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

Li Zhang, 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, Mengfeng Li

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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.

Original languageEnglish (US)
Article number15870
JournalNature Communications
Volume8
DOIs
StatePublished - Jun 19 2017

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Catenins
metastasis
MicroRNAs
Non-Small Cell Lung Carcinoma
lungs
cancer
Neoplasm Metastasis
Chemotherapy
Epithelial-Mesenchymal Transition
prognosis
chemotherapy
Cells
cells
inhibitors
Down-Regulation
Drug Therapy
proteins
Proteins
Neoplasms

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. / Zhang, Li; Cai, Junchao; Fang, Lishan; Huang, Yongbo; Li, Rong; Xu, Xiaonan; Hu, Zhihuang; Zhang, Le; Yang, Yi; Zhu, Xun; Zhang, Heng; Wu, Jueheng; Huang, Yan; Li, Jun; Zeng, Musheng; Song, Erwei; He, Yukai; Li, Mengfeng.

In: Nature Communications, Vol. 8, 15870, 19.06.2017.

Research output: Contribution to journalArticle

Zhang, L, Cai, J, Fang, L, Huang, Y, Li, R, Xu, X, Hu, Z, Zhang, L, Yang, Y, Zhu, X, Zhang, H, Wu, J, Huang, Y, Li, J, Zeng, M, Song, E, He, Y & Li, M 2017, 'Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC', Nature Communications, vol. 8, 15870. https://doi.org/10.1038/ncomms15870
Zhang, Li ; Cai, Junchao ; Fang, Lishan ; Huang, Yongbo ; Li, Rong ; Xu, Xiaonan ; Hu, Zhihuang ; Zhang, Le ; Yang, Yi ; Zhu, Xun ; Zhang, Heng ; Wu, Jueheng ; Huang, Yan ; Li, Jun ; Zeng, Musheng ; Song, Erwei ; He, Yukai ; Li, Mengfeng. / Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. In: Nature Communications. 2017 ; Vol. 8.
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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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AU - Xu, Xiaonan

AU - Hu, Zhihuang

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AU - Zhang, Heng

AU - Wu, Jueheng

AU - Huang, Yan

AU - Li, Jun

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AU - Song, Erwei

AU - He, Yukai

AU - Li, Mengfeng

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