Induction of ZEB Proteins by Inactivation of RB Protein Is Key Determinant of Mesenchymal Phenotype of Breast Cancer
Induction of ZEB Proteins by Inactivation of RB Protein Is Key Determinant of Mesenchymal Phenotype of Breast Cancer
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DOI：
10.1074/jbc.m111.313759
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发表时间：
2012-03-09
影响因子：
4.8
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Arima, Yoshimi;Hayashi, Hidemi;Saya, Hideyuki
我们以前发现，视网膜母细胞瘤蛋白（RB）的耗竭诱导下调的粘附分子E-钙粘蛋白，从而触发上皮间质转化。为了进一步表征RB失活对癌细胞表型的影响，我们现在已经检查了RB在人乳腺癌细胞系和临床标本中的表达。我们发现，RB非活性细胞表现出间充质样形态，是高度侵入性的。我们还发现，ZEB蛋白，E-cadherin基因的转录抑制因子，在这些细胞中以对miR-200家族microRNA敏感的方式显著上调。此外，在RB-非活性细胞中ZEB的耗尽抑制细胞侵袭和增殖，并诱导上皮标记物表达。这些结果暗示ZEB在诱导上皮-间充质转化，以及在RB失活细胞中维持间充质表型。我们还开发了一种筛选ZEB 1表达抑制剂的程序，从而确定了几种细胞周期蛋白依赖性激酶抑制剂，阻断ZEB 1表达和RB磷酸化。总之，我们的研究结果表明，RB失活有助于肿瘤的进展，不仅通过细胞周期控制的损失，但也通过上调ZEB表达和诱导的侵袭性表型。
We previously showed that depletion of the retinoblastoma protein (RB) induces down-regulation of the adhesion molecule E-cadherin and thereby triggers the epithelial-mesenchymal transition. To further characterize the effect of RB inactivation on the phenotype of cancer cells, we have now examined RB expression in human breast cancer cell lines and clinical specimens. We found that RB-inactive cells exhibit a mesenchymal-like morphology and are highly invasive. We also found that ZEB proteins, transcriptional repressors of the E-cadherin gene, are markedly up-regulated in these cells in a manner sensitive to the miR-200 family of microRNAs. Moreover, depletion of ZEB in RB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial marker expression. These results implicate ZEB in induction of the epithelial-mesenchymal transition, as well as in maintenance of the mesenchymal phenotype in RB-inactive cells. We also developed a screening program for inhibitors of ZEB1 expression and thereby identified several cyclin-dependent kinase inhibitors that blocked both ZEB1 expression and RB phosphorylation. Together, our findings suggest that RB inactivation contributes to tumor progression not only through loss of cell cycle control but also through up-regulation of ZEB expression and induction of an invasive phenotype.