miR-22 Promotes HBV-Related Hepatocellular Carcinoma Development in Males
miR-22 Promotes HBV-Related Hepatocellular Carcinoma Development in Males
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DOI：
10.1158/1078-0432.ccr-10-1734
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发表时间：
2011-09-01
影响因子：
11.5
通讯作者：
Sun, Beicheng
中科院分区：
文献类型：
--
作者：
Jiang, Runqiu;Deng, Lei;Sun, Beicheng
目的：已有报道表明IL-1α-MyD88-IL-6信号转导通路在二乙基亚硝胺(DEN)诱导的小鼠肝细胞癌的发生发展中起重要作用。目的：探讨白细胞介素1α(IL-1α)对人肝细胞癌发生发展的调控作用。方法：采集80例男性和36例女性患者的肝细胞癌组织、癌旁组织和正常组织标本。用实时定量聚合酶链式反应和免疫印迹法检测IL-1α、ERα、IL-6和MyD88的表达。用茎环聚合酶链式反应检测miR-22的表达。结果：IL-1α在男性癌旁组织中较正常组织高表达(P=0.025)，而在女性组织中表达不明显。男性癌旁组织中IL-1α表达升高与ERα表达降低呈线性关系(r=-0.616，P=0.004)。我们的结果还表明，雌激素(E2)对ERα过表达的肝癌细胞IL-1α的分泌有抑制作用。我们检测到miR-22在男性癌旁组织中的高表达(P=0.027)；此外，我们还发现miR-22通过靶向3‘-非翻译区而下调ERα的转录。在DEN诱导的模型中，IL-1α在萌芽肿瘤中高表达，并随着肝癌的发展逐渐降低。结论：男性肿瘤旁组织中miR-22的过度表达与ERα的表达下调有关，可能是通过减弱雌激素的保护作用而导致IL-1α的表达增加。这些结果可能解释了为什么乙肝病毒相关性肝癌在男性人群中的高发病率。临床癌症资源；17(17)；5593-603。(C)2011年AACR。
Purpose: Previous reports have shown that IL-1 alpha-MyD88-IL- 6 signaling is essential in promoting hepatocellular carcinoma (HCC) development in a diethylnitrosamine (DEN)- induced mouse model. We aimed to determine whether interleukin (IL)-1 alpha regulates HCC development in humans.Methods: HBV-associated HCC tissue, corresponding adjacent tissue, and normal tissue samples were obtained from 80 male and 36 female patients. IL-1 alpha, ER alpha, IL-6, and MyD88 were quantified by using real-time PCR and Western blot. Stem-loop PCR was used to quantify miR-22 expression. Luciferase reporter assays were used to study transcriptional regulation.Results: IL-1 alpha was highly expressed in male tumor adjacent tissue compared with normal tissue (P = 0.025); however, this was not the case for female subjects. A linear relationship was observed between increased IL-1 alpha and decreased ER alpha expression in male tumor adjacent tissue (r = - 0.616, P = 0.004). Our results also indicated that estrogen (E2) was suppressed upon IL-1 alpha secretion in ER alpha-overexpressed HCC cells. We detected high expression of miR-22 in male tumor adjacent tissue compared with controls (P = 0.027); furthermore, we showed that miR-22 downregulates ER alpha transcription by targeting the 3'- untranslated region. In the DEN-induced model, IL-1 alpha was highly expressed in sprouting tumors and gradually decreased in conjunction with HCC development.Conclusion: Overexpression of miR-22 in male tumor adjacent tissue was associated with down-regulated ER alpha expression, potentially by attenuating the protective effect of estrogen and causing increased IL-1 alpha expression. These results may explain the high incidence of HBV-associated HCC in the male population. Clin Cancer Res; 17(17); 5593-603. (C)2011 AACR.