Lambeth Luke S, Yao Yongxiu, Smith Lorraine P, Zhao Yuguang, Nair Venugopal
Division of Microbiology, Institute for Animal Health, Compton, Berkshire RG20 7NN, UK.
The Jenner Institute, University of Oxford, Compton, Berkshire RG20 7NN, UK.
J Gen Virol. 2009 May;90(Pt 5):1164-1171. doi: 10.1099/vir.0.007831-0. Epub 2009 Mar 4.
MicroRNAs (miRNAs) are a class of short RNAs that function as post-transcriptional suppressors of protein expression and are involved in a variety of biological processes, including oncogenesis. Several recent studies have implicated the involvement of miR-221 and miR-222 in tumorigenesis as these miRNAs are upregulated in a number of cancers and affect the expression of cell cycle regulatory proteins such as the cyclin-dependent kinase (cdk) inhibitor p27(Kip1). Marek's disease virus (MDV) is a highly oncogenic herpesvirus that affects poultry, causing acute neoplastic disease with lymphomatous lesions in several organs. MDV-encoded oncogenes such as Meq are directly implicated in the neoplastic transformation of T cells and have been well studied. More recently, however, the involvement of both host and virus-encoded miRNAs in the induction of MD lymphomas is being increasingly recognized. We analysed the miRNA expression profiles in the MDV-transformed lymphoblastoid cell line MSB-1 and found that endogenous miRNAs miR-221 and miR-222 were significantly upregulated. Demonstration of the conserved binding sites for these miRNAs in the chicken p27(Kip1) 3'-untranslated region sequence and the repression of luciferase activity of reporter constructs indicated that miR-221 and miR-222 target p27(Kip1) in these cells. We also found that overexpression of miR-221 and miR-222 decreased p27(Kip1) levels and that treatment with retrovirally expressed antagomiRs partially alleviated this suppression. These data show that an oncogenic herpesvirus, as in the case of many cancers, can exploit the miRNA machinery for suppressing cell cycle regulatory molecules such as p27(Kip1) in the induction and progression of T-cell lymphomas.
微小RNA（miRNA）是一类短RNA，作为蛋白质表达的转录后抑制因子发挥作用，并参与包括肿瘤发生在内的多种生物学过程。最近的几项研究表明，miR-221和miR-222参与肿瘤发生，因为这些miRNA在多种癌症中上调，并影响细胞周期调节蛋白如细胞周期蛋白依赖性激酶（cdk）抑制剂p27（Kip1）的表达。马立克氏病病毒（MDV）是一种高度致癌的疱疹病毒，可感染家禽，导致急性肿瘤性疾病，在多个器官出现淋巴瘤样病变。MDV编码的癌基因如Meq直接参与T细胞的肿瘤转化，并且已经得到了充分研究。然而，最近人们越来越认识到宿主和病毒编码的miRNA都参与了MD淋巴瘤的诱导。我们分析了MDV转化的淋巴母细胞系MSB-1中的miRNA表达谱，发现内源性miRNA miR-221和miR-222显著上调。这些miRNA在鸡p27（Kip1）3'-非翻译区序列中的保守结合位点的证实以及报告构建体荧光素酶活性的抑制表明，miR-221和miR-222在这些细胞中靶向p27（Kip1）。我们还发现，miR-221和miR-222的过表达降低了p27（Kip1）水平，并且用逆转录病毒表达的抗miR处理可部分缓解这种抑制。这些数据表明，与许多癌症一样，一种致癌疱疹病毒可以利用miRNA机制在T细胞淋巴瘤的诱导和进展中抑制细胞周期调节分子如p27（Kip1）。
