MOLECULAR GENETICS OF AROMATIC AMINE INDUCED BLADDER CANCER

膀胱癌常常与职业有关。 暴露和/或吸烟。在人类膀胱癌中，失活 P53基因突变和杂合性丢失是 很普通。然而，我们没有观察到失活 冷SSCP分析p53等位基因外显子5-9的突变 聚合酶链式反应扩增基因外显子5-8的限制性测序 芳香胺诱发膀胱癌的P53等位基因研究P53基因缺失 以同系半合子小鼠为LacI中性报告基因 基因在16-24周内发展为膀胱癌并显示出剂量 早在30天后LacI突变频率的相关增加 最初的接触。这表明膀胱发生了突变。 在没有P53突变的情况下使用LacI基因突变。 还需要进一步的研究来确定哪些其他关键基因 在与p53相关的基因组稳定性降低的情况下可能发生改变 缺乏症。我们最近还观察到IGF-1信号 可能在膀胱肿瘤的发生和卡路里限制中起作用 降低血清IGF-1，抑制膀胱癌生长 通过增加细胞凋亡率。我们缺乏关于IGF-1和 IGF-1R在膀胱癌中的作用及其信号转导途径 牵涉其中。EGFR的配基特异性可能从EGF转移到TGFa 在膀胱癌发生中的作用及提高膀胱癌发生率 进步。我们需要检验IGF-1和TGFa的假设 分别与IGF-1R和EGFR协同作用，推动 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 用于研究改变易感性的基因和 风险以及对生物学的了解才能更好地发展 干预和预防战略。

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.