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.
Carcinogenesis. 2009 Dec;30(12):2064-9. doi: 10.1093/carcin/bgp283.
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.
肝细胞癌（HCC）是由环境和遗传因素引起的第五种最常见的恶性肿瘤。微小 RNA（miRNA）是一类具有转录后调控功能的短非编码 RNA。它们参与多种生物途径，并作为基因调节剂发挥作用。miRNA 靶 3'非翻译区（3'UTR）的遗传多态性改变了 miRNA 结合的强度，从而影响靶基因的调节，进而影响个体的癌症风险。我们之前预测了 miRNA 结合区癌症基因的多态性。我们选择了白细胞介素（IL）-1alpha（IL1A）3'UTR 中的插入/缺失（Indel）多态性（rs3783553）进行中国人群的病例对照研究。在 403 例 HCC 患者和 434 例健康对照个体的样本中，观察到该变体纯合子与疾病强烈相关。在第二个独立的 HCC 病例对照研究中，对 1074 例 HCC 患者和 1239 例健康对照个体进行了验证（比值比=0.62；95%置信区间=0.49-0.78）。我们进一步表明，rs3783553 的'TTCA'插入等位基因破坏了 miR-122 和 miR-378 的结合位点，从而增加了体外和体内 IL-1alpha 的转录。这些发现表明，IL1A 中的功能性多态性 rs3783553 可能导致 HCC 易感性。由于 IL-1alpha 不仅影响恶性过程的各个阶段，如癌变、肿瘤生长和侵袭性，还影响恶性细胞与宿主免疫系统之间的相互作用模式，我们的结果表明，IL-1alpha 可能是 HCC 免疫治疗、早期诊断和干预的有前途的靶点。
