RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo-Yap Pathway
RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo-Yap Pathway
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RARγ 下调通过抑制 Hippo-Yap 通路促进结直肠肿瘤发生和转移
DOI：
10.1158/0008-5472.can-15-2882
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Hua
中科院分区：
文献类型：
--
作者：
Guo, Peng-Da;Lu, Xing-Xing;Wu, Hua
Hippo-Yap通路传递致癌信号，但其在癌症发展过程中的调控尚不清楚。在这里，我们确定核受体RAR γ作为调节器的Hippo-Yap通路在结直肠肿瘤的发生和转移。RAR γ在人结直肠癌组织中下调，其表达与肿瘤大小、TNM分期和远处转移呈负相关。功能研究证实RAR γ的沉默驱动结直肠癌细胞在体外和体内的生长、侵袭和转移特性。从机制上讲，RAR γ控制Hippo-雅普信号传导以抑制结直肠癌的发展，从而促进Lats 1与其转录辅激活因子雅普的磷酸化和结合，从而使雅普靶基因表达失活。在临床标本中，RAR γ表达与结直肠癌患者的总体生存结局和关键Hippo-Yap通路效应分子的表达相关。总的来说，我们的研究结果将RAR γ定义为结直肠癌中的肿瘤抑制因子，其作用是通过Hippo-Yap途径限制致癌信号传导，这对结直肠癌治疗的新方法具有潜在意义。(C)2016年AACR。
The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RAR gamma as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RAR gamma is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNMstage, and distant metastasis. Functional studies established that silencing of RAR gamma drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RAR gamma controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RAR gamma expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RAR gamma as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy. (C) 2016 AACR.