title: Functional variants in TNFAIP8 associated with cervical cancer susceptibility and clinical outcomes.
abstract: 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.
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Ting-Yan
authors.initials: TY
authors.lastname: Shi
authors.forename: Xi
authors.initials: X
authors.lastname: Cheng
authors.forename: Ke-Da
authors.initials: KD
authors.lastname: Yu
authors.forename: Meng-Hong
authors.initials: MH
authors.lastname: Sun
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
authors.forename: Meng-Yun
authors.initials: MY
authors.lastname: Wang
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Chen
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhou
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002681:China; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D017239:Paclitaxel / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; C404190:TNFAIP8 protein, human; C053989:nedaplatin; D017239:Paclitaxel; D002945:Cisplatin