Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer.
Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer.
复制标题
基因毒性治疗诱导 miRNA-181a 促进乳腺癌化疗耐药和转移
作者：
Niu J;Xue A;Chi Y;Xue J;Wang W;Zhao Z;Fan M;Yang CH;Shao ZM;Pfeffer LM;Wu J;Wu ZH
获得性治疗抗性是癌症有效系统治疗的主要缺点。侵袭性三阴性乳腺癌（TNBC）对化疗迅速产生耐药性，而其潜在机制尚未完全了解。在这里，我们表明，基因毒性治疗显着增加miR-181 a在TNBC细胞中的表达，这增强了TNBC细胞的生存和转移后，阿霉素治疗。一致地，高miR-181 a水平与乳腺癌患者治疗后的无病生存期和总生存期相关。miR-181 a的上调由转录因子STAT 3协调，转录因子STAT 3的激活依赖于遗传毒性处理后TNBC细胞中NF-κ B介导的IL-6诱导。有趣的是，激活的STAT 3不仅直接结合MIR 181 A1启动子以驱动转录，而且还促进了MSK 1的募集到相同的区域，其中MSK 1通过磷酸化组蛋白H3促进局部活性染色质状态。我们进一步鉴定了BAX作为miR-181 a的直接功能靶标，其抑制降低了Dox处理后TNBC细胞的凋亡并增加了侵袭。这些结果进一步得到以下证据的证实：在TNBC原位模型中，miR-181 a的抑制显著增强治疗反应并减少肺转移。总的来说，我们的数据表明，miR-181 a诱导在促进TNBC细胞在遗传毒性处理后的治疗抗性和侵袭行为中具有关键作用。拮抗miR-181 a可能是一种有希望的策略，可以使TNBC细胞对化疗敏感并减轻转移。
Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-κB-mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis.