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类组蛋白去乙酰化酶（HDAC I/II）的作用， 糖原合成酶激酶-3 β（GSK-3β）、酵母相关蛋白（雅普）及其下游信号转导 巨噬细胞刺激蛋白（MSP）及其受体罗恩（Recepteur d 'Origine Nantais）激酶，促进肝脏中的癌症转移。该项目认为， 癌细胞通路和肝星状细胞（HSC）和枯否细胞的募集 （肝脏中的巨噬细胞）构成一个微环境，以增强生长的 转移这些通路对癌症转移的潜在作用来自我们的研究。 使用我们设计的抑制HDAC的新化学实体促进转移的观察结果 I/II和GSK-3β，胰腺、前列腺和结直肠中过度激活的两种关键酶 癌此外，我们初步显示HDAC I/II和GSK-3β在调节雅普、MSP、 罗恩和转移。 根据初步研究结果，我们提出以下具体目标：（1）调查 HDAC和GSK-3β调节癌细胞中雅普信号传导以促进肿瘤细胞增殖的机制 研究雅普信号通路在肝转移瘤生长中的调节和作用。 HSCs可用于重塑肝脏中的肿瘤微环境，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 胰腺癌、结肠癌和前列腺癌中的雅普和MSP/罗恩信号传导，并确定 这些信号与脂肪肝和高脂饮食的关系。该项目的成果将 显著提高我们对癌症促进机制的理解 转移到肝脏，有明确的见解，应用知识的预防和 治疗癌症转移。

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.