自然·癌基因：中美科学家发现三阴性乳腺癌化疗耐药和转移的重要原因

　　获得性治疗耐药是全身性癌症治疗的主要缺点。侵袭性三阴性乳腺癌会在很短时间内对化疗产生耐药，但其中的机制仍不清楚。

　　2016年3月10日，《自然》（Nature）旗下《癌基因》（Oncogene）杂志正式发表了美国田纳西大学健康科学中心、复旦大学上海医学院、复旦大学附属肿瘤医院的一项最新研究结果，对化疗方法治疗三阴性乳腺癌产生治疗耐药的机制进行了深入探讨。

　　该研究发现基因毒性治疗方法能够显著增加三阴性乳腺癌细胞中微核糖核酸（miR）-181a的表达，miR-181a进而增强三阴性乳腺癌细胞存活，并在多柔比星（阿霉素）治疗下增强癌细胞的转移能力。同时，miR-181a的高水平表达还与乳腺癌患者进行化疗治疗后的无病生存率和整体生存率低下有密切关系。

　　该研究对miR-181a过度表达的分子机制进行了深入探讨，他们发现转录因子STAT3直接上调了miR-181a的表达水平，而STAT3的激活则依赖于三阴性乳腺癌细胞在接受基因毒性治疗后NF-kB介导的IL-6的诱导作用。有趣的是，激活的STAT3不仅能够直接结合到miR-181a的启动子上驱动其发生转录，还能够促进对MSK1的募集，MSK1结合到同一区域通过磷酸化组蛋白H3促进染色质产生局部活化。除此之外，该研究还发现BAX是miR-181a的一个直接靶向目标，BAX表达受到抑制会降低凋亡发生，增强多柔比星（阿霉素）治疗过的三阴性乳腺癌细胞侵袭能力。

　　因此，该研究发现了化疗药物治疗三阴性乳腺癌细胞产生耐药的重要原因之一是miR-181a表达上调，提示miR-181a可能是一个重要的靶向位点，对于解决化疗耐药，提高癌症治疗效果具有重要意义。

Oncogene. 2016 Mar 10;35(10):1302-13.

Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer.

Niu J, Xue A, Chi Y, Xue J, Wang W, Zhao Z, Fan M, Yang CH, Shao ZM, Pfeffer LM, Wu J, Wu ZH.

Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.

Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China.

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.

PMID: 26028030

DOI: 10.1038/onc.2015.189