DNA repair mechanisms in the pathogenesis of hepatocellular carcinoma

肝细胞癌或起源于肝脏的癌症在全球肿瘤中的发病率位居第5位，是本地区第三大致癌原因。在包括澳大利亚、日本和美国在内的大多数国家，发病率都在上升。总体预后很差，80%的患者死于这种疾病。肝细胞癌的危险因素是众所周知的，包括慢性乙肝或丙型肝炎病毒感染、酒精中毒和肝脏铁蓄积。尽管有大量关于这些危险因素的信息，但它们如何改变正常肝细胞使其癌变的方式仍未确定。大多数肝癌，无论原因如何，都是在严重的疤痕形成，或在慢性肝脏炎症的情况下发展为肝硬变。这种环境导致通常稳定且不分裂的肝细胞继续复制，以应对损伤；这种持续的细胞分裂可能导致这些细胞DNA中的遗传信息受损。许多癌症与染色体损伤有关，包括断端和遗传物质缺失。这个项目的主要重点是研究受损肝细胞中染色体DNA中包含的受损遗传信息的缺陷修复如何有助于肝癌的发展。利用缺乏特定遗传信息的小鼠修复DNA双链断裂，我们计划研究二乙基亚硝胺(DEN)损伤的肝细胞DNA修复机制的异常是否容易导致肝细胞异常再生，从而进展为癌症。我们发现染色体上有7个特定位置的关键基因缺失可能促进肝细胞癌的形成。这些研究将极大地增强我们对肝细胞癌发生的分子基础的了解。这项研究的最终目标是开发有效的筛查和治疗策略，以预防或中断高危个体的肝癌发展过程。

Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of information available regarding these risk factors, the way in which they alter normal liver cells to make them cancerous remains undefined. The majority of liver cancers, regardless of cause, develop in severely scarred, or cirrhotic liver in the presence of chronic liver inflammation. Such an environment causes liver cells, which are usually stable and not dividing, to continue replicating in response to injury; such continued cell division can lead to damaged genetic information in the DNA of these cells. Many cancers are associated with chromosomal damage, including broken ends and deleted genetic material. The main focus of this project to investigate how defective repair of disrupted genetic information contained in DNA of chromosomes in damaged liver cells contributes to the development of liver cancer. Using mice lacking specific genetic information to repair DNA double strand breaks, we plan to investigate whether abnormalities in DNA repair mechanisms in liver cells damaged by diethylnitrosamine (DEN) predisposes liver cells to regenerate abnormally thereby progressing to cancer. We have clues that 7 specific sites in chromosomes where loss of key genes may promote HCC formation. These studies will greatly enhance our understanding of the molecular basis by which HCC develops. The ultimate goal of this research is to develop effective screening and treatment strategies to prevent or interrupt the process of liver cancer development in at-risk individuals.