Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition
Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition
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DOI：
10.1158/0008-5472.can-07-5680
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Taya, Yoichi
中科院分区：
文献类型：
--
作者：
Arima, Yoshimi;Inoue, Yasumichi;Taya, Yoichi
视网膜母细胞瘤肿瘤抑制蛋白（Rb）在几种肿瘤类型中突变或以非常低的水平表达，包括视网膜母细胞瘤和骨肉瘤，以及小细胞肺癌、结肠癌、前列腺癌、膀胱癌和乳腺癌。Rb表达的丢失或减少最常见于高级别乳腺腺癌，这表明Rb功能丢失与低分化状态、增殖增加和高转移潜能之间可能存在关系。在这项研究中，我们发现，在MCF 7乳腺癌细胞中通过小干扰RNA敲低Rb破坏细胞间粘附并诱导间充质样表型。上皮细胞向间质细胞转化（EMT）是胚胎形态发生中的关键事件，与原发肿瘤的转移有关。此外，Rb在生长因子和精氨酸诱导的EMT过程中减少，Rb的过表达抑制MCF 10A人乳腺上皮细胞中的EMT。Rb的异位表达和敲低导致E-cadherin表达的增加或减少，E-cadherin特异性地参与上皮细胞-细胞粘附。其他EMT相关的转录因子，包括Slug和Zeb-1，也诱导Rb耗竭。此外，我们证实Rb与转录因子激活蛋白-2 α相关的E-钙粘蛋白启动子序列结合。最后，在乳腺癌标本中，我们观察到Rb和E-cadherin表达在间质样浸润性癌中同时下调。这些研究结果表明，Rb失活有助于肿瘤的进展，由于不仅失去细胞增殖控制，但也转化为侵袭性表型和EMT的抑制是一种新的Rb肿瘤抑制功能。
The retinoblastoma tumor suppressor protein (Rb) is mutated or expressed at very low levels in several tumor types, including retinoblastoma and osteosarcoma, as well as small cell lung, colon, prostate, bladder, and breast carcinomas. Loss or reduction of Rb expression is seen most commonly in high-grade breast adenocarcinomas, suggesting that a relationship may exist between loss of Rb function and a less-differentiated state, increased proliferation, and high metastatic potential. In this study, we found that knockdown of Rb by small interfering RNA in MCF7 breast cancer cells disrupts cell-cell adhesion and induces a mesenchymal-like phenotype. The epithelial-to-mesenchymal transition (EMT), a key event in embryonic morphogenesis, is implicated in the metastasis of primary tumors. Additionally, Rb is decreased during growth factor- and cytokine-induced EMT and overexpression of Rb inhibits the EMT in MCF10A human mammary epithelial cells. Ectopic expression and knockdown of Rb resulted in increased or reduced expression of E-cadherin, which is specifically involved in epithelial cell-cell adhesion. Other EMT-related transcriptional factors, including Slug and Zeb-1, are also induced by Rb depletion. Furthermore, we confirmed that Rb binds to an E-cadherin promoter sequence in association with the transcription factor activator protein-2 alpha. Finally, in breast cancer specimens, we observed a concurrent down-regulation of Rb and E-cadherin expression in mesenchymal-like invasive cancers. These findings suggest that Rb inactivation contributes to tumor progression due to not only loss of cell proliferation control but also conversion to an invasive phenotype and that the inhibition of EMT is a novel tumor suppressor function of Rb.