Molecular Pathogenesis of Hepatocellular Carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是全球第三大癌症死亡原因。HCC发生和发展的遗传变化尚未完全了解。我实验室的长期目标是了解HCC的分子发病机制，并将新的研究结果转化为HCC的预防，早期诊断，预后预测和治疗方法。在初步研究中，我们已经鉴定了一个新的基因，hSulfl，其在相当大比例的人HCC和HCC细胞系中下调，hSulfl是质膜相关硫酸酯酶。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抗性。相反，hSulfl的强制表达显著降低了细胞生长，并增加了HCC细胞系对促凋亡剂的敏感性;因此，hSulfl可以阻断细胞存活途径或激活细胞死亡途径。通过许多生长因子，特别是成纤维细胞生长因子（FGF）的细胞存活信号传导依赖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HSGAGs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活化，导致细胞生长信号传导途径的活化降低的假设。在特定目标2中，我们将检验hSulfl表达失活通过生长因子增加细胞存活信号和/或肝细胞对凋亡的敏感性降低而导致恶性表型的假设。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/或超甲基化在HCC中失活。这些研究的成功完成将提供深入了解肝癌的分子发病机制，并可能导致新的化疗策略的发展对肝癌。

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.