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

Hakan Kucuksayan,S. Akgun,O. N. Ozes,A. Alikanoğlu,M. Yıldız,Egemen Dal,H. Akça

Published 2018 in Carcinogenesis

ABSTRACT

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

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