镍是人类在职业和环境中广泛接触的一种致癌性金属，目前镍致癌机制研究主要是细胞实验、动物实验和病例对照研究，缺乏大样本的前瞻性队列研究。我们在镍致癌机制的前期研究中发现：镍冶炼暴露时间延长可导致 STAT/Cited2信号通路出现误调节（Misregulation），该现象不能用现有的信号通路理论解释。据此首次提出了“长期暴露于镍冶炼环境使肺癌基因激活调控通路基因甲基化模式出现变异，进而激活或抑制了相关的癌基因活性，最终导致该人群肺癌发生概率增高”的假说。在建立的全球首个大型镍暴露人群队列基础上，通过前瞻性队列研究观察长期镍暴露对转录激活因子STAT和转录共激活因子Cited2基因甲基化模式变异及其效应，结合巢式病例对照研究揭示肺癌患者STAT和Cited2启动子甲基化模式变异如何误调控原癌基因Nkx2.1和抑癌基因P53转录，为揭示镍致癌机制提供前瞻性队列人群研究的关键性证据和理论支撑。

Nickel is a metal of strong human toxicity and carcinogenicity contacted in the occupation and environment. Our earlier study on nickel carcinogenic mechanism in nickel smelting population found that nickel smelting extended exposure could lead to the STAT/ Cited2 signaling pathway appear mistake adjustment-Misregulation, and this kind of error adjustment could not be explained by existing theories of signaling pathways. Accordingly our hypothesis is that nickel smelting exposure in long-term could make the lung cancer gene activation factor Cited2 and regulation pathways STAT gene methylation patterns appear abnormal variation, then activating or inhibiting the related cancer gene activity, eventually lead to the population increased probability of lung cancer. This study will rely on the world's bigest nickel exposure occupational cohort, by a prospective cohort study is observing the long-term nickel exposure with nickel smelting environment how to effect on both the gene methylation patterns variation and its effect of transcriptional activation factor STAT and transcriptional activation factor Cited2, and combining the nested case-control study of patients with lung cancer to reveal the long-term exposured nickel environment how to change STAT and Cited2 promoter CpG island methylation pattern and how to participate in the transcriptional regulation of the original oncogene Nkx2.1 and tumor suppressor gene P53. The perspective study would provide key scientific evidence and theory for revealing nickel cancer molecular mechanisms.