Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29
Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29
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宫颈癌发生过程中进展性 miRNA 表达谱及 miR-29 HPV 相关靶基因的鉴定
DOI：
10.1002/path.2873
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发表时间：
2011-08-01
影响因子：
7.3
通讯作者：
Xie, Xing
中科院分区：
文献类型：
--
作者：
Li, Yang;Wang, Fenfen;Xie, Xing
miRNA具有作用于不同下游基因的潜力，并且HPV感染组织的miRNA特征可以提供对HPV相关致癌作用的深入了解。我们着手分析HPV感染样本中的miRNA表达，并将其与体内宫颈癌发生谱中的组织学和等级特异性改变联系起来。共有31个miRNAs在正常宫颈组织中沿着持续表达，其中6个miRNAs在133个样本中得到验证。通过生物信息学分析，我们建立了一个假定的HPV相关的miRNA-mRNA调控网络，显示miR-29是最高度富集的。我们还发现YY 1和CDK 6均与E6/E7 RNA表达呈正相关，并被肿瘤抑制性miR-29靶向。miR-29参与HPV感染的证据在患者样本中和通过各种实验方法进一步验证。综上所述，我们的研究结果表明HPV至少部分通过重塑细胞miRNA的环境而具有致癌特性。miR-29通过YY 1和CDK 6促进HPV诱导的恶性转化，抑制细胞周期进程并诱导细胞凋亡，但miR-29在HPV感染细胞中的异常可能是通过间接方式调节的。版权所有（C）2011大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
miRNAs have the potential to act on diverse downstream genes, and miRNA signatures of HPV-infected tissues may provide insight into HPV-related carcinogenesis. We set out to profile miRNA expression in HPV-infected samples and relate this to histological and grade-specific alterations in the spectrum of cervical carcinogenesis in vivo. A total of 31 miRNAs showed significant and continuous expression along with the progression from normal cervical tissue to cancer, and six of them were validated in 133 samples. By bioinformatics analyses, we established a putative HPV-associated miRNA-mRNA regulatory network, showing that miR-29 is the most highly enriched. We also found that YY1 and CDK6 were both positively correlated with E6/E7 RNA expression and targeted by tumour-suppressive miR-29. Evidence of miR-29 involvement in HPV infection was further verified in patient samples and by various experimental approaches. Taken together, our results suggest that HPVs have oncogenic properties at least in part by reshaping the milieu of cellular miRNAs. miR-29 restrains cell cycle progression and induces apoptosis via YY1 and CDK6 promoting malignant transformation induced by HPV, although the abnormality of miR-29 in HPV-infected cells might be regulated in an indirect way. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.