GENETIC CONTROL OF MURINE HEPATOCARCINOGENESIS

本研究项目的主要重点是识别和识别 控制疾病易感性的特定基因的特征 近交系小鼠肝癌的发生。这个项目将有助于 阐明癌症易感性的一般机制将是 了解高危人群遗传变异的价值 用于癌症的发展。先前的研究导致了这种识别 Hcs基因座，这是导致Hcs高易感性的原因 C3H小鼠对肝脏肿瘤的诱导作用，并证明该基因 调节癌前和正常肝细胞的增殖。 本申请的头两个目的是针对 利用反向遗传技术对HCS基因进行分子特征分析 接近。Hcs基因的染色体位置将被确定。 C3H/HeJ小鼠与耐药小鼠杂交的动物分析 近交系小鼠的致癌物敏感度和DNA- 基于遗传标记的研究，包括内源性非嗜性小鼠白血病 病毒、限制性片段长度多态和微卫星。 包含hcs基因座的染色体区域的物理图谱将 通过对小鼠酵母基因组文库的分析构建 人造染色体。来自该区域的候选序列 在小鼠肝脏中的RNA水平表达将被评估，以便 鉴定编码hcs基因的cdna。第三个目标是调查 小鼠肝癌易感基因与肿瘤易感基因的相互作用 C-Ha-ras基因突变在肝癌发生中的作用 原癌基因。氨基甲酸乙烯酯治疗诱发肿瘤10例 对肝癌易感性不同的近交系菌株将 分析是否存在突变的c-Ha-ras等位基因。第四， DBA/2J男性高易感性的生物学和遗传学基础 将通过研究癌前病变的发展来调查小鼠 致癌物治疗动物的肝脏损伤，并试图 从基因上定位导致这种疾病敏感性的主要基因 用与使用的方法相似的方法诱导肝肿瘤 目的1.最后，肝肿瘤诱导的激素调节 将通过直接研究抑制作用来进行研究 雌激素对C57BL/6J、C3H/HeJ和C57BR/CDJ小鼠肝癌发生的影响 通过对老鼠和遗传学的研究得出了异常高的基础 雌性C57BR/CDJ小鼠对诱发肝癌的敏感性。

The primary focus of this research project is the identification and characterization of specific genes that control the susceptibility of inbred mice to hepatocarcinogenesis. This project will aid in elucidating general mechanisms of cancer susceptibility that will be of value in understanding genetic variation in human populations in risk for cancer development. Previous studies resulted in the identification of the Hcs locus, which is responsible for the high susceptibility of C3H mice to liver tumor induction, and the demonstration that this gene regulates the proliferation of preneoplastic and normal hepatocytes. The first two aims of the present application are directed toward the molecular characterization of the Hcs gene using a reverse genetic approach. The chromosomal location of the Hcs gene will be determined by analysis of animals from crosses between C3H/HeJ mice and resistant inbred mice for cosegregation between carcinogen sensitivity and DNA- based genetic markers, including endogenous nonectropic murine leukemia viruses, restriction fragment length polymorphisms, and microsatellites. A physical map of the chromosomal region containing the Hcs locus will be constructed by analysis of a mouse genomic library of yeast artificial chromosomes. Candidate sequences from the region that are expressed at the RNA level in mouse liver will be evaluated in order to identify a cDNA encoding the Hcs gene. The third aim is to investigate the interaction between mouse liver cancer susceptibility genes and the initiation of hepatocarcinogenesis by mutations induced in the c-Ha-ras proto-oncogene. tumors induced by treatment with vinyl carbamate in 10 inbred strains of varying susceptibilities to hepatocarcinogenesis will be analyzed for the presence of mutant c-Ha-ras alleles. Fourth, the biological and genetic basis for the high susceptibility of DBA/2J male mice will be investigated by studying the development of preneoplastic hepatic lesions in carcinogen-treated animals, and by attempting to genetically map the major gene responsible for the sensitivity of this strain to liver tumor induction by using methods similar to those used in Aim 1. Finally, the hormonal regulation of liver tumor induction will be investigated by directly studying the inhibitory effects of estrogen on hepatocarcinogenesis in C57BL/6J, C3H/HeJ, and C57BR/cdJ mice and by genetic studies of the basis for the unusually high susceptibility of female C57BR/cdJ mice to liver tumor induction.