Critical role of the virus-encoded microRNA-155 ortholog in the induction of Marek's disease lymphomas.
Critical role of the virus-encoded microRNA-155 ortholog in the induction of Marek's disease lymphomas.
复制标题
DOI：
10.1371/journal.ppat.1001305
复制
发表时间：
2011-02
期刊：
影响因子：
6.7
通讯作者：
Nair V
中科院分区：
文献类型：
--
作者：
Zhao Y;Xu H;Yao Y;Smith LP;Kgosana L;Green J;Petherbridge L;Baigent SJ;Nair V
尽管许多癌基因在肿瘤转化中的作用已明确，但微小RNA（miRNAs）越来越多地与多种人类癌症相关联。在几种致癌疱疹病毒（如卡波西肉瘤相关疱疹病毒KSHV）中发现miRNAs，进一步凸显了病毒编码的miRNAs对其致癌能力的潜在作用。然而，尽管已确定了几个可能与癌症相关的基因作为其靶标，但在缺乏合适模型的情况下，很难证明病毒编码的miRNAs在肿瘤疾病（如KSHV诱导的疾病）中的直接体内作用。不过，鸡快速发作的马立克氏病（MD）淋巴瘤的优良自然疾病模型允许对病毒编码的miRNAs的致癌潜力进行研究。利用通过对马立克氏病病毒（MDV）致癌RB - 1B株的感染性细菌人工染色体（BAC）克隆进行反向遗传学改造的病毒，我们发现从病毒基因组中删除6个miRNA的簇1会消除病毒的致癌性。这种致癌性的丧失似乎主要是由于簇内的单个miRNA，即miR - M4（细胞miR - 155的直系同源物），因为其缺失或其种子区域内的2个核苷酸突变足以抑制淋巴瘤的诱导。通过表达miR - M4或细胞同源物gga - miR - 155的回复病毒挽救致癌表型，进一步证实了这种miR - 155直系同源物在致癌性中的决定性作用。这是首次在自然感染模型中证明病毒编码的miRNA在诱导肿瘤中的直接体内作用。此外，使用缺失miRNAs的病毒作为针对强毒MDV攻击的有效疫苗，为生产基因明确的减毒疫苗提供了前景。
微小RNA（miRNAs）存在于包括多种病毒在内的许多生物体的基因组中，属于一类小RNA分子，可作为基因表达的关键调节因子，影响包括癌症在内的各种生物过程和疾病。在所有的miRNAs中，miR - 155因其在包括鸡在内的许多物种中的直接致癌作用而有充分的文献记载。值得注意的是，分别由致癌的卡波西肉瘤相关疱疹病毒（KSHV）和马立克氏病病毒（MDV）编码的miR - K12 - 11和miR - M4已被证明是miR - 155的功能性直系同源物。没有KSHV诱导肿瘤的动物模型来研究miR - K12 - 11的致癌潜力。然而，在其天然鸡宿主中利用马立克氏病病毒（MDV）诱导淋巴瘤的优良模型中的重组突变病毒，我们证明了miR - M4对肿瘤诱导至关重要。这是第一项明确证明单个miRNA在体内动物模型中诱导癌症的直接作用的研究。gga - miR - 155挽救miR - M4缺失病毒致癌潜力的能力证明了这两种miRNAs致癌功能的保守性。此外，我们还表明，通过删除miRNAs而减毒的病毒可作为针对强毒病毒感染的疫苗，为生产新型分子定义的疫苗提供了前景。
Notwithstanding the well-characterised roles of a number of oncogenes in neoplastic transformation, microRNAs (miRNAs) are increasingly implicated in several human cancers. Discovery of miRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential of virus-encoded miRNAs to contribute to their oncogenic capabilities. Nevertheless, despite the identification of several possible cancer-related genes as their targets, the direct in vivo role of virus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate in the absence of suitable models. However, excellent natural disease models of rapid-onset Marek's disease (MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs. Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of MDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus. This loss of oncogenicity appeared to be primarily due to the single miRNA within the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutation within its seed region was sufficient to inhibit the induction of lymphomas. The definitive role of this miR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype by revertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155. This is the first demonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infection model. Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDV challenge, enables the prospects of generating genetically defined attenuated vaccines. MicroRNAs (miRNAs), encoded in the genomes of a number of organisms including several viruses, belong to a class of small RNA molecules that can function as key regulators of gene expression influencing various biological processes and diseases including cancer. Among all the miRNAs, miR-155 has been well documented for its direct role of oncogenesis in a number of species including chickens. Remarkably, miR-K12-11 and miR-M4, the miRNAs encoded by the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) and Marek's disease virus (MDV) respectively, have been shown to be functional orthologs of miR-155. There are no animal models of KSHV-induced tumors to examine the oncogenic potential of miR-K12-11. However, using recombinant mutant viruses in excellent models of MDV-induced lymphomas in their natural chicken hosts, we demonstrate that miR-M4 is critical for the induction of tumors. This is the first study that clearly demonstrates a direct role for a single miRNA in inducing cancer in an in vivo animal model. The ability of gga-miR-155 to rescue the oncogenic potential of miR-M4-deleted virus demonstrated the conservation of oncogenic functions the two miRNAs. Moreover, we show that virus attenuated by deleting the miRNAs can function as vaccines against virulent virus infection, enabling the prospects of generating novel molecularly-defined vaccines.
登录
查看更多内容
影响因子：
5.4
作者：
Skalsky, Rebecca L.;Samols, Mark A.;Renne, Rolf
通讯作者：
Renne, Rolf
影响因子：
64.8
作者：
Cullen, Bryan R.
通讯作者：
Cullen, Bryan R.
DOI：
10.1073/pnas.0404508101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Lupiani, B;Lee, LF;Reddy, SM
通讯作者：
Reddy, SM
影响因子：
5.4
作者：
Petherbridge, L;Howes, K;Nair, V
通讯作者：
Nair, V
影响因子：
5.4
作者：
Petherbridge, L;Brown, AC;Nair, VK
通讯作者：
Nair, VK