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）：本申请的中心重点是了解粘着斑激酶（FAK）在肝癌中的作用。肝细胞癌（HCC）是美国增长最快的癌症。目前，HCC 的潜在机制尚不完全清楚。了解驱动或介导 HCC 发展的分子信号通路对于确定预防或治疗 HCC 的新治疗靶点非常重要。 FAK已被证明在多种组织的肿瘤发生和癌症进展中发挥重要作用，然而，由于缺乏体内研究，FAK在肝癌中的作用仍然难以捉摸。目前，几种 FAK 抑制剂正在早期临床试验中用作有前途的抗实体瘤药物。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张力蛋白同源物 (PTEN) 缺陷小鼠的脂肪性肝炎、肝纤维化和肝增殖。由于脂肪性肝炎、肝纤维化和肝脏增殖增强被认为会促进肝癌，因此我们提出，在肝细胞特异性 PTEN 缺陷小鼠模型中，肝脏中 FAK 的缺失会促进肝癌的发生。然后我们打算了解 FAK 在肝癌发生中的作用，其中 FAK 的激活不是由于 PTEN 的丢失。为了实现这一目标，我们计划使用致癌物二乙基亚硝胺 (DEN) 诱导的 HCC 小鼠模型，其中 FAK 的激活不是由于 PTEN 的丢失。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非常重要。