Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

被引：181

作者：

Cai, Junchao ^{[1
,2
,3
]}

Fang, Lishan ^{[1
,2
,4
]}

Huang, Yongbo ^{[5
,6
]}

Li, Rong ^{[1
,2
]}

Xu, Xiaonan ^{[1
,2
]}

Hu, Zhihuang ^{[7
]}

Zhang, Le ^{[1
,2
]}

Yang, Yi ^{[8
]}

Zhu, Xun ^{[1
,2
]}

Zhang, Heng ^{[9
]}

Wu, Jueheng ^{[2
]}

Huang, Yan ^{[7
]}

Li, Jun ^{[10
]}

Zeng, Musheng ^{[11
]}

Song, Erwei ^{[12
]}

He, Yukai ^{[13
,14
]}

Zhang, Li ^{[7
]}

Li, Mengfeng ^{[1
,2
,7
,8
]}

机构：

[1] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Microbiol, Guangzhou 510080, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Minist Educ, Key Lab Trop Dis Control, Guangzhou 510080, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Guangdong Engn & Technol Res Ctr Disease Model An, Guangzhou 510006, Guangdong, Peoples R China

[4] Sun Yat Sen Univ, Affiliated Hosp 8, Cent Lab, Shenzhen 518033, Peoples R China

[5] Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China

[6] Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Dis, Guangzhou 510120, Guangdong, Peoples R China

[7] Fudan Univ, Shanghai Canc Ctr, Dept Med Oncol, Shanghai 200032, Peoples R China

[8] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Guangzhou 510080, Guangdong, Peoples R China

[9] Sun Yat Sen Univ, Affiliated Hosp 1, Neurosurg Intens Care Unit, Guangzhou 510080, Guangdong, Peoples R China

[10] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, Guangzhou 510080, Guangdong, Peoples R China

[11] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Dept Expt Res, Guangzhou 510060, Guangdong, Peoples R China

[12] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Breast Surg, Guangzhou 510120, Guangdong, Peoples R China

[13] Augusta Univ, Georgia Canc Ctr, Dept Med, Augusta, GA 30912 USA

[14] Augusta Univ, Georgia Canc Ctr, Dept Biochem & Mol Biol, Augusta, GA 30912 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

CANCER STEM-CELLS; LUNG-CANCER; BREAST-CANCER; MESENCHYMAL TRANSITION; WNT PATHWAY; HEPATOCELLULAR-CARCINOMA; RESISTANCE; CHEMOTHERAPY; GROWTH; INVASION;

D O I：

10.1038/ncomms15870

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/beta-catenin and TGF-beta pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/beta-catenin and TGF-beta activities. Notably, correlations among miR-128-3p levels, activated beta-catenin and TGF-beta signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

引用

页数：18

共 65 条

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