Pasquinelli C, Bhavani K, Chisari F V
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037.
Cancer Res. 1992 May 15;52(10):2823-9.
In the current study we sought to elucidate the molecular mechanisms which might contribute to hepatocarcinogenesis in a hepatitis B virus (HBV) envelope transgenic mouse model in which chronic hepatocellular injury and inflammation lead to regenerative hyperplasia and eventually to the development of chromosomal abnormalities and hepatocellular carcinoma (HCC), thereby reiterating many of the pathophysiological events that occur prior to the development of HCC in chronic HBV infection in humans. We have previously demonstrated that HBV envelope gene expression is decreased in regenerating hepatocytes and preneoplastic nodules early in the disease process and that expression of alpha-fetoprotein and the multidrug transporter gene mdr-III is activated in the tumors that develop in this model, but not prior to tumor development. In the current study, we examined the structure and expression of a large panel of dominant acting oncogenes and tumor suppressor genes in the liver at all stages of the disease process in order to determine the extent to which they contribute to hepatocarcinogenesis in these transgenic mice. To our surprise, no changes were observed in the structure or function of any of these genes, many of which are commonly activated in other rodent models of hepatocarcinogenesis but rarely activated in human HCC. These findings suggest that the HBV transgenic mouse model is different from most other rodent models of hepatocarcinogenesis and that it may relate more closely to the events involved in HBV-induced human hepatocarcinogenesis, where generalized chromosomal abnormalities are common, while structural and functional changes in most of the commonly studied positive-acting oncogenes examined herein are not. Since p53 and RB mutations have recently been reported to be late events in human hepatocarcinogenesis, the structural integrity of the RB locus and the absence of p53 mutations in the HBV transgenic mouse model suggest that they may represent a relatively early stage of hepatocellular tumorigenesis and that further manipulation of this model is warranted in order to more fully reproduce the molecular-genetic events that characterize HBV-induced HCC in humans.
在当前研究中，我们试图阐明在乙型肝炎病毒（HBV）包膜转基因小鼠模型中可能导致肝癌发生的分子机制。在该模型中，慢性肝细胞损伤和炎症会导致再生性增生，最终发展为染色体异常和肝细胞癌（HCC），从而重现了人类慢性HBV感染中HCC发生之前的许多病理生理事件。我们之前已经证明，在疾病过程早期，再生肝细胞和癌前结节中HBV包膜基因表达降低，并且在该模型中发生的肿瘤中，甲胎蛋白和多药转运蛋白基因mdr-III的表达被激活，但在肿瘤发生之前未被激活。在当前研究中，我们检查了疾病过程各个阶段肝脏中大量显性作用癌基因和肿瘤抑制基因的结构和表达，以确定它们在这些转基因小鼠肝癌发生中的作用程度。令我们惊讶的是，这些基因中没有任何一个的结构或功能发生变化，其中许多基因在其他肝癌发生的啮齿动物模型中通常被激活，但在人类HCC中很少被激活。这些发现表明，HBV转基因小鼠模型与大多数其他肝癌发生的啮齿动物模型不同，并且它可能与HBV诱导的人类肝癌发生中涉及的事件更密切相关，在人类肝癌发生中普遍存在全身性染色体异常，而本文研究的大多数常见的正向作用癌基因的结构和功能变化则不存在。由于最近报道p53和RB突变是人类肝癌发生中的晚期事件，HBV转基因小鼠模型中RB基因座的结构完整性和p53突变的缺失表明它们可能代表肝细胞肿瘤发生的相对早期阶段，因此有必要对该模型进行进一步操作，以便更充分地重现表征人类HBV诱导的HCC的分子遗传事件。
