Project 3 - HDAC/GSK-3B/YAP signaling network in the liver metastatic microenvironment

摘要 项目3旨在确定I类和II类组蛋白脱乙酰酶(HDAC I/II)的作用， 糖原合成酶β-3β、YAP与下游信号转导 涉及巨噬细胞刺激蛋白(MSP)及其受体RON(受体)的通路 D‘Origine South tais)在促进肝脏肿瘤转移中的作用。该项目考虑了这些因素 癌细胞途径与肝星状细胞和枯否细胞的募集 (肝脏中的巨噬细胞)构成促进小鼠生长的微环境 转移。这些途径在癌症转移中的潜在作用来自我们的 使用我们设计的抑制HDAC的新化学实体促进转移的观察 I/II和GSK-3β，两种在胰腺、前列腺和结直肠中过度激活的关键酶 癌症。此外，我们的初步研究表明，HDAC I/II和GSK-3β在调节YAP、MSP、 RON和转移。 根据初步结果，我们提出了以下具体目标：(1)调查 HDAC和GSK-3β调控肿瘤细胞YAP信号转导机制的研究 (2)探讨YAP信号转导通路在肝细胞癌中的调控和作用。 肝星状细胞重塑肝脏肿瘤微环境促进肝脏生长 转移。项目3将与本计划的其他项目合作，研究 YAP和MSP/RON信号在胰腺癌、结肠癌和前列腺癌中的表达 这些信号与脂肪肝和高脂饮食的关系。该项目的成果将 显著提高我们对促进癌症的机制的理解 肝转移，有清晰的洞察力，应用知识预防和 癌症转移的治疗。

ABSTRACT Project 3 is designed to determine the roles of class I and II histone deacetylase (HDAC I/II), glycogen synthase kinase-3β (GSK-3β), Yes-associated protein (YAP) and downstream signaling pathways involving the macrophage-stimulating protein (MSP) and its receptor, RON (Recepteur d'Origine Nantais) kinase, in promoting cancer metastasis in the liver. The project considers these cancer cell pathways and the recruitment of hepatic stellate cells (HSCs) and Kupffer cells (macrophages in the liver) to constitute a microenvironment for enhancing the growth of the metastasis. The potential role of these pathways on cancer metastasis comes from our observations in metastasis promotion using a new chemical entity we designed to inhibit HDAC I/II and GSK-3β, two key enzymes that are overactivated in pancreatic, prostate and colorectal cancer. Further, our preliminary shows roles for HDAC I/II and GSK-3β in regulating YAP, MSP, RON and metastasis. Based on preliminary results, we propose the following specific aims: (1) to investigate the mechanisms by which HDAC and GSK-3β regulate YAP signaling in cancer cells to promote the growth of metastasis in the liver; and (2) to investigate the regulation and role of YAP signaling in HSCs for remodeling of cancer microenvironment in the liver to promote the growth of liver metastasis. In collaboration with other projects of this Program, Project 3 will study the roles of YAP and MSP/RON signaling in pancreatic, colon, and prostate cancers and determine the relationship of these signals with fatty liver and high fat diet. The outcomes of this project will significantly enhance our understanding of the mechanisms underlying the promotion of cancer metastasis to the liver, with clear insights for application of the knowledge to the prevention and treatment of cancer metastasis.