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: 6162134
• 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/6162134
• 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

Summary of Work: 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.

工作总结：膀胱癌通常与职业性 暴露和/或吸烟。在人类膀胱癌中，失活p53 p53基因座的突变和杂合性丢失是常见的。 然而，我们没有观察到失活突变的外显子5-9， 通过冷SSCP分析或限制性测序， 单个PCR扩增芳香胺中p53等位基因的外显子5-8 诱发膀胱癌同系半合子p53缺陷小鼠 对于lacI中性报告基因，在16-24 周，并显示lacI突变频率的剂量相关性增加， 首次接触后30天。 这证明了 在p53缺失的情况下使用lacI基因突变的膀胱 突变。需要进一步的研究来确定其他关键的 在与p53相关的基因组稳定性降低的情况下， 缺陷 我们最近也观察到IGF-1信号可能在 在膀胱肿瘤发生中的作用， 血清IGF-1和抑制膀胱癌的生长，通过增加 凋亡 我们缺乏关于IGF-1和IGF-1 R在膀胱中作用的信息 癌症和相关的信号通路。EGFR配体特异性 可能在膀胱肿瘤发生过程中从EGF转变为TGF α， 膀胱肿瘤进展率。 我们需要验证一个假设 IGF-1和TGF α分别与IGF-1 R和EGFR协同作用， 驱动膀胱细胞增殖。如果这个模型与人类的 膀胱癌，该模型的进一步发展将提供一种工具， 用于研究改变易感性和风险的基因 以及更好地理解生物学， 干预和预防战略。