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

被引：14

作者：

Kucuksayan, Hakan ^{[1
]}

Akgun, Sakir ^{[1
]}

Ozes, Osman Nidai ^{[2
]}

Alikanoglu, Arsenal Sezgin ^{[3
]}

Yildiz, Mustafa ^{[4
]}

Dal, Egemen ^{[5
]}

Akca, Hakan ^{[1
]}

机构：

[1] Pamukkale Univ, Sch Med, Med Biol Dept, Denizli, Turkey

[2] ALTAY Biopharma, San Bruno, CA USA

[3] Antalya Training & Res Hosp, Pathol Dept, Antalya, Turkey

[4] Antalya Training & Res Hosp, Med Oncol, Antalya, Turkey

[5] Pamukkale Univ, Fac Med, Denizli, Turkey

来源：

CARCINOGENESIS | 2019年 / 40卷 / 05期

关键词：

GROWTH-FACTOR-BETA; TO-MESENCHYMAL TRANSITION; TGF-BETA; LUNG-CANCER; EXPRESSION; RECEPTOR; MICRORNA-520E; PROGRESSION; ZEB1;

D O I：

10.1093/carcin/bgy166

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. We demonstrate that low TGFBR2 and high miR-520e expression correlated with increased metastatic capacity of non-small cell lung cancer cells. Furthermore, our findings provide a novel mechanism by which miR-520e-mediated the self-limiting of transforming growth factor-beta in metastasis of lung cancer cells.

引用

页码：695 / 705

页数：11

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