食管癌是发病率、死亡率较高的环境相关性恶性肿瘤，是一种多因素作用、多基因参与、多发展阶段的复杂性疾病。本项目建立在食管癌中HPV异常高暴露和miR-218特异性抑癌功能的前期研究基础上，以HPV协同亚硝胺诱导食管癌发生的分子机制为研究主线，结合人群暴露水平，构建HPV协同亚硝胺诱导食管癌的细胞和动物模型 。通过高通量转录组（RNA-seq）筛选分析，创新性的将HPV感染引入经典的亚硝胺致食管癌研究，重点观察miR-218及其靶基因调控的下游信号通路和关键环节变化，结合人群病例-对照研究进一步验证亚硝胺暴露、HPV感染和miR-218调控通路之间的关联强度，建立亚硝胺和HPV联合作用及环境因素与基因调控交互作用模式，以发现食管癌发生发展中的生物标志，初步探讨导致食管癌高发的环境因素及可能分子机制，为构建食管癌综合防制策略与措施提供科学依据。

Esophageal cancer is an environment-related malignancy with high incidence and mortality. Our preliminary data indicated that HPV was more highly exposed in esophageal cancer patients than healthy controls and miR-218 exerted a tumor-suppressive function in cancers. To elucidate the development of esophageal carcinoma and the related molecular mechanisms in carcinogenesis, the synergistic role of nitrosamines and HPV is the highlight according to type distribution and exposure levels of HPV in populations. At this point, we plan to build nitrosamine and HPV synergistically-induced cell and animal models of malignant transformation. The key genes and related pathways involved in malignant transformation are to be identified by high-throughput transcriptome analysis (RNA-seq) screening. The association of nitrosamine exposure level in drinking water, HPV infection and miR-218 expression will be verified in case-control study. Finally models of nitrosamine and HPV synergistically-induced esophageal cancer and gene-environment interaction are to be established in attempt to identify biomarkers of esophageal cancer, to explore the possible molecular mechanism of esophageal cancer, and finally to build a scientific and rational control strategies and measures for preventing esophageal cancer.