MiR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C.

Jiefang Li,Wei Yang,Ruiling Wen,Xiaoling Zhong,Dongxiang Su,Jun Tang,Jieman Liang,Qinrong Wang

doi:10.1111/jcmm.12666

Abstract

Non-small-cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide with a poor 5-year survival rate. Recent studies indicated that miRNAs have been involved in the tumorigenic driver pathways in NSCLC, but the relevant molecular mechanisms are not well-understood. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in human NSCLC. The effects of miR-138 on the NSCLC cell growth and epithelial-mesenchymal transition (EMT) were first examined. Then the targeting connections of miR-138 with G-protein-coupled receptor kinase-interacting protein 1 (GIT1) and semaphorin 4C (SEMA4C) were confirmed by dual luciferase reporter assays. Finally, the effects of GIT1 and SEMA4C on the NSCLC cell growth and EMT were investigated respectively. We found that the ectopic expression of miR-138 resulted in a significant inhibition of NSCLC growth and reversion of EMT. GIT1 and SEMA4C were identified as two novel targets of miR-138. Furthermore, GIT1 and SEMA4C knockdown inhibited the cell growth and reversed EMT, just like the effects of miR-138 overexpression on NSCLC cells, whereas ectopic expression of GIT1 and SEMA4C partly rescued the suppressive effects of miR-138 in NSCLC cells. These data represent a crucial step towards the understanding of the novel roles and molecular mechanism of miR-138, GIT1 and SEMA4C in NSCLC progression, which may provide some new targets or prognostic biomarkers for NSCLC treatment, thus having implications in translational oncology.

Highlights

Non-small-cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide and accounts for about 80% of the total lung cancer cases [1,2,3]
We even found that the overexpression of miR-138 could reverse the epithelial-mesenchymal transition (EMT) by inhibiting the expressions of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) and semaphorin 4C (SEMA4C)
Our results revealed that GIT1 was down-regulated by the miR-138 overexpression

Summary

Introduction

Non-small-cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide and accounts for about 80% of the total lung cancer cases [1,2,3]. To provide new insight that will facilitate the development of new diagnosis and therapeutic strategies, it is crucial to understand the molecular mechanisms that promote the development and progression of NSCLC cells. Cell proliferation and epithelial-mesenchymal transition (EMT) are two of the most important malignant characteristics in NSCLC cells [7, 8]. MicroRNAs have been reported to regulate different properties of cancers, such as cancer cell proliferation, migration, invasiveness, EMT, and so on, by repressing their target gene expression [5, 8, 16,17,18]. It is of great concern to investigate the roles and potential mechanisms of key miRNAs in tumorigenic a 2015 The Authors

Methods

Results

Conclusion