肿瘤坏死因子-α通过上调YAP活性增强原发性肝癌胆管表型的机制研究

原发性肝癌胆管表型增加提示肝癌组织异质性升高，恶性度增加，预后不良。慢性炎症诱导肝前体细胞异常激活、分化在肝癌胆管表型增强中发挥重要作用。Hippo通路参与肝癌发生发展，其关键蛋白YAP与肝前体细胞激活、分化及肝癌胆管表型增强密切相关。前期研究发现，TNF-α参与肝癌胆管表型形成，伴YAP活性上调，提示TNF-α可能通过调控YAP参与肝癌异质性增加，但具体机制不明确。本研究拟利用TNF-α及其受体基因敲除大鼠，采用DEN诱导原发肝癌模型，联合肝癌手术标本，探明YAP、TNF-α及其受体与肝癌胆管表型增加的相关性；筛选介导TNF-α调控YAP活性的关键分子，阐明关键分子介导TNF-α调控YAP活性的分子机制；联合肝癌标本和病例资料,验证TNF-α参与肝癌胆管表型增加的关键因子表达与患者预后的相关性及功能作用模式。预期研究结果有助于我们认识炎症微环境参与肝癌异质性及恶性程度增加的内在机制。

Increased biliary phenotype in primary hepatocellular carcinoma suggests increased hepatic tissue heterogeneity, increased malignancy, and poor prognosis. Chronic inflammation induces abnormal activation and differentiation of hepatic progenitor cells (HPCs) and plays an important role in the enhancement of bile duct phenotype. Hippo pathway is involved in the development of liver cancer, and its key protein YAP is closely related to the activation and differentiation of HPCs and the enhancement of bile duct phenotype in liver cancer. Our previous study found that TNF-α was involved in the formation of biliary phenotype in liver cancer, accompanied by up-regulation of YAP activity, suggesting that TNF-α could participate in the heterogeneity of liver cancer by regulating YAP, but the specific mechanism is still unclear. This study intends to use TNF-α and its receptors knockout rats to induce primary liver cancer models using DEN and determine the correlation between TNF-α and its receptors, activity of YAP and the increase of bile duct phenotype. Screen for key molecules in the process of TNF-α up-regulating YAP activity; clarify the molecular mechanism of key molecules mediating TNF-α regulation of YAP activity; using liver cancer specimens and prognostic data to verify the relationship between the key molecules and the prognosis of patients. The results of this study help us to understand the mechanism of the inflammatory microenvironment involved in the heterogeneity and malignancy of liver cancer.