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， 糖原合成酶激酶-3β (GSK-3β)、Yes 相关蛋白 (YAP) 和下游信号传导 涉及巨噬细胞刺激蛋白 (MSP) 及其受体 RON（受体 d'Origine Nantais）激酶，促进癌症在肝脏中的转移。项目考虑了这些 癌细胞通路以及肝星状细胞 (HSC) 和库普弗细胞的募集 （肝脏中的巨噬细胞）构成促进巨噬细胞生长的微环境 转移。这些途径对癌症转移的潜在作用来自于我们 使用我们设计用于抑制 HDAC 的新化学实体促进转移的观察结果 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，我们的初步结果表明 HDAC I/II 和 GSK-3β 在调节 YAP、MSP、 RON 和转移。 根据初步结果，我们提出以下具体目标：（1）调查 HDAC 和 GSK-3β 调节癌细胞中 YAP 信号传导以促进 肝脏转移瘤的生长； (2) 研究 YAP 信号在 HSC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 胰腺癌、结肠癌和前列腺癌中的 YAP 和 MSP/RON 信号传导并确定 这些信号与脂肪肝和高脂肪饮食的关系。该项目的成果将 显着增强我们对促进癌症的机制的理解 肝脏转移，对将知识应用于预防和治疗有清晰的见解 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.