title: An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1alpha 3' untranslated region confers risk for hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common malignancy caused by environmental and genetic factors. MicroRNAs (miRNAs) are a class of short non-coding RNAs with posttranscriptional regulatory functions. They participate in diverse biological pathways and function as gene regulators. Genetic polymorphisms in 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding, with consequences on regulation of target genes thereby affecting the individual's cancer risk. We have previously predicted polymorphisms falling in miRNA-binding regions of cancer genes. We selected an insertion/deletion (Indel) polymorphism (rs3783553) in the 3' UTR of interleukin (IL)-1alpha (IL1A) for a case-control study in a Chinese population. With samples from 403 HCC patients and 434 healthy control individuals, strong evidence of association was observed for the variant homozygote. This association was validated in a second independent case-control study with 1074 HCC patients and 1239 healthy control individuals (odds ratio = 0.62; 95% confidence interval = 0.49-0.78). We further show that the 'TTCA' insertion allele for rs3783553 disrupts a binding site for miR-122 and miR-378, thereby increasing transcription of IL-1alpha in vitro and in vivo. These findings suggest that functional polymorphism rs3783553 in IL1A could contribute to HCC susceptibility. Considering IL-1alpha affects not only various phases of the malignant process, such as carcinogenesis, tumor growth and invasiveness, but also patterns of interactions between malignant cells and the host's immune system, our results indicated that IL-1alpha may be a promising target for immunotherapy, early diagnosis and intervention of HCC.
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Medical College, Soochow University, Suzhou 215123, Jiangsu, People's Repubic of China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Ding
authors.forename: Kang
authors.initials: K
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Bingnan
authors.initials: B
authors.lastname: Guo
authors.forename: Yueping
authors.initials: Y
authors.lastname: Shen
authors.forename: Debora
authors.initials: D
authors.lastname: Landi
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D012323:RNA Processing, Post-Transcriptional; D012306:Risk
chemical_list: D020413:3' Untranslated Regions; D053582:Interleukin-1alpha; C531907:MIRN122 microRNA, human; D035683:MicroRNAs