The role of FAK in hepatocarcinogenesis

FAK在肝癌发生中的作用

• 批准号: 8836506
• 负责人: Wei Qiu
• 金额: $ 7.55万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-09 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836506
• 关键词: Affect; Brain; CD36 gene; Carcinogens; Cells; Clinical Trials; Data; Development; Diethylnitrosamine; Disease; Environment; Fatty Liver; Focal Adhesion Kinase 1; Goals; Hepatic; Hepatocarcinogenesis; Hepatocyte; Human; Inflammation; Inflammatory; Intestines; Knockout Mice; Liver; Liver Fibrosis; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mammary gland; Mediating; Modeling; Molecular; Mus; Nonesterified Fatty Acids; PTEN gene; Pathogenesis; Patients; Phase; Phosphorylation; Play; Primary carcinoma of the liver cells; Research; Role; Signal Pathway; Solid Neoplasm; Steatohepatitis; Testing; Time; Tissues; United States; cancer type; drug metabolism; in vivo; inhibitor/antagonist; insight; kinase inhibitor; liver injury; mouse model; new therapeutic target; prevent; public health relevance; tumor progression; tumorigenesis; uptake

DESCRIPTION (provided by applicant): The central focus of this application is to understand the role of focal adhesion kinase (FAK) in liver cancer. Hepatocellular carcinoma (HCC) is the most rapidly increasing cancer in the United States. Currently, the underlying mechanisms of HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for identifying novel therapeutic targets for preventing or treating HCC. FAK has been shown to play an important role in tumorigenesis and cancer progression in several tissues, however, the role of FAK in liver cancer remains elusive due to the lack of in vivo studies. Currently, several FAK inhibitors are being used as promising anti-solid tumor agents in early-phase clinical trials. As most drug metabolism occurs in the liver, it s critical to understand the effect of inhibition of FAK on liver. We have found that deletion of FAK promotes steatohepatitis, hepatic fibrosis and hepatic proliferation in hepatocyte-specific Phosphatase and Tensin Homolog (PTEN)-deficient mice. As steatohepatitis, hepatic fibrosis and enhanced hepatic proliferation are thought to promote liver cancer, we propose that deletion of FAK in liver promotes hepatocarcinogenesis in hepatocyte- specific PTEN-deficient mice model. We then intend to understand the role of FAK in hepatocarcinogenesis in which activation of FAK is not due to loss of PTEN. To achieve this goal, we plan to use a carcinogen, diethylnitrosamine(DEN)-induced HCC mouse model in which activation of FAK is not due to loss of PTEN. This study will provide new insights into the role of FAK in liver cancer, which is important for treating either liver cancer or other types of cancers by targeting FAK.

描述（由申请人提供）：本应用的主要重点是了解局灶性粘附激酶（FAK）在肝癌中的作用。肝细胞癌（HCC）是美国最快增加的癌症。目前，HCC的基本机制尚不完全清楚。了解驱动或介导HCC发展的分子信号通路对于鉴定预防或治疗HCC的新型治疗靶标非常重要。 FAK已被证明在几个组织的肿瘤发生和癌症进展中起着重要作用，但是，由于缺乏体内研究，FAK在肝癌中的作用仍然难以捉摸。目前，在早期临床试验中，几种FAK抑制剂被用作有前途的抗固肿瘤剂。由于大多数药物代谢发生在肝脏中，因此了解抑制FAK对肝脏的影响至关重要。我们发现fak的删除 促进肝细胞特异性磷酸酶和Tensin同源物（PTEN）缺陷小鼠的脂肪性肝炎，肝纤维化和肝增殖。作为脂肪性肝炎，认为肝纤维化和增强的肝增殖被认为可以促进肝癌，我们认为肝脏中FAK的缺失会促进肝细胞 - 特异性PTEN缺陷缺陷型小鼠模型中的肝癌发生。然后，我们打算了解FAK在肝癌发生中的作用，在肝癌发生中，FAK的激活不是由于PTEN的损失。为了实现这一目标，我们计划使用致癌物，二乙基硝基胺（DEN）诱导的HCC小鼠模型，其中FAK的激活不是由于PTEN的损失。这项研究将为FAK在肝癌中的作用提供新的见解，这对于通过靶向FAK来治疗肝癌或其他类型的癌症很重要。