TNF-α/TNFR1凋亡信号复合物的遗传变异与宫颈癌易感性的关系及其分子机制研究

Cervical cancer is one of the most common cancers among women worldwide. Epidemiological and laboratory-based studies have identified the infection with high-risk HPV types as a necessary but not sufficient cause of cervical cancer. The prevalence of genital HPV infections in developing countries is very high in young women, but most of the infections regress without intervention. Genetic susceptibility may play important roles in the pathogenicity of high-risk HPV. Previous data have identified that HPV E6 oncoprotein can inhibit tumor necrosis factor alpha (TNF-α)/ TNF-α receptor 1 (TNFR1) mediated apoptosis by binding to the death domain of the TNFR1, preventing it from interacting with TRADD and accelerating the degradation of FADD. Single nucleotide polymorphisms (SNPs) in TNF-α/TNFR1 apoptotic complex genes may modulate genomic instability to high-risk HPV infection and contribute to inter-individual diversity in cervical cancer susceptibility. The aim of this relatively large sample-size case-control study is to investigate the associations between potentially functional SNPs in TNF-α/TNFR1 apoptotic complex genes and cervical cancer susceptibility, as well as the effect of gene-gene/ gene-environment (especially with high-risk HPV infection) interactions on cervical carcinogenesis. Further functional experiments and apoptotic detection analyses are performed to clarify the underlying mechanism of this association. This study can give an insight in biological mechanisms of TNF-α/TNFR1 apoptotic complex involving in the development of cervical cancer and may provide biomarkers for the disease risk predication.

高危型人乳头瘤病毒(HPV)是导致宫颈癌发生的必要条件，但仅少数持续感染者最终发展为宫颈癌，提示遗传差异可能影响女性感染HPV后的不同结局。有报道显示，HPV E6蛋白能靶向作用于肿瘤坏死因子α(TNF-α)/TNF-α受体1(TNFR1)凋亡信号复合体，保护细胞逃避其介导的凋亡途径。我们前期研究发现TNF-α诱导蛋白8的功能性单核苷酸多态性(SNP)与宫颈癌易感性相关。因此，TNF-α/TNFR1凋亡信号复合物的SNP可能影响高危型HPV的致病性，进而与宫颈癌的易感性相关。本研究通过大样本的病例-对照研究，筛选潜在功能性SNP进行基因型检测，结合高危型HPV感染，研究其与宫颈癌发病风险的相关性，并分析基因-基因/基因-环境交互作用对宫颈癌易感性的影响；同时对阳性关联SNP进行组织学和细胞学功能实验，探讨其与宫颈癌易感性的关联机制；并进行一系列细胞凋亡检测，研究其可能的分子机制。

【主要研究内容】.通过大样本病例-对照研究，发现TNF-α/TNFR1 凋亡信号相关基因的潜在功能性SNPs 与宫颈癌易感性相关，并在细胞学、组织学水平得到验证；同时，构建基因-基因、基因-环境交互作用模型。并在此基础上，继续深入开展探索性研究，通过构建HPV16/18 E6/E7特异性敲除的宫颈癌细胞系，进行表达谱芯片分析，阐明TNF-α/TNFR1 凋亡信号相关基因参与HPV16/18致癌基因E6/E7作用的分子机制。.【重要结果】.发现CASP7基因SNP位点通过调控CASP7基因mRNA及蛋白表达水平，与中国女性宫颈癌的易感性相关；另一方面，构建基因-环境交互作用模型，证实CASP7基因SNP位点间存在联合效应，并与环境暴露因素之间存在交互作用。.TNF-α基因rs1800629位点，通过调节TNF-α基因表达，激活PD-1/PD-L1免疫通路，参与HPV16/18致癌基因E6/E7的作用机制。.【科学意义】.探讨宫颈癌易感性相关的分子关联机制，为宫颈癌的早期预防及高危人群筛查、干预提供一定的理论基础。在临床实际工作中，基于一系列肿瘤遗传变异相关的成熟研究结果，开展妇科肿瘤的遗传易感性评估、高危人群预防，普惠大众。