Molecular Pathogenesis of Hepatocellular Carcinoma

描述(申请人提供)：肝细胞癌是全球第三大癌症死亡原因。肝细胞癌的发生和发展背后的基因变化还不完全清楚。我的实验室的长期目标是了解肝癌的分子发病机制，并将新的研究成果转化为预防、早期诊断、预后预测和治疗的方法。在初步研究中，我们已经发现了一个新的基因hSulf1，它在相当大一部分人肝癌细胞系中下调，hSulf1是一种质膜相关的硫酸酯酶。我们观察到，缺乏hSulfl表达的肝癌细胞系对诱导凋亡具有更强的抵抗力。相反，强制表达hSulfl显著抑制细胞生长，增加肝癌细胞系对促凋亡药物的敏感性；因此，hSulfl可以灭活细胞生存途径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(成纤维细胞生长因子)对细胞生存的信号转导依赖于细胞表面硫酸乙酰肝素糖胺聚糖(HSGAGs)的硫酸盐化状态。基于这些数据，我们假设hSulf1的失活导致细胞表面HSGAGs的硫酸盐化状态增加，从而促进细胞的生长和存活。我们的目标是阐明hSulf1在肝癌发生发展中的作用。在特定的目标1中，我们将测试假设，即hSulf1直接脱硫细胞表面HSGAGs，导致细胞生长信号通路的激活减少。在特定的目标2中，我们将验证hSulfl表达失活通过生长因子增加细胞生存信号和/或降低肝细胞对凋亡的敏感性而导致恶性表型的假说。最后，在特定的目标3中，我们将确定hSulf1在肝癌中的表达是否通过等位基因丢失和/或高甲基化而失活。这些研究的成功完成将为深入了解肝癌的分子发病机制提供线索，并可能导致开发新的抗肝癌化疗策略。

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.