HEPATOCARCINOGENESIS AND DRUG RESISTANCE GENE EXPRESSION

多药耐药/P-糖蛋白(MDR/Pgp)已有报道。 基因在许多小鼠肝细胞癌模型中过表达， 而不考虑致癌疗法。这一发现表明多药耐药基因 表达可能是一个有用的表型标记来检验这一假设 不同肝癌模型中不同的肝癌发生途径可能是 会聚在肿瘤的发展过程中。为了检验这一假设，我们建议在这里 应用原位杂交和免疫细胞化学分析方法研究 多药耐药基因在不同肝癌模型单细胞水平的表达 包括携带乙肝病毒肝靶向表达的转基因小鼠 发展起来的病毒大包膜蛋白基因和SV40T抗原基因 肝细胞癌遵循同步和可预测的发病动力学。这 研究可能有助于我们理解耐药的演变。 肝癌的发生。此外，这些小鼠肝细胞癌模型可能提供一种 研究MDR基因分子机制的诱人体系 在肿瘤发生过程中的激活。描述分子的方法 多药耐药基因转录和/或表达的机制 已建立的肝细胞癌来源的细胞系和 提出了原代肝癌细胞的概念。这些研究可能会提供重要的 对基因表达的分子基础的洞察 肝癌的发生。此外，我们建议厘定 多药耐药基因在人肝细胞癌中的表达 多药耐药基因表达在肺癌内在耐药中的可能作用 这种病。这项研究具有临床相关性，并可能导致 抗击人肝癌的有效化疗策略的发展。

It has been reported that the multidrug-resistance/P-glycoprotein (mdr/pgp) gene is overexpressed in many mouse hepatocellular carcinoma (HCC) models, irrespective of carcinogenic regimens. This finding suggests that mdr gene expression may be a useful phenotypic marker to test the hypothesis that different hepatocarcinogenetic pathways in different HCC models may be converged in tumor development. To test this hypothesis, we propose here using in situ hybridization and immunocytochemical analyses to investigate mdr gene expression at the single cell level in various HCC models, including transgenic mice carrying liver targeted expression of hepatitis B viral large envelope protein gene and SV40 T-antigen gene which develope HCC following synchronous and predictable pathogenetic kinetics. This study may help us to understand the evolution of drug-resistance during hepatocarcinogenesis. Furthermore, these mouse HCC models may offer an attractive system for investigation on molecular mechanism of mdr gene activation during oncogenesis. Approaches to delineate the molecular mechanisms of mdr gene expression at transcriptional and/or posttranscriptional levels in established HCC-derived cell lines and primary HCC cells are proposed. These studies may provide important insights into the molecular basis of gene expression during hepatocarcinogenesis. In addition, we propose to determine the levels of mdr mRNA in human HCC in hoping to gain a preclinical assessment on the possible role of mdr gene expression in the intrinsic drug-resistance of this disease. This study is clinically relevant and may lead to development of effective chemotherapeutic strategy in combating human HCC.