预防肝癌发生仍是医学界难题，但其有效治疗则取决于早期发现。我们前期研究发现肝癌特异表达Wnt3a并分泌入血，推测Wnt3a作为Wnt/β-catenin通路关键信号分子具癌胚性，能促进肝细胞的恶性转化。尚不知在慢性肝病进展期的表达规律及可否为早期癌变预警标志。本研究拟在此基础上，利用高危人群随访资料进行病例-对照和回顾性队列研究设计，比较HBV慢性感染组、肝硬化组和健康对照组的外周血Wnt3a表达水平，探讨Wnt3a表达与HBV慢性感染进展到肝癌的相关性；以HBV阳性肝癌组织和癌旁肝组织解析Wnt3a调控机制；以HBx转基因动物诱发肝癌模型观察正常、变性、癌前和癌变病理过程中肝组织Wnt3a表达及基因转录动态变化，分析Wnt3a转录-肝细胞恶转化-HBV致癌基因之间的交互作用，为阻断Wnt3a信号通路或减缓HBV慢性化进程以及肝细胞恶性转化的早期预警提供科学依据。

Prophylaxis of hepatocellular carcinoma (HCC) occurrence remains to be hard in medical society. The effective treatment for HCC depends on early discovery. Previously, we found that Wnt3a was specially expressed in HCC cells and could be released into the circulation, implying that Wnt3a, the key signaling molecule in Wnt/β-catenin pathway, is carcinoembryonic and can promote malignant transformation of hepatocytes. However, it remains to know the regulation of Wnt3a appearance during the progression of chronic liver diseases and to clarify if Wnt3a can function as a warning biomarker to indicate the occurrence of early HCC. Based on these previous observations, we propose to carry out the following researches. First, population-based case-control study and retrospective cohort study will be performed utilizing follow-up data of the high-risk HBV-infected populations. The expression levels of Wnt3a in peripheral blood will be compared among the subjects chronically infected with HBV, patients with HBV-related cirrhosis, and those with HBV-related HCC to elucidate the correlation of the Wnt3a expression levels with the progression from chronic HBV infection to HCC occurrence. Second, regulatory mechanisms of Wnt3a will be revealed using surgically removed HCC tissues and adjacent hepatic tissues. Third, with the use of HBx-transgenic mice, dynamic changes of Wnt3a expression and related transcriptional activities will be investigated during hepatocarcinogenesis from normal liver, degenerated liver, precancerous alterations to HCC; furthermore, interaction among Wnt3a transcription-malignant transformation- HBV oncogenic genes will be assessed in details. This study will provide rational to block and slow down the progression of HBV-induced hepatocarcinogenesis via targeting Wnt3a signaling and establish a novel warning biomarker for HBV-HCC occurrence.