Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature
Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature
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DOI：
10.1038/sj.onc.1202934
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发表时间：
1999-10-07
期刊：
影响因子：
8
通讯作者：
Fusenig, NE
中科院分区：
文献类型：
--
作者：
Boukamp, P;Popp, S;Fusenig, NE
紫外线辐射是非黑色素瘤皮肤癌的主要危险因素，会导致P53肿瘤抑制基因的特定突变和其他遗传变异。我们在这里提出，温度升高，如在晒伤地区发现的，可能也有助于皮肤癌的发生。永生化的人HaCaT皮肤角质形成细胞(具有UV型P53突变)连续暴露于40-C可重复地导致致瘤转化，并在肿瘤再培养后稳定地保持致瘤性。40摄氏度下的生长与PARP的出现有关，PARP是一种由DNA链断裂激活的酶，其水平与5Gy伽马辐射后的水平相对应。同时，比较基因组杂交(CGH)分析表明，细胞中染色体的得失在40℃时保持不变，而在37℃时基本不存在，除个别染色体异常外，所有肿瘤来源的细胞都显示出染色体物质的获得。11q，最小公共区域为11q13.2至q14.1。该区域的候选基因Cyclin DI在所有肿瘤来源的细胞中高表达，但Cyclin D1/CDK4/CDK6的活性没有增加。因此，这些数据表明，在这个相关的皮肤癌模型中，长期的热应激是一个潜在的致癌因素，通过诱导遗传不稳定导致选择以11q增益为特征的致瘤细胞来介导其作用。
UV-radiation is a major risk factor for non-melanoma skin cancer causing specific mutations in the p53 tumor suppressor gene and other genetic aberrations. We here propose that elevated temperature, as found in sunburn areas, may contribute to skin carcinogenesis as well. Continuous exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 40-C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors. Growth at 40 degrees C was correlated with the appearance of PARP, an enzyme activated by DNA strand breaks and the level corresponded to that seen after 5 Gy gamma-radiation. Concomitantly, comparative genomic hybridization (CGH) analyis demonstrated that chromosomal gains and losses a;ere present in cells maintained at 40 degrees C while largely absent at 37 degrees C, Besides individual chromosomal aberrations, all tumor-derived cells showed gain of chromosomal material on. 11q with the smallest common region being 11q13.2 to q14.1. Cyclin DI, a candidate gene of that region was overexpressed in all tumor-derived cells but cyclinD1/cdk4/cdk6 kinase activity was not increased. Thus, these data demonstrate that long-term thermal stress is a potential carcinogenic factor in this relevant skin cancer model, mediating its effect through induction of genetic instability which results in selection of tumorigenic cells characterized by gain of 11q.