Takahashi S, Ikeda Y, Kimoto N, Okochi E, Cui L, Nagao M, Ushijima T, Shirai T
First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
Mutat Res. 2000 Feb 14;447(2):275-80. doi: 10.1016/s0027-5107(99)00217-1.
Some chronic mechanical irritations induce cancers, and it is speculated that mutations are induced by increased rate of cell proliferation caused by the irritation. In this study, it was investigated using chronic mechanical irritation to urothelium caused by urolithiasis, whether mutations are really induced by such cell proliferation or not. Male rats transgenic for lacI (Big Blue(R) rats), in which lacI mutations accumulated in tissue can be measured, were fed 3% uracil, a component of RNA, to induce urolithiasis associated with papillomatosis, and eventually with bladder cancers. The frequency of independent mutations in the bladders of the treated rats showed 3-5 fold increases at weeks 10, 20, and 51 (P=0.01 at week 51) while the frequency was not elevated at week 2. The mutation frequencies in the control bladders ranged from 3 to 9x10(-6). In both groups, G to A transitions at CpG sites, indicative of spontaneous mutations, constituted the most prevalent mutations. Mechanical irritation caused by uracil was shown to induce a 3-5 fold increase of mutations, possibly through an elevation of spontaneous mutations by vigorous cell proliferation.
一些慢性机械刺激可诱发癌症，据推测，刺激引起的细胞增殖速率增加会诱发突变。在本研究中，利用尿石症对尿路上皮造成的慢性机械刺激，研究了突变是否真的由这种细胞增殖所诱发。对携带lacI基因的转基因雄性大鼠（大蓝鼠）进行实验，这种大鼠可检测组织中积累的lacI突变，给它们喂食3%的尿嘧啶（RNA的一种成分）以诱发与乳头瘤病相关的尿石症，并最终诱发膀胱癌。在第10周、20周和51周时，处理组大鼠膀胱中独立突变的频率增加了3至5倍（第51周时P=0.01），而在第2周时频率并未升高。对照组膀胱中的突变频率在3至9×10⁻⁶之间。在两组中，CpG位点处由G到A的转换，即自发突变的标志，是最常见的突变类型。结果表明，尿嘧啶引起的机械刺激可能通过活跃的细胞增殖提高自发突变率，从而使突变增加3至5倍。
