Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Carcinogenesis. 2013 Apr;34(4):770-8. doi: 10.1093/carcin/bgt001. Epub 2013 Jan 8.
Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is an anti apoptotic and pro-oncogenic signaling molecule involved in the process of immunity, carcinogenesis and tumor progression. Single nucleotide polymorphisms (SNPs) at microRNA-binding sites may change messenger RNA target gene function, thus leading to cancer susceptibility and tumor progression. In this study of 1584 cervical cancer cases and 1394 cancer-free female controls, we investigated associations between three potentially functional SNPs in TNFAIP8 family genes and cervical cancer risk as well as platinum resistance and clinical outcomes in Eastern Chinese women. We found that the TNFAIP8-rs11064 variant GG genotype was associated with an increased risk of cervical cancer compared with AA/AG genotypes (adjusted odds ratio = 2.16, 95% confidence interval = 1.16-4.03, P = 0.015). Further in vitro and ex vivo functional experiments demonstrated that the TNFAIP8-rs11064 variant G allele weakened the binding affinity of miR-22 to the TNFAIP8 3'-untranslated region (UTR) in four cancer cell lines, resulting in increased production of the TNFAIP8 protein in the patients' cervical tissues. In the survival subset, the high TNFAIP8 protein expression was significantly associated with both resistance to cisplatin and nedaplatin, recurrence and death from cervical cancer. Taken together, in the absence of information on human papillomavirus (HPV) infection, the TNFAIP8-rs11064 SNP may function by affecting the affinity of miR-22 binding to the 3'-UTR of TNFAIP8 and regulating TNFAIP8 expression, thus contributing to cervical cancer risk. Additionally, the increased TNFAIP8 protein expression may predict platinum resistance and clinical outcomes in cervical cancer patients. Larger, prospective studies with detailed HPV infection data are warranted to validate our findings.
肿瘤坏死因子-α诱导蛋白 8（TNFAIP8）是一种抗凋亡和致癌信号分子，参与免疫、癌变和肿瘤进展过程。微 RNA 结合位点的单核苷酸多态性（SNP）可能改变信使 RNA 靶基因的功能，从而导致癌症易感性和肿瘤进展。在这项对 1584 例宫颈癌病例和 1394 例无癌女性对照的研究中，我们研究了 TNFAIP8 家族基因中三个潜在功能 SNP 与宫颈癌风险以及华东女性铂类耐药和临床结局的关系。我们发现，与 AA/AG 基因型相比，TNFAIP8-rs11064 变异 GG 基因型与宫颈癌风险增加相关（调整后的优势比=2.16，95%置信区间=1.16-4.03，P=0.015）。进一步的体外和体内功能实验表明，TNFAIP8-rs11064 变异 G 等位基因削弱了 miR-22 与 4 种癌细胞系中 TNFAIP8 3'-非翻译区（UTR）的结合亲和力，导致患者宫颈组织中 TNFAIP8 蛋白的产生增加。在生存亚组中，高 TNFAIP8 蛋白表达与顺铂和奈达铂耐药、宫颈癌复发和死亡显著相关。总之，在缺乏人乳头瘤病毒（HPV）感染信息的情况下，TNFAIP8-rs11064 SNP 可能通过影响 miR-22 与 TNFAIP8 3'-UTR 的结合亲和力并调节 TNFAIP8 表达来发挥作用，从而导致宫颈癌风险增加。此外，TNFAIP8 蛋白表达增加可能预测宫颈癌患者的铂类耐药和临床结局。需要更大的、前瞻性的研究，并结合详细的 HPV 感染数据来验证我们的发现。
