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

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.

MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α

“…Furthermore, miR-138 was found to be involved in the regulation of dendritic spine morphogenesis, in addition to the osteogenic differentiation of mesenchymal stem cells (21,22). Previously, deregulation of miR-138 was demonstrated to be associated with multiple types of human malignancies, generally acting as a tumor suppressor (23,24). For instance, miR-138 is able to suppress invasion and promote apoptosis in head and neck squamous cell carcinoma cells, via inhibition of the Rho GTPase signaling pathway (25)(26)(27).…”

MicroRNA‑138 suppresses cell proliferation and invasion of renal cell carcinoma by directly targeting SOX9

“…Long et al demonstrated that inhibition of miR-138 in colorectal cancer cells resulted in a significant reduction of migration and invasion capacity by directly targeting TWIST2 (25). In non-small cell lung cancer, miR-138 decreased cell proliferation, migration in vitro and tumor growth in vivo, and increased cisplatin sensitivity through targeting multiple genes, including G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1), semaphorin 4C, cyclin D3, Glucose regulated protein 124 (GRP124), enhancer of zeste homolog 2 and pyruvate dehydrogenase kinase 1 (26,(33)(34)(35). In oral squamous cell carcinoma, miR-138 inhibited cell proliferation via blockade of yes-associated protein 1 (28).…”

Emerging Roles of Epigenetic Regulator Sin3 in Cancer

“…These include two miRNAs, miR-210 and miR-138 (Ramachandran et al, 2012;Shang, Hong, Guo, Liu, & Xue, 2014). In relation to cancer biology miR-138 is identified as tumor-suppressive microRNA that inhibits cancer stem cell (CSC) phenotype, epithelial-to-mesenchymal transition (EMT), and metastasis in many cancer including lung, colorectal, and pancreas (Cristobal et al, 2015;Gao, Wang, Xie, Zhang, & Dong, 2015;Li et al, 2015;Xu et al, 2015).…”