Yin Qinyan, Wang Xia, Fewell Claire, Cameron Jennifer, Zhu Hanqing, Baddoo Melody, Lin Zhen, Flemington Erik K
Tulane Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
J Virol. 2010 Jul;84(13):6318-27. doi: 10.1128/JVI.00635-10. Epub 2010 Apr 28.
MicroRNA miR-155 is expressed at elevated levels in human cancers including cancers of the lung, breast, colon, and a subset of lymphoid malignancies. In B cells, miR-155 is induced by the oncogenic latency gene expression program of the human herpesvirus Epstein-Barr virus (EBV). Two other oncogenic herpesviruses, Kaposi's sarcoma-associated herpesvirus and Marek's disease virus, encode functional homologues of miR-155, suggesting a role for this microRNA in the biology and pathogenesis of these viruses. Bone morphogenetic protein (BMP) signaling is involved in an array of cellular processes, including differentiation, growth inhibition, and senescence, through context-dependent interactions with multiple signaling pathways. Alteration of this pathway contributes to a number of disease states including cancer. Here, we show that miR-155 targets the 3' untranslated region of multiple components of the BMP signaling cascade, including SMAD1, SMAD5, HIVEP2, CEBPB, RUNX2, and MYO10. Targeting of these mediators results in the inhibition of BMP2-, BMP6-, and BMP7-induced ID3 expression as well as BMP-mediated EBV reactivation in the EBV-positive B-cell line, Mutu I. Further, miR-155 inhibits SMAD1 and SMAD5 expression in the lung epithelial cell line A549, it inhibits BMP-mediated induction of the cyclin-dependent kinase inhibitor p21, and it reverses BMP-mediated cell growth inhibition. These results suggest a role for miR-155 in controlling BMP-mediated cellular processes, in regulating BMP-induced EBV reactivation, and in the inhibition of antitumor effects of BMP signaling in normal and virus-infected cells.
微小RNA miR-155在包括肺癌、乳腺癌、结肠癌以及一部分淋巴系统恶性肿瘤在内的人类癌症中表达水平升高。在B细胞中，miR-155由人类疱疹病毒爱泼斯坦-巴尔病毒（EBV）的致癌潜伏基因表达程序诱导产生。另外两种致癌疱疹病毒，即卡波西肉瘤相关疱疹病毒和马立克氏病病毒，编码miR-155的功能同源物，这表明这种微小RNA在这些病毒的生物学特性和发病机制中发挥作用。骨形态发生蛋白（BMP）信号传导通过与多种信号通路的上下文依赖性相互作用，参与一系列细胞过程，包括分化、生长抑制和衰老。该信号通路的改变会导致包括癌症在内的多种疾病状态。在此，我们表明miR-155靶向BMP信号级联反应的多个组分的3'非翻译区，包括SMAD1、SMAD5、HIVEP2、CEBPB、RUNX2和MYO10。对这些介质的靶向作用导致在EBV阳性B细胞系Mutu I中，BMP2、BMP6和BMP7诱导的ID3表达以及BMP介导的EBV再激活受到抑制。此外miR-155在肺上皮细胞系A549中抑制SMAD1和SMAD5的表达，它抑制BMP介导的细胞周期蛋白依赖性激酶抑制剂p21的诱导，并逆转BMP介导的细胞生长抑制。这些结果表明miR-155在控制BMP介导的细胞过程、调节BMP诱导的EBV再激活以及抑制正常细胞和病毒感染细胞中BMP信号传导的抗肿瘤作用方面发挥作用。
