BMP-2通过Rb和CD44诱导EMT和乳腺癌干。,Cell Death Discovery

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BMP-2通过Rb和CD44诱导EMT和乳腺癌干。
Cell Death Discovery ( IF 6.1 ) Pub Date : 2017-01-01 , DOI: 10.1038/cddiscovery.2017.39
Peide Huang , Anan Chen , Weiyi He , Zhen Li , Guanglin Zhang , Zhong Liu , Ge Liu , Xueting Liu , Shuilian He , Gang Xiao , Feicheng Huang , Jan Stenvang , Nils Brünner , An Hong , Ju Wang

据报道，在乳腺癌异种移植模型中，骨形态发生蛋白2（BMP-2）可促进上皮向间质转化（EMT）和骨转移。为了研究BMP-2在乳腺癌干细胞（BCSCs）发育中的作用，并进一步阐明其对乳腺癌转移的影响机制，我们使用乳腺癌细胞系和临床样品进行了全面的分子研究。我们的结果表明，BMP-2对Rb的下调与通过PI3K / AKT信号途径使Rb磷酸化激活的遍在蛋白介导的降解有关。此外，Smad信号通路与BMP-2上调CD44蛋白表达有关。有人建议在Rb和CD44信号通路之间存在串扰，因为发现重组人BMP-2（rhBMP-2）部分通过Rb信号调节CD44表达。在临床组织中，BMP-2分别与CD44和Rb表达呈正相关和负相关。基于在体外和体内结果中，我们建立了一个整合的机制，rhBMP-2通过Rb和CD44信号传导途径诱导乳腺癌细胞的EMT和干性，进而促进乳腺癌的转移。这些发现可能有助于制定治疗晚期乳腺癌的新策略。

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BMP-2 induces EMT and breast cancer stemness through Rb and CD44.

Bone morphogenetic protein 2 (BMP-2) has been reported to facilitate epithelial-to-mesenchymal transition (EMT) and bone metastasis in breast cancer xenograft models. To investigate the role of BMP-2 in the development of breast cancer stem cells (BCSCs), and to further elucidate the mechanisms underlying its influence on breast cancer metastasis, we conducted a comprehensive molecular study using breast cancer cell lines and clinical samples. Our results showed that downregulation of Rb by BMP-2 was associated with ubiquitin-mediated degradation activated by phosphorylation of Rb via the PI3K/AKT signal pathway. In addition, the Smad signaling pathways are implicated in upregulation of CD44 protein expression by BMP-2. It was suggested that cross-talk exists between Rb and CD44 signaling pathways, as recombinant human BMP-2 (rhBMP-2) was found to regulate CD44 expression partly through Rb signals. In clinical tissues, BMP-2 was positively and negatively correlated with CD44 and Rb expression, respectively. Based on the in vitro and in vivo results, we have established an integrated mechanism by which rhBMP-2 induces EMT and stemness of breast cancer cells via the Rb and CD44 signaling pathways, which then contribute to breast cancer metastasis. These findings may be helpful for developing new strategies for the treatment and prognosis of advanced breast cancer.

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