Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC.
Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC.
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miR-128-3p 同时过度激活 Wnt/β-catenin 和 TGF beta 信号传导导致 NSCLC 中化疗耐药相关的转移
DOI：
10.1038/ncomms15870
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发表时间：
2017-06-19
影响因子：
16.6
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
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;Zhang L;Li M
癌症化学抗性和转移是紧密相关的特征。然而，它们是否具有共同的分子机制，从而可以用一种共同的策略靶向非小细胞肺癌（NSCLC）仍不清楚。在这里，我们报告了高水平的microRNA-128- 3 p（miR-128- 3 p）是在重复化疗后存活的残留NSCLC细胞中伴随产生化疗耐药性和转移的关键，并且与NSCLC患者的化疗耐药性、侵袭性和不良预后相关。从机制上讲，miR-128- 3 p通过下调Wnt/β-catenin和TGF-β途径的多种抑制剂诱导间充质和干细胞样性质，导致其过度活化。重要的是，miR-128- 3 p的拮抗作用可有效逆转高度恶性NSCLC细胞的转移和化疗耐药性，这可通过恢复Wnt/β-catenin和TGF-β活性而完全逆转。值得注意的是，在NSCLC患者标本中验证了miR-128- 3 p水平、活化β-连环蛋白和TGF-β信号传导以及促上皮间质转化/促转移蛋白水平之间的相关性。这些发现表明miR-128- 3 p可能是NSCLC转移和化疗耐药的潜在靶点。化疗耐药和转移是非小细胞肺癌（NSCLC）中密切相关的特征。在这里，作者表明耐药NSCLC具有高水平的miR-128- 3 p，其通过调节Wnt/B-连环蛋白和TGF-β途径促进EMT和癌症干细胞存活。
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. Chemoresistance and metastasis are tightly associated features in non-small cell lung cancer (NSCLC). Here, the authors show that resistant NSCLCs have high levels of miR-128-3p which promotes EMT and cancer stem cell survival through the modulation of both Wnt/B-catenin and TGF-β pathway.