Molecular Pathogenesis of Hepatocellular Carcinoma

肝细胞癌是全球第三大癌症死亡原因。基因的变化 肝细胞癌的发生和发展的基础尚不完全清楚。长期目标 我实验室的任务是了解肝癌的分子发病机制，并将新的研究成果转化为 肝细胞癌的预防、早期诊断、预后预测和治疗方法。在预赛中 研究发现，我们发现了一种新的基因hSulfl，它在相当大一部分人类体内表达下调 HSulf1是一种质膜相关的硫酸酯酶。我们观察到肝癌细胞 缺乏hSulfl表达的品系对诱导细胞凋亡的抗性更强。相反，强迫表达 HSulfl显著抑制细胞生长并增加肝癌细胞系对促凋亡的敏感性 因此，药物hSulf1可以使细胞存活途径失活，也可以激活细胞死亡途径。细胞 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)发出的生存信号依赖于 细胞表面硫酸乙酰肝素糖胺聚糖(HSGAGs)的硫化状态。根据这些数据，我们 假设hSulf1失活导致细胞表面HSGAGs硫酸盐化状态增加，因此 促进细胞生长和存活。我们的目标是阐明hSulf1在肝癌发生发展中的作用。在……里面 具体目标1我们将测试hSulf1直接脱硫细胞表面HSGAGs的假设，导致 细胞生长信号通路激活减少。在具体目标2中，我们将检验假设 HSulfl表达失活通过增加细胞存活率而导致恶性表型 生长因子的信号转导和/或降低肝细胞对凋亡的敏感性。最后，在具体目标上 3我们将确定hSulfl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有助于深入了解肝细胞癌的分子发病机制，并可能 导致针对肝癌的新的化疗策略的发展。

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.