Molecular Pathogenesis of Hepatocellular Carcinoma

肝细胞癌（HCC）是世界范围内第三大癌症死亡原因。的基因变化 HCC发生和发展的潜在机制尚不完全清楚。长期目标 我实验室的主要任务是了解HCC的分子发病机制，并将新的研究成果转化为 用于HCC的预防、早期诊断、预后预测和治疗的方法。初步 研究中，我们已经确定了一个新的基因，hSulfl，这是下调在一个显着比例的人类 在HCC和HCC细胞系中，hSulfl是质膜相关硫酸酯酶。我们观察到HCC细胞 缺乏hSulf 1表达的细胞系对细胞凋亡的诱导更有抗性。相反，强迫表达 hSulfl显著降低细胞生长，并增加HCC细胞系对促凋亡的敏感性。 因此，hSulfl可以抑制细胞存活途径或激活细胞死亡途径。细胞 许多生长因子，特别是成纤维细胞生长因子（FGF）的存活信号传导依赖于 细胞表面硫酸乙酰肝素糖胺聚糖（HSGAGs）的硫酸化状态。根据这些数据，我们 假设hSulf 1失活导致细胞表面HSGAG硫酸化状态增加，因此 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 具体目的1我们将检验hSulfl直接修饰细胞表面HSGAG的假设，导致 减少细胞生长信号通路的激活。在具体目标2中，我们将检验以下假设： hSulfl表达的失活通过增加细胞存活而促成恶性表型 通过生长因子的信号传导和/或降低肝细胞对凋亡的敏感性。最后，具体目标 3我们将确定hSulfl表达在HCC中是否通过等位基因丢失和/或超甲基化而失活。 这些研究的成功完成将为深入了解HCC的分子发病机制提供帮助， 导致开发针对HCC的新的化疗策略。

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.