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

Junchao Cai, Lishan Fang, Yongbo Huang, Rong Li, Xiaonan Xu, Zhihuang Hu, Le Zhang, Yi Yang, Xun Zhu, Heng Zhang, Jueheng Wu, Yan Huang, Jun Li, Musheng Zeng, Erwei Song, Yukai He, Li Zhang () and Mengfeng Li ()
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Junchao Cai: Sun Yat-sen University Zhongshan School of Medicine
Lishan Fang: Sun Yat-sen University Zhongshan School of Medicine
Yongbo Huang: State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University
Rong Li: Sun Yat-sen University Zhongshan School of Medicine
Xiaonan Xu: Sun Yat-sen University Zhongshan School of Medicine
Zhihuang Hu: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Le Zhang: Sun Yat-sen University Zhongshan School of Medicine
Yi Yang: Zhongshan School of Medicine, Sun Yat-sen University
Xun Zhu: Sun Yat-sen University Zhongshan School of Medicine
Heng Zhang: Neurosurgery Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University
Jueheng Wu: Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education
Yan Huang: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Jun Li: Sun Yat-sen University Zhongshan School of Medicine
Musheng Zeng: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Erwei Song: Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Yukai He: Georgia Cancer Center, Augusta University
Li Zhang: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Mengfeng Li: Sun Yat-sen University Zhongshan School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15870

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