Dergi makalesi Açık Erişim

TGF-beta-SMAD-miR-520e axis regulates NSCLC metastasis through a TGFBR2-mediated negative-feedback loop

2019    Kucuksayan, Hakan; Akgun, Sakir; Ozes, Osman Nidai; Alikanoglu, Arsenal Sezgin; Yildiz, Mustafa; Dal, Egemen; Akca, Hakan

Transforming growth factor-beta (TGF-beta) pathway plays crucial roles during the carcinogenesis and metastasis. TGF-beta receptor 2 (TGFBR2) is a key molecule for the regulation of TGF-beta pathway and frequently downregulated or lost in several cancer types including non-small cell lung cancer (NSCLC), and TGF-beta pathway is often regulated by negative-feedback mechanisms, but little is known about the mechanism of TGFBR2 downregulation in NSCLC. Here, we found that the expression of miR-520e is upregulated in metastatic tumor tissues compared with non-metastatic ones, and its expression is inversely correlated with that of TGFBR2 in clinical samples. We also discovered that TGF-beta dramatically increased the expression of miR-520e, which targeted and downregulated TGFBR2, and the suppression of miR-520e significantly impaired TGF-beta-induced TGFBR2 downregulation. Chromatin immunoprecipitation-PCR experiments further showed that miR-520e is transcriptionally induced by SMAD2/3 in response to TGF-beta. Our findings reveal a novel negative-feedback mechanism in TGF-beta signaling and the expression level of miR-520e could be a predictive biomarker for NSCLC metastasis.