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发生和发展背后的基因变化尚不完全清楚。我的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，我们发现了一个新的基因，hsull，它在人类HCC和HCC细胞系中显著下调，hsull是一种质膜相关硫酸酯酶。我们观察到缺乏h硫表达的HCC细胞系对诱导凋亡更有抵抗力。相反，强制表达h硫显著降低细胞生长，增加HCC细胞系对促凋亡药物的敏感性；因此，h硫可以灭活细胞存活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（FGF）的细胞存活信号依赖于细胞表面硫酸肝素糖胺聚糖（HSGAGs）的硫酸化状态。基于这些数据，我们假设h硫的失活导致细胞表面HSGAGs的硫化状态增加，从而促进细胞的生长和存活。我们的目标是阐明h硫在hcc发展中的作用。在Specific Aim 1中，我们将验证h硫直接使细胞表面HSGAGs脱硫，导致细胞生长信号通路激活降低的假设。在Specific Aim 2中，我们将验证h硫表达失活通过增加生长因子的细胞存活信号和/或降低肝细胞对凋亡的敏感性来促进恶性表型的假设。最后，在Specific Aim 3中，我们将确定h硫表达是否通过等位基因丢失和/或超甲基化而在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的新型化疗策略的发展。

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.