MiR‐142‐3p represses TGF‐β‐induced growth inhibition through repression of TGFβR1 in non‐small cell lung cancer

• Published in: The FASEB journal 2014-06, Vol.28 (6), p.2696-2704
• Main Authors: Lei, Zhe, Xu, Guili, Wang, Longqiang, Yang, Haiping, Liu, Xia, Zhao, Jun, Zhang, Hong‐Tao
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - drug effects; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; cell proliferation; Cell Proliferation - drug effects; Down-Regulation; epigenetic mechanism; Eukaryotic Initiation Factor-3 - biosynthesis; Eukaryotic Initiation Factor-3 - genetics; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - metabolism; MicroRNAs - biosynthesis; MicroRNAs - physiology; miRNAs; NSCLC; p‐SMAD3; Signal Transduction - drug effects; Transforming Growth Factor beta1 - metabolism; Up-Regulation
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.13-247288

ABSTRACT TGFβR1 plays an important role in TGF‐β signaling transduction and serves as a tumor suppressor. Our previous studies show that reduced expression of TGFβR1 is common in non‐small cell lung cancer (NSCLC) and TGFβR1 variants confer risk of NSCLC. However, the epigenetic mechanisms underlying the role of TGFβR1 in NSCLC carcinogenesis are still elusive. We investigated the function and regulation of TGF‐β signaling‐based miRNAs in NSCLC. Computational algorithms predicted that the 3′‐untranslated region (3′‐UTR) of TGFβR1 is a target of miR‐142‐3p. Here a luciferase reporter assay confirmed that miR‐142‐3p can directly bind to 3′‐UTR of TGFβR1. Overexpression of miR‐142‐3p in NSCLC A549 cells suppressed expression of TGFβR1 mRNA and protein, while knockdown of endogenous miR‐142‐3p led to increased expression of TGFβR1. On TGF‐β1 stimulation, stable overexpression of miR‐142‐3p attenuated phosphorylation of SMAD3, an indispensable downstream effector in canonical TGF‐β/Smad signaling, via repression of TGFβR1 in A549 cells. Furthermore, miR‐142‐3p‐mediated down‐regulation of TGFβR1 weakened TGF‐β‐induced growth inhibition effect, and this effect was reversed by stable knockdown of endogenous miR‐142‐3p in A549 cells. In NSCLC tissues, miR‐142‐3p expression was increased and inversely correlated with TGFβR1 expression. These data demonstrate that miR‐142‐3p influences the proliferation of NSCLC cells through repression of TGFβR1.—Lei, Z., Xu, G., Wang, L., Yang, H., Liu, X., Zhao, J., Zhang, H.‐T. MiR‐142‐3p represses TGF‐β‐induced growth inhibition through repression of TGFβR1 in non‐small cell lung cancer. FASEB J. 28, 2696–2704 (2014). www.fasebj.org