Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Pathology Center and Department of Pathology, Soochow University, Suzhou, China. The First Affiliated Hospital of Soochow University, Suzhou, China.
Cancer Res. 2016 Jul 1;76(13):3813-25. doi: 10.1158/0008-5472.CAN-15-2882. Epub 2016 Jun 20.
The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo Mechanistically, RARγ 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, RARγ expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ 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. Cancer Res; 76(13); 3813-25. ©2016 AACR.
Hippo-Yap 通路传递致癌信号，但它在癌症发展过程中的调控机制尚不清楚。在这里，我们鉴定出核受体 RARγ 是结直肠肿瘤发生和转移过程中 Hippo-Yap 通路的一个调节因子。RARγ 在人结直肠癌组织中表达下调，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，沉默 RARγ 可促进结直肠癌细胞的体外和体内生长、侵袭和转移特性。在机制上，RARγ 通过控制 Hippo-Yap 信号通路来抑制结直肠癌的发生，促进 Lats1 对其转录共激活因子 Yap 的磷酸化和结合，从而使 yap 靶基因的表达失活。在临床标本中，RARγ 的表达与结直肠癌患者的总体生存结果和关键 Hippo-Yap 通路效应分子的表达相关。综上所述，我们的研究结果将 RARγ 定义为结直肠癌的肿瘤抑制因子，通过限制 Hippo-Yap 通路的致癌信号来发挥作用，这可能为结直肠癌的治疗提供新的方法。Cancer Res; 76(13); 3813-25. ©2016 AACR.
