MOLECULAR GENETICS OF AROMATIC AMINE INDUCED BLADDER CANCER

芳香胺诱发膀胱癌的分子遗传学

• 批准号: 6106601
• 负责人: J E FRENCH
• 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/6106601
• 关键词: aniline; bladder neoplasm; carcinogen testing; chemical carcinogen; chemical carcinogenesis; gene dosage; gene mutation; growth factor receptors; immunocytochemistry; insulinlike growth factor; laboratory mouse; molecular genetics; mutagen testing; mutagens; neoplasm /cancer genetics; polymerase chain reaction; single strand conformation polymorphism; transcription factor; tumor suppressor genes

Bladder cancer is often associated with occupational exposure and/or smoking. In human bladder cancer, inactivating p53 mutations and loss of heterozygosity at the p53 locus are common. However, we have failed to observe inactivating mutations in exons 5-9 of the p53 alleles by cold SSCP analysis or limited sequencing of individual PCR amplified exons 5-8 of the p53 alleles in aromatic amine induced bladder cancer. p53 deficient mice of the same strain hemizygous for the lacI neutral reporter gene develop bladder tumors within 16-24 weeks and show a dose related increase in lacI mutant frequency as early as 30 days after initial exposure. This demonstrates mutagenization of the bladder using the lacI gene mutations in the absence of p53 mutations. Further studies are required to determine what other critical genes may be altered under reduced genomic stability associated with p53 deficiency. We have also recently observed that IGF-1 signaling may play a role in bladder tumorigenesis and that calori restriction decreases serum IGF-1 and suppresses bladder cancer growth through increased apoptosis. We lack information on IGF-1 and IGF-1R roles in bladder cancer and the signaling pathways involved. Ligand specificity for EGFR may shift from EGF to TGFa during bladder tumorigenesis and increase the rate of bladder tumor progression. We need to test the hypothesis that IGF-1 and TGFa act synergistically with IGF-1R and EGFR, respectively, to drive bladder cell proliferation. If this model is consistent with human bladder cancer , further development of this model will provide a tool for investigation of the the genes that modify susceptibility and risk as well as understanding the biology better in order to develop strategies for intervention and prevention.

膀胱癌常与职业有关