ROLE OF TUMOR SUPPRESSOR GENES AND ONCOGENES IN CHEMICAL CARCINOGENESIS

抑癌基因和癌基因在化学致癌中的作用

• 批准号: 3777501
• 负责人: J C BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3777501
• 关键词: Wilms' tumor; adenocarcinoma; chemical carcinogenesis; chromosome deletion; clone cells; cytogenetics; gene expression; genetic mapping; human genetic material tag; human tissue; hybrid cells; laboratory rat; lung neoplasms; metastasis; neoplasm /cancer genetics; oncogenes; prostate neoplasms; tissue /cell culture; transfection; tumor suppressor genes

There is increasing evidence for the existence of a family of tumor suppressor genes that are involved in different cancers. Using a technique known as microcell-mediated chromosome transfer, the Laboratory of Molecular Carcinogenesis, in collaboration with Dr. Mitsuo Oshimura (Tottori University, Japan), has mapped tumor suppressor genes involved in human and rodent cancers to chromosome 1 (endometrial cancer, fibrosarcomas), chromosome 3 (renal cancer, lung cancer), chromosome 6 (endometrial cancer), chromosome 7 (choriocarcinoma), chromosome 9 (endometrial cancer), and chromosome 11 (cervical cancer, Wilms' tumor, rhabdomyosarcoma, lung cancer, fibrosarcoma). To map tumor suppressor genes for lung adenocarcinomas, we have introduced various normal human chromosomes into the A549 tumor cell line by microcell-mediated chromosome transfer to test which chromosomes had the ability to suppress tumorigenicity. These results indicate that chromosome 3 and 11 can suppress the tumorigenicity of A549 lung adenocarcinoma cells. Previous studies using somatic cell hybridization of highly metastatic and non-metastatic rat prostatic cancer cells demonstrated that the resultant hybrids were non-metastatic if all of the parental chromosomes were retained. Somatic hybrid segregants which underwent non-random chromosomal losses reexpressed high metastatic ability. These results demonstrated that there are gene(s) whose expression can suppress metastatic ability of prostatic cancer cells. To identify the location of homologous gene(s) in the human, specific human chromosomes were introduced into highly metastatic rat prostatic cancer cells using the microcell-mediated chromosome transfer. Introduction of human chromosome 11 into highly metastatic rat prostate cancer cells results in suppression of metastatic ability without suppression of the in vivo growth rate or tumorigenicity of the hybrid cells. Spontaneous deletion of portions of human chromosome 11 in some of the clones delineated the minimal portion of human chromosome 11 capable of suppressing prostatic cancer metastases. A candidate gene for this metastasis suppressor was isolated.

越来越多的证据表明存在一个肿瘤家族 与不同癌症有关的抑制基因。 使用 一种称为微细胞介导的染色体转移技术， 分子致癌实验室，与Mitsuo博士合作 Oshimura（日本鸟取大学），已经绘制了肿瘤抑制因子， 与人类和啮齿动物1号染色体癌症有关的基因 （子宫内膜癌，纤维肉瘤），3号染色体（肾癌，肺癌） 癌症），染色体6（子宫内膜癌），染色体7 （绒毛膜癌），9号染色体（子宫内膜癌），和染色体 11例（宫颈癌，肾母细胞瘤，横纹肌肉瘤，肺癌， 纤维肉瘤）。 定位肺癌的肿瘤抑制基因 腺癌，我们已经引入了各种正常的人类染色体， 通过微细胞介导的染色体转移进入A549肿瘤细胞系 以测试哪些染色体具有抑制肿瘤发生的能力。 这些结果表明，3号和11号染色体可以抑制 A549肺腺癌细胞的致瘤性。 以前的研究 使用高转移性和非转移性的体细胞杂交 大鼠前列腺癌细胞证明， 如果保留了所有亲本染色体，则为非转移性。 体细胞杂种分离子经历了非随机的染色体 丢失再表达高转移能力。 这些结果证明 有一些基因的表达可以抑制转移能力 前列腺癌细胞。 确定同源基因的位置 在人类中，特定的人类染色体被引入到高度 转移性大鼠前列腺癌细胞，使用微细胞介导的 染色体转移 将人类11号染色体导入高度 转移性大鼠前列腺癌细胞导致转移性前列腺癌抑制 不抑制体内生长速率或致瘤性的能力 的混合细胞。 人类基因组部分的自发缺失 一些克隆中的11号染色体描绘了 具有抑制前列腺癌作用的人11号染色体 转移 这种转移抑制因子的候选基因是 与世隔绝