乙肝病毒进化及其对肝细胞癌的促进作用

Evolution of hepatitis B virus and its promotion effect on hepatocellular carcinoma

乙肝病毒慢性感染是我国肝细胞癌发生的主要病因。慢性炎症导致的肝细胞癌发生过程符合“变异-选择-适应”的达尔文进化规律。炎症诱变分子促进体细胞变异的产生,大部分变异细胞会被炎症微环境清除,而少部分变异细胞通过激活致癌通路获得干性特征而在选择压力下幸存,并发展为癌症起始细胞。伴随这一过程,乙肝病毒也在炎症微环境压力下发生进化,表现为促癌的病毒变异累积而感染新个体的能力降低,高危变异株随着宿主的死亡而淘汰,因此是“末路进化”。乙肝病毒的进化促进了癌症进化,包括维持炎症微环境、激活致癌通路、诱导体细胞变异、改变代谢模式。乙肝病毒联合变异以及乙肝病毒整合变异可以预测肝细胞癌的发生和预后。抗病毒治疗可以缓解炎症并降低癌症风险。本文综述了乙肝病毒和肝细胞癌共进化的相关分子流行病学证据和机制研究进展。明确病毒与癌症的共进化规律以及其中的关键分子事件,有利于提供新的生物标志物和治疗靶标,从而完善肝细胞癌的防治策略。

Chronic infection of hepatitis B virus(HBV)is the major cause of hepatocellular carcinoma(HCC)in China.The occurrence of HCC through chronic inflammation follows the Darwinian evolutionary law,known as"mutation-selectionadaptation".Inflammatory mutagenic molecules promote the generation of somatic mutations,and the most mutant cells are eliminated by inflammatory microenvironment.However,a minority of mutant cells survive the selective pressure and develop to tumor initial cells by activating oncogenic signaling pathway and acquiring“stemness”characteristics.Alongside this process,HBV also evolves under the pressure of inflammatory microenvironment,which is characterized by the accumulation of cancer-promoting viral mutations,reducing the ability to infect new individuals.The high-risk mutant strains are eliminated with the death of hosts,leading to a phenomenon termed as“dead-end evolution”.HBV evolution contributes to cancer evolution by maintaining the inflammatory microenvironment,activating oncogenic pathways,inducing somatic cell mutations,and altering metabolic patterns.The combo mutations of HBV and HBV integrations can be applied to predict the occurrence and prognosis of HCC.Anti-viral treatment reduces the risk of HCC by relieving inflammation.This article reviews the molecular epidemiological evidence and mechanistic advances related to the co-evolution of HBV and HCC.Clarifying the coevolutionary pattern of virus and cancer and the key molecular events involved,is beneficial for identifying new biomarkers and therapeutic targets,thus improving the prevention and treatment strategies for HCC.