Simultaneous Overactivation of Wnt/β-catenin and TGFβ Signalling by MiR-128-3p Confers Chemoresistance-associated Metastasis in NSCLC

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Jun 20

PMID 28627514

Citations 95

Authors

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

Mengfeng Li

Affiliations

Soon will be listed here.

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.

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