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

TGF beta R1 plays an important role in TGF-beta signaling transduction and serves as a tumor suppressor. Our previous studies show that reduced expression of TGF beta R1 is common in non-small cell lung cancer (NSCLC) and TGF beta R1 variants confer risk of NSCLC. However, the epigenetic mechanisms underlying the role of TGF beta R1 in NSCLC carcinogenesis are still elusive. We investigated the function and regulation of TGF-beta signaling-based miRNAs in NSCLC. Computational algorithms predicted that the 3'=untranslated region (3'=UTR) of TGF beta R1 is a target of miR-142-3p. Here a luciferase reporter assay confirmed that miR-142-3p can directly bind to 3'=UTR of TGF beta R1. Overexpression of miR-142-3p in NSCLC A549 cells suppressed expression of TGF beta R1 mRNA and protein, while knockdown of endogenous miR142-3p led to increased expression of TGF beta R1. On TGF-beta 1 stimulation, stable overexpression of miR142-3p attenuated phosphorylation of SMAD3, an indispensable downstream effector in canonical TGF-beta/Smad signaling, via repression of TGF beta R1 in A549 cells. Furthermore, miR-142-3p-mediated down-regulation of TGF beta R1 weakened TGF-beta-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 TGF beta R1 expression. These data demonstrate that miR-142-3p influences the proliferation of NSCLC cells through repression of TGF beta R1.