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.
Highlights
Cancer chemoresistance and metastasis are tightly associated features
As several independent databases show that miR-128-3p is the predominantly expressed miRNA species, we sought to investigate the potential role of miR-128-3p in the progression of non-small cell lung cancer (NSCLC)
This result is consistent with a published large-scale, detailed analysis of the miRNA profiles in 540 specimens of six types of solid tumours, which showed that miR-128-3p is among the most commonly upregulated microRNAs in lung cancer and highly expressed in colon and pancreatic cancers[15]
Summary
Cancer chemoresistance and metastasis are tightly associated features. whether they share common molecular mechanisms and can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Correlations among miR-128-3p levels, activated b-catenin and TGF-b 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. Despite having been studied separately in the past, accumulating evidence suggests that tumour metastasis and chemoresistance commonly present simultaneously clinically but might be intrinsically associated biological events[4,5] It was observed, for example, that NSCLC patients with stage IV disease exhibit a substantially lower overall response rate to chemotherapy than patients with locally advanced disease[6,7], suggesting that metastatic NSCLC patients are prone to be more resistant to chemotherapy in the clinic.
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