HEPATOCARCINOGENESIS AND DRUG RESISTANCE GENE EXPRESSION

多药耐药/P-糖蛋白（mdr/pgp）是近年来发现的耐药基因， 基因在许多小鼠肝细胞癌（HCC）模型中过表达， 无论致癌方案如何。 这一发现表明mdr基因 表达可能是一个有用的表型标记，以检验这一假设， 在不同的HCC模型中， 聚集在肿瘤的发展中。 为了验证这一假设，我们在这里提出 用原位杂交和免疫细胞化学分析来研究 mdr基因在各种HCC模型中在单细胞水平的表达， 包括携带肝靶向表达B型肝炎的转基因小鼠 病毒大包膜蛋白基因和SV40 T抗原基因， HCC遵循同步和可预测的发病动力学。 这 这项研究可能有助于我们了解耐药性的演变， 肝癌发生 此外，这些小鼠HCC模型可以提供一种新的治疗方法。 用于多药耐药基因分子机制研究的吸引系统 在肿瘤发生过程中激活。 描绘分子生物学的方法 mdr基因在转录和/或转录水平的表达机制 在已建立的HCC衍生细胞系中的转录后水平， 提出了原代HCC细胞。 这些研究可能提供重要的 深入了解基因表达的分子基础， 肝癌发生 此外，我们建议厘定 mdr mRNA在人肝癌中的表达，希望获得对肝癌的临床前评估。 mdr基因表达在原发性耐药中的作用 这种疾病。 本研究具有临床相关性，可能导致 开发有效的抗人HCC的化疗策略。

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.