Molecular Pathogenesis of Hepatocellular Carcinoma

肝细胞癌的分子发病机制

• 批准号: 7282303
• 负责人: LEWIS R ROBERTS
• 金额: $ 0.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282303
• 关键词: apoptosis; athymic mouse; biological signal transduction; capillary electrophoresis; cell growth regulation; clinical research; early diagnosis; enzyme inhibitors; gene expression; gene induction /repression; gene mutation; growth factor; heparan sulfate; hepatocellular carcinoma; high performance liquid chromatography; human tissue; loss of heterozygosity; methylation; molecular pathology; neoplasm /cancer diagnosis; neoplasm /cancer therapy; neoplastic growth; phosphorylation; polymerase chain reaction; prognosis; sulfatases

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The genetic changes underlying the development and progression of HCC are incompletely understood. The long-term objective of my laboratory is to understand the molecular pathogenesis of HCC and translate new research findings into methods for prevention, early diagnosis, prognostic prediction, and treatment of HCC. In preliminary studies, we have identified a novel gene, hSulfl, which is downregulated in a significant proportion of human HCCs and HCC cell lines, hSulfl is a plasma membrane associated sulfatase. We observed that HCC cell lines lacking hSulfl expression are more resistant to induction of apoptosis. Conversely, forced expression of hSulfl significantly decreased cell growth and increased the sensitivity of HCC cell lines to pro-apoptotic agents; hSulfl therefore may either inactivate a cell survival pathway or activate a cell death pathway. Cell survival signaling by a number of growth factors, particularly fibroblast growth factor (FGF), is dependent on the sulfation state of cell surface heparan sulfate glycosaminoglycans (HSGAGs). Based on these data, we hypothesize that inactivation of hSulfl leads to an increased sulfation state of cell surface HSGAGs, thus promoting cell growth and survival. Our goal is to elucidate the role of hSulfl in the development of HCCs. In Specific Aim 1 we will test the hypothesis that hSulfl directly desulfates cell surface HSGAGs, leading to decreased activation of cellular growth signaling pathways. In Specific Aim 2 we will test the hypothesis that inactivation of hSulfl expression contributes to the malignant phenotype through increased cellular survival signaling by growth factors and/or decreased sensitivity of hepatocytes to apoptosis. Finally, in Specific Aim 3 we will determine if hSulfl expression is inactivated in HCCs through allelic loss and/or hypermethylation. Successful completion of these studies will provide insight into the molecular pathogenesis of HCC, and may lead to the development of novel chemotherapeutic strategies against HCC.

描述（由申请人提供）：肝细胞癌（HCC）是全世界癌症死亡的第三大原因。 HCC 发生和进展背后的基因变化尚不完全清楚。我实验室的长期目标是了解 HCC 的分子发病机制，并将新的研究成果转化为 HCC 的预防、早期诊断、预后预测和治疗方法。在初步研究中，我们发现了一个新基因 hSulfl，该基因在相当比例的人类 HCC 和 HCC 细胞系中下调，hSulfl 是一种质膜相关硫酸酯酶。我们观察到缺乏 hSulfl 表达的 HCC 细胞系对细胞凋亡的诱导更具抵抗力。相反，hSulfl 的强制表达显着降低了细胞生长并增加了 HCC 细胞系对促凋亡剂的敏感性；因此，hSulfl可以使细胞存活途径失活或激活细胞死亡途径。许多生长因子，特别是成纤维细胞生长因子 (FGF) 的细胞存活信号传导取决于细胞表面硫酸乙酰肝素糖胺聚糖 (HSGAG) 的硫酸化状态。基于这些数据，我们假设 hSulfl 的失活导致细胞表面 HSGAG 的硫酸化状态增加，从而促进细胞生长和存活。我们的目标是阐明 hSulfl 在 HCC 发展中的作用。在具体目标 1 中，我们将测试 hSulfl 直接使细胞表面 HSGAG 脱硫，从而导致细胞生长信号通路激活减少的假设。在具体目标 2 中，我们将检验以下假设：hSulfl 表达失活通过增加生长因子的细胞存活信号传导和/或降低肝细胞对细胞凋亡的敏感性而导致恶性表型。最后，在具体目标 3 中，我们将确定 hSulfl 表达是否通过等位基因丢失和/或高甲基化在 HCC 中失活。这些研究的成功完成将有助于深入了解 HCC 的分子发病机制，并可能导致针对 HCC 的新型化疗策略的开发。