Regulation of the Tumor Microenvironment in Hepatocellular Carcinoma

描述（由申请人提供）：肝细胞癌（HCC）每年导致约70万人死亡，其在美国的发病率在过去30年中增加了两倍。现有的治疗方法仅对早期HCC有效。更好的早期检测方法和治疗将需要更好地了解调节HCC发生和生长的分子机制。我们已经确定了硫酸酯酶2 （sulfatase 2，一种细胞外硫酸酯酶）在HCC发病机制中的作用，并对最近在肝脏中过表达硫酸酯的转基因小鼠中自发发展的肝癌感到特别兴奋。我们之前的研究表明，硫酸肝素糖胺聚糖（HSGAG）在细胞外的储存位点释放肝素结合生长因子，增加生长因子信号传导，促进HCC的发生。这些结果表明，巯基硫在HCC中的作用部分是通过调节Wnt信号通路实现的。我们现在已经确定了这个新发现的sulg2 - wnt信号的靶分子是转录因子GLI1，它是Hedgehog通路的效应因子。此外，我们发现这个新发现的sul2 - wnt - gli1轴激活了HCC肿瘤微环境的两个主要调节因子，转化生长因子（TGF）和白细胞介素6 （IL-6）。我们将使用生化和细胞生物学方法，结构和功能分析，以及体外和体内方法系统地研究新型硫- 2- wnt - gli1轴在HCC微环境和肿瘤发生中的机制作用。这些研究的成功完成将增加我们对HCC发病机制的理解，并允许基于这些发现的HCC治疗的合理策略的未来测试。总的来说，鉴于缺乏对晚期HCC的有效治疗，这一建议具有潜在的高影响。这项研究的发现也可能推广到其他类型的癌症，因为已知其他肿瘤中也涉及到sulg2、Wnt通路和GLI1。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) causes about 700,000 deaths each year, and its incidence in the US has tripled over the past 30 years. Available therapies are curative only in early-stage HCC. Better early-detection methods and treatments will require a greater understanding of the molecular mechanisms regulating the initiation and growth of HCC. We have identified a role for sulfatase 2 (SULF2), an extracellular endosulfatase, in HCC pathogenesis and are especially excited about the recent spontaneous development of liver cancers in our transgenic mice overexpressing SULF2 in the liver. Our previous work has shown that SULF2 releases heparin-binding growth factors from heparan sulfate glycosaminoglycan (HSGAG) storage sites in the extracellular compartment, increases growth factor signaling, and promotes HCC tumorigenesis. These results show that SULF2 exerts its effects in HCC in part through modulation of the Wnt signaling pathway. We have now identified the target molecule of this newly identified SULF2-Wnt signaling as the transcriptional factor GLI1, an effector of the Hedgehog pathway. Moreover, we have discovered that this newly identified SULF2-Wnt-GLI1 axis activates two major regulators of the HCC tumor microenvironment, transforming growth factor ¿ (TGF¿) and interleukin 6 (IL-6). We will use biochemical and cell biology methods, structural and functional analyses, and in vitro and in vivo approaches to systemically investigate the mechanistic role of the novel SULF2-Wnt-GLI1 axis in the HCC microenvironment and tumorigenesis. Successful completion of these studies will increase our understanding of the pathogenesis of HCC and allow future testing of rational strategies for treatment of HCC based on these findings. Overall, this proposal is potentially of high impact given the lack of effective treatments for advanced HCC. The findings from this research will also likely be generalizable to other cancer types because of the known involvement of SULF2, the Wnt pathway, and GLI1 in other tumors.