β-连环蛋白维持 YES 相关蛋白癌基因活性并对其有需求作用在胆管细胞癌中。
β-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma.
机构信息
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.
Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
出版信息
Gastroenterology. 2022 Aug;163(2):481-494. doi: 10.1053/j.gastro.2022.04.028. Epub 2022 Apr 27.
BACKGROUND & AIMS: YES-associated protein (YAP) aberrant activation is implicated in intrahepatic cholangiocarcinoma (iCCA). Transcriptional enhanced associate domain (TEAD)-mediated transcriptional regulation is the primary signaling event downstream of YAP. The role of Wnt/β-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and β-Catenin cascades in iCCA.
METHODS
Activated AKT (Myr-Akt) was coexpressed with YAP (YapS127A) or Tead2VP16 via hydrodynamic tail vein injection into mouse livers. Tumor growth was monitored, and liver tissues were collected and analyzed using histopathologic and molecular analysis. YAP, β-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine β-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or β-Catenin. Immunostaining of total and nonphosphorylated/activated β-Catenin staining was performed in mouse and human iCCAs.
RESULTS
We discovered that TEAD factors are required for YAP-dependent iCCA development. However, transcriptional activation of TEADs did not fully recapitulate YAP's activities in promoting cholangiocarcinogenesis. Notably, β-Catenin physically interacted with YAP in human and mouse iCCA. Ctnnb1 ablation strongly suppressed human iCCA cell growth and Yap-dependent cholangiocarcinogenesis. Furthermore, RNA-sequencing analysis revealed that YAP/ transcriptional coactivator with PDZ-binding motif (TAZ) regulate a set of genes significantly overlapping with those controlled by β-Catenin. Importantly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs.
CONCLUSION
YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with β-Catenin. β-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.
背景与目的
在肝内胆管癌（iCCA）中，YAP（Yes 相关蛋白）异常激活。TEAD（转录增强相关结构域）介导的转录调控是 YAP 下游的主要信号事件。Wnt/β-连环蛋白信号在胆管癌发生中的作用尚不确定。在这里，我们研究了 YAP 和 β-连环蛋白级联在 iCCA 中可能的分子相互作用。
方法
通过尾静脉注射表达激活 AKT（Myr-Akt）的质粒与 YAP（YapS127A）或 Tead2VP16 的质粒，共表达到小鼠肝脏中。监测肿瘤生长情况，并通过组织病理学和分子分析收集和分析肝组织。通过免疫共沉淀研究 iCCAs 中的 YAP、β-连环蛋白和 TEAD 相互作用。使用条件性 Ctnnb1 敲除小鼠确定β-连环蛋白在小鼠 iCCA 模型中的功能。进行 RNA 测序以分析受 YAP 和/或 β-连环蛋白调控的基因。对小鼠和人 iCCA 进行总β-连环蛋白和非磷酸化/激活β-连环蛋白染色的免疫染色。
结果
我们发现 TEAD 因子是 YAP 依赖性 iCCA 发展所必需的。然而，TEAD 的转录激活并没有完全再现 YAP 促进胆管癌发生的作用。值得注意的是，β-连环蛋白在人 iCCA 和小鼠 iCCA 中与 YAP 物理相互作用。Ctnnb1 缺失强烈抑制人 iCCA 细胞生长和 Yap 依赖性胆管癌发生。此外，RNA 测序分析显示，YAP/含有 PDZ 结合基序的转录共激活因子（TAZ）调控一组与β-连环蛋白调控的基因显著重叠的基因。重要的是，超过 80%的人 iCCA 中检测到激活/非磷酸化的β-连环蛋白。
结论
YAP 通过 TEAD 依赖性转录激活和与β-连环蛋白相互作用诱导胆管癌发生。β-连环蛋白在 iCCA 中与 YAP 结合，并需要 YAP 的完全转录活性，揭示了 YAP 和β-连环蛋白途径在胆管癌发生中的功能串扰。
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