribulin treatment. These results highlight the potential use of miR-195 expression level as a biomarker to predict patient response to MTAs and of miR-195 mimics as a therapeutic agent or adjuvant to chemotherapy. This project was supported by NIH R01 CA129632 and CPRIT Training Grant RP140105. Citation Format: Xiaojie Yu, Xiuye Ma, Yiqiang Zhang, Zhenze Zhao, Liqin Du, Alexander Pertsemlidis. Therapeutic potential of miR-195 in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5444. doi:10.1158/1538-7445.AM2017-5444