【摘要】 乙肝病毒(HBV)致肝细胞癌(HCC)过程中,免疫/炎症分子遗传易感性与HBV交互作用维持了乙肝慢性化。HBV蛋白如大S抗原和HBx通过抑制免疫维持了非可控性炎症。促炎细胞因子反式激活核酸编辑酶如胞苷脱氨酶的表达,促进病毒和宿主基因组变异。绝大部分变异细胞在生存竞争中被淘汰,只有极其少数细胞通过改变细胞生存依赖的信号通路,具备了上皮细胞向间质细胞转化等逆向分化的潜能,获得了克服衰老、掠夺营养、无限增值和化疗抵抗等"干性"特征而被选择出来,成为癌症起始细胞。这类细胞逐渐适应了促癌炎症微环境,演绎了"变异—选择—适应"的进化过程。癌症进化发育学理论可能为癌症监测、预防和预后预测提供可靠生物标志和靶向治疗有效靶标。更多还原

【Abstract】 Chronic infection with hepatitis B virus(HBV)mainly contributes to the development of hepatocellular carcinoma(HCC)worldwide.In the mainland of China,90%of HCC is caused by chronic HBV infection,and HBV genotype C2 is more carcinogenic than genotype B2.Non-resolving inflammation,which is characterized by frequent necrosis and regeneration of affected hepatic tissues,is indispensible in HBVinduced hepatocarcinogenesis.In this article,we present a theoretical framework of Cancer Evo-Dev as followed.Interactions of genetic predisposition of immunological and inflammatory molecules with the infection of HBV maintain chronic infection and non-resolving inflammation.Some HBV-encoding proteins such as large HBV surface antigen and HBV X proteins can suppress immune functions,leading to immune escape and the maintenance of non-resolving inflammation.In the inflammatory microenvironment,proinflammatory cytokines and chemokines can trans-activate the expression of some nucleotide editing enzymes such as cytosine deaminases,and thus disequilibrate pro-mutagenesis and DNA repairment.As a result,viral mutations and somatic mutations are greatly increased.The majority of mutated cells or viruses are eliminated in survival competition.A tiny percentage of mutated cells with altered survival signal pathways or models can undergo retro-differentiation viaepithelial-to-mesenchymal transition and acquire the"stemness"capacities of overcoming senescence,rubbing nutrition,proliferating immortally,and chemo-resistant.These cells are subsequently selected in inflammatory environment,gradually adapt to the cancer-promoting environment and function as cancer-initiating cells,thus contributing to the development and progression of cancer.HBV-induced carcinogenesis represents a typical"mutation-selection-adaptation"evolutionary process.The inflammatory environment plays an important role in maintaining the"stemness"of cancer cells and promoting cancer metastasis and postoperative recurrence.The theoretical framework of Cancer Evo-Dev may reflect a general law of inflammation-induced malignant transformation,which may provide robust biomarkers for cancer surveillance,prophylaxis,and prognosis prediction as well as therapeutic targets for targeted therapy via targeting to critical survival pathways of cancers.更多还原