A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance.
A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance.
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miR-20a/MAPK1/c-Myc 调节反馈环路调节乳腺癌发生和化疗耐药
DOI：
10.1038/cdd.2017.176
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发表时间：
2018-03
影响因子：
12.4
通讯作者：
Fan W
中科院分区：
文献类型：
--
作者：
Si W;Shen J;Du C;Chen D;Gu X;Li C;Yao M;Pan J;Cheng J;Jiang D;Xu L;Bao C;Fu P;Fan W
化疗耐药常常导致乳腺癌治疗失败。MicroRNAs （miRNAs）在癌症的进展和化疗耐药中起着重要作用。然而，由于化疗耐药机制的复杂性以及miRNA调控在不同细胞类型中的特异性，miR-20a在乳腺癌化疗耐药中的作用尚不清楚。本研究通过miRNA微阵列和高含量筛选技术，我们发现miR-20a/b在乳腺癌组织中较正常乳腺组织明显下调，miR-20a/b低表达与乳腺癌患者生存差相关。miR-20a的异位过表达使乳腺癌细胞对广谱化疗药物敏感，并在体外和体内抑制其增殖。进一步研究表明，miR-20a直接靶向MAPK1的3'非翻译区，从而通过抑制MAPK/ERK信号通路下调P-gp和c-Myc的表达，而c-Myc可以结合miR-20a基因的启动子区促进miR-20a的表达。总之，我们的研究确定了一种新的miR-20a/MAPK1/c-Myc反馈回路，它调节乳腺癌的生长和化疗耐药。这些发现表明，miR-20a与抗癌药物的协同作用将是一种很有前景的治疗策略，特别是对于化疗耐药患者。
Chemoresistance often leads to the failure of breast cancer treatment. MicroRNAs (miRNAs) play an important role in the progression and chemoresistance of cancer. However, because of the complexity of the mechanisms of chemoresistance and the specificity of miRNA regulation in different cell types, the function of miR-20a in breast cancer chemoresistance is still unclear. Here, by using miRNA microarray and high-content screening techniques, we found that miR-20a/b were significantly downregulated in breast cancer tissues compared with normal breast tissues, and low miR-20a/b expression was correlated with poor survival in breast cancer patients. Ectopic overexpression of miR-20a sensitized breast cancer cells to a broad spectrum of chemotherapy drugs and suppress their proliferation both in vitro and in vivo. Further study demonstrated that miR-20a directly targeted the 3'untranslated region of MAPK1, and thus downregulated the expression of P-gp and c-Myc by inhibiting the MAPK/ERK signaling pathway, whereas c-Myc can bind to the promoter region of the miR-20a gene to promote the expression of miR-20a. Together, our study identified a novel miR-20a/MAPK1/c-Myc feedback loop that regulates breast cancer growth and chemoresistance. These findings suggest that miR-20a synergizing with anticancer drugs will be a promising treatment strategy, especially for chemoresistant patients.
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