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Nat Commun. 2017 Jun 19;8:15870. doi: 10.1038/ncomms15870.

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

Cai J1,2,3, Fang L1,2,4, Huang Y5, Li R1,2, Xu X1,2, Hu Z6, Zhang L1,2, Yang Y7, Zhu X1,2, Zhang H8, Wu J2, Huang Y6, Li J9, Zeng M10, Song E11, He Y12, Zhang L6, Li M1,2.

Author information

1
Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.
2
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
3
Guangdong Engineering and Technology Research Center for Disease-Model Animals, Sun Yat-sen University, Guangzhou 510006, China.
4
Central Laboratory of The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China.
5
State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
6
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
7
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
8
Neurosurgery Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
9
Department of Biochemistry, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.
10
State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
11
Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
12
Department of Medicine and Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912, USA.

Abstract

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/β-catenin and TGF-β 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/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β 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.

PMID:
28627514
PMCID:
PMC5481840
DOI:
10.1038/ncomms15870
[Indexed for MEDLINE]
Free PMC Article

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