MOLECULAR GENETICS OF AROMATIC AMINE INDUCED BLADDER CANCER

工作总结：膀胱癌通常与职业有关 暴露和/或吸烟。在人类膀胱癌中，P53失活 P53基因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第5-9号外显子 冷SSCP分析或限制性测序分析P53等位基因 个体聚合酶链式反应扩增芳香胺P53等位基因外显子5-8 诱发膀胱癌。同品系半合子p53基因缺陷小鼠 LacI中性报告基因在16-24岁内发生膀胱癌 并表现出剂量相关的LacI突变频率早些时候增加 在初次接触后30天。这演示了对 在P53缺失的情况下使用LacI基因突变的膀胱 突变。还需要进一步的研究来确定哪些关键的 在与p53相关的基因组稳定性降低的情况下，基因可能会发生改变 缺乏症。我们最近还观察到IGF-1信号可能起作用 卡路里限制减少在膀胱肿瘤发生中的作用 血清IGF-1水平升高抑制膀胱癌生长 细胞凋亡。我们缺乏关于IGF-1和IGF-1R在膀胱中作用的信息 癌症及其所涉及的信号通路。表皮生长因子受体的配体特异性 可能在膀胱癌发生过程中由EGF向TGFa转化，并增加 膀胱肿瘤进展率。我们需要检验这一假设 IGF-1和TGFa分别与IGF-1R和EGFR协同作用，从而 促进膀胱细胞增殖。如果这个模型与人类的模型一致 膀胱癌，这一模型的进一步发展将提供一个工具 用于研究改变易感性和风险的基因 以及更好地了解生物学以发展 干预和预防战略。

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.