文章：

肝癌的发病机制：从基因到环境

Hepatocellular carcinoma pathogenesis: from genes to environment

原文发布日期：2006-09-01

DOI: 10.1038/nrc1934

类型: Review Article

开放获取: 否

要点：

1. Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and affects many of the world's populations.
2. Various aetiologies have been linked to HCC development, the most prominent of which include chronic hepatitis B (HBV) and C (HCV) viral infection, chronic alcohol consumption and aflatoxin-B1-contaminated food. Virtually all cirrhosis-inducing conditions can cause HCC, pointing to important interactions with the host microenvironment.
3. HBV-induced hepatocarcinogenesis can involve an array of processes, including host–viral interactions, sustained cycles of necrosis–inflammation–regeneration, viral–endoplasmic-reticulum interactions (induction of oxidative stress), viral integration into the host genome (and associated host DNA deletions) and the targeted activation of oncogenic pathways by various viral proteins.
4. HCV-induced hepatocarcinogenesis also provokes similar biological processes, but is associated with a propensity of HCV to evade the host's immune responses and to promote cirrhosis.
5. Alcohol-induced hepatocarcinogenesis is associated with the induction of inflammation and, consequently, cycles of hepatocyte necrosis and regeneration, oxidative stress and cirrhosis. Aflatoxin-B1-induced hepatocarcinogenesis is mostly associated with carcinogenic mutations.
6. Various genetic events have been associated with the development of HCC, such as the inactivation of the tumour suppressor p53, mutations in β-catenin, overexpression of various ErbB receptor family members and overexpression of the Met receptor. In addition, various cancer-relevant genes seem to be targeted on the epigenetic level (methylation) in human HCC.
7. Genomic instability is a common feature of human HCC. Various mechanisms are thought to contribute, including telomere erosion, chromosome segregation defects and alterations in the DNA-damage-response pathways.
8. There are many genomic alterations in HCC. Comparative genomic hybridization studies so far have pointed to frequent chromosomal gains in 1q, 6p, 8q, 11q and 17q, and losses in 1p, 4q, 8p, 13q and 17p. Attempts have also been made to relate particular genomic alterations to aetiology and tumour-stage, albeit to a limited extent.
9. Gene-expression analyses of human HCCs have led to the successful molecular classification of HCCs on the basis of prognosis, aetiology and intrahepatic recurrence.
10. Many challenges and opportunities exist in this field, including the need for a more detailed and clinically grounded genomic characterization of human HCCs, deeper understanding of the mechanisms of genomic instability, host–viral interactions, microenvironmental processes (inflammation and cirrhosis), cell of origin in hepatocarcinogenesis and the identification of biomarkers to identify early stage disease as well as those at greatest risk of developing HCC.

要点翻译：

1. 肝细胞癌（HCC）是致死率最高的恶性肿瘤之一，影响全球众多人群。
2. 该病的发生与多种病因相关，最主要包括慢性乙型肝炎（HBV）和丙型肝炎（HCV）病毒感染、长期酒精摄入及黄曲霉毒素B1污染食物。几乎所有导致肝硬化的病变都可能引发肝细胞癌，这提示宿主微环境在癌变过程中具有重要相互作用。
3. HBV相关肝癌发生机制涉及多重过程，包括宿主-病毒相互作用、坏死-炎症-再生循环持续进行、病毒-内质网相互作用（诱导氧化应激）、病毒整合入宿主基因组（伴随宿主DNA缺失）以及多种病毒蛋白对致癌通路的特异性激活。
4. HCV相关肝癌发生同样会激发类似生物学过程，但其特征更倾向于病毒逃逸宿主免疫应答及促进肝硬化发展。
5. 酒精相关肝癌发生与炎症诱导及其后续的肝细胞坏死-再生循环、氧化应激和肝硬化密切相关。黄曲霉毒素B1主要通过致癌突变诱发肝癌。
6. 肝细胞癌发展涉及多种遗传学事件，例如肿瘤抑制因子p53失活、β-连环蛋白突变、多种ErbB受体家族成员过表达以及Met受体过表达。此外，表观遗传学层面（甲基化）的调控似乎也影响着多个癌症相关基因在人肝细胞癌中的表达。
7. 基因组不稳定性是人类肝细胞癌的常见特征，其形成机制包括端粒损耗、染色体分离缺陷及DNA损伤应答通路改变等。
8. 肝细胞癌中存在大量基因组变异，比较基因组杂交研究已发现1q、6p、8q、11q和17q染色体区域频繁获得，而1p、4q、8p、13q和17p区域频繁缺失。目前已有研究尝试将特定基因组变异与病因及肿瘤分期建立关联，但成果仍有限。
9. 基于基因表达分析的人肝细胞癌分子分型已能成功根据预后、病因和肝内复发情况进行分类。
10. 该领域仍面临诸多挑战与机遇，包括需要更精细且基于临床的基因组特征解析、深化对基因组不稳定性机制的理解、阐明宿主-病毒相互作用及微环境进程（炎症与肝硬化）、确定肝癌发生的起源细胞，以及建立用于早期诊断和高危人群筛查的生物标志物体系。

英文摘要：

Hepatocellular carcinoma is among the most lethal and prevalent cancers in the human population. Despite its significance, there is only an elemental understanding of the molecular, cellular and environmental mechanisms that drive disease pathogenesis, and there are only limited therapeutic options, many with negligible clinical benefit. This Review summarizes the current state of knowledge of this, the most common and dreaded liver neoplasm, and highlights the principal challenges and scientific opportunities that are relevant to controlling this accelerating global health crisis.

摘要翻译： 

肝细胞癌是人类中最致命且最常见的癌症之一。尽管其意义重大，目前对驱动疾病发生的分子、细胞及环境机制仅有初步了解，且治疗选择有限，许多疗法的临床获益微乎其微。本综述总结了关于这一最常见且最令人畏惧的肝脏肿瘤的最新研究进展，并重点阐述了控制这一日益加剧的全球健康危机所面临的主要挑战和科学机遇。

原文链接：

Hepatocellular carcinoma pathogenesis: from genes to environment