URGCP/URG4对原发性肝癌治疗效果及肝癌血管增生调控的分子机制

Previously，Studies have found that URGCP/URG4 expression was associated with tumorigenesis,proliferation and metastasis in tumor, but the influence and mechanism of angiogenesis about URGCP/URG4 remains to be elucidated.In the present study we have found that URGCP/URG4 was increased in hepatocellular carcinoma tissues and cells.Furthermore,our preliminary data showed that overexpress URGCP/URG4 promote the angiogenesis and activation of NF κ B signal pathway. The overexpress and knockdown URGCP/URG4 stable cell line were tested by Western blot, chromatin immunoprecipitation and luciferase reporter gene, explore the molecular mechanism of URGCP/URG4 regulating NF κ B, Jak/Stat3 and TGF- β /Smad signal pathway; in vitro function test and in vivo liver cancer model in primary cancer. Meanwhile we analyse URGCP/URG4 with clinical samples. Hence, in the current project, we aim to explore the molecular regulation of verification of URGCP/URG4 on hepatocellular carcinoma angiogenesis and the effect of treatment for primary hepatocellular carcinoma. URGCP/URG4 provide new biomarkers and targets for the diagnosis and treatment of hepatocellular carcinoma.

有研究发现URGCP/URG4的表达与肿瘤发生发展相关，对肿瘤的增殖转移能力有重要的影响，但是URGCP/URG4对肿瘤的血管增生及其对肿瘤调控的分子机制尚待阐明。我们的前期研究发现URGCP/URG4蛋白在肝癌组织及细胞中的表达显著上升，并且URGCP/URG4的高表达可促进肝癌血管的生成，同时激活NFκB 信号通路。本项目将以高表达或抑制URGCP/URG4 的细胞为模型，通过免疫印迹、染色体免疫共沉淀及荧光素酶报告基因分析等方法,探讨URGCP/URG4对NFκB 、Jak/Stat3和TGF-β/Smad信号通路的具体分子机制；并通过体外功能试验、体内原位肝癌动物模型试验及结合临床样本，验证URGCP/URG4对肝癌血管增生的分子调控机制及其对原发性肝癌的治疗效果；从而验证URGCP/URG4可作为肝癌的诊断分子，为后续研发肝癌靶向基因治疗提供新的诊治分子靶标。

URGCP/URG4在多种肿瘤中过度表达，并且能被乙型肝炎病毒X蛋白上调，促进肝细胞的生长和存活，进而发展为肝癌细胞。高水平的血管增生与肝细胞癌高度侵袭性表型以及预后不良相关。在肝癌细胞中URG4/URGCP对肿瘤血管增生的影响尚未阐明。本研究发现：在肝癌细胞中URG4/URGCP蛋白质和mRNA的表达显著上调，过度表达URG4/URGCP促进肝癌细胞的血管增生和VEGFC表达，沉默URG4/URGCP抑制肝癌细胞的血管增生和VEGFC表达，过度表达URG4/URGCP促进NF-κB信号通路的激活，抑制NF-κB信号活力会导致URG4/URGCP诱导的血管增生能力丧失。以上结果提示：URG4/URGCP在肝癌细胞系中上调，并且通过激活NF-κB信号传导途径来增强肝癌细胞的血管生成能力。本研究部分揭示了肝癌细胞血管生成的新机制， URG4/URGCP可能成为新的治疗靶点。