Marek’s disease virus serotype 1 (MDV-1) is an important oncogenic α-herpesvirus that induces immunosuppressive and rapid-onset T-cell lymphomatous disease in poultry commonly referred to as Marek's disease (MD). As an excellent biomodel for the study of virally-induced cancers in natural hosts, MDV-1 encoded microRNAs (miRNAs) have been previously demonstrated with the potential roles to act as critical regulators in virus replication, latency, pathogenesis and especially in oncogenesis. Similar to the oncogenic γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), miR-M4-5p, the cellular microRNA-155 (miR-155) ortholog encoded by MDV-1, is also involved in MD oncogenesis. In lymphoblastoid cell lines derived from MDV-induced T-cell lymphomas, miR-M4-5p has been shown to be highly expressed and participate in inducing MD lymphomagenesis by regulating multiple signal pathways. Herein we report the new identification of the host WW domain-containing oxidoreductase (WWOX) as a biological target for miR-M4-5p. Further experiments revealed that as a critical oncomiRNA, miR-M4-5p promotes the proliferations of both chicken embryo fibroblast (CEF) and MSB-1 cells via suppressing cell apoptosis by targeting WWOX, a well-known tumor suppressor. Our data presents a novel insight in elucidating the regulatory mechanisms mediated by the viral analog of miR-155 that potentially contribute to MD tumorigenesis.

马立克氏病病毒血清型1（MDV-1）是一种重要的致癌性α疱疹病毒，可诱导家禽中免疫抑制和快速发作的T细胞淋巴瘤病，通常称为马立克氏病（MD）。作为研究天然宿主中病毒诱发的癌症的出色生物模型，以前已经证明MDV-1编码的microRNA（miRNA）具有潜在的作用，在病毒复制，潜伏期，发病机理，尤其是在肿瘤发生中起关键调节剂的作用。与致癌性γ-疱疹病毒类似，卡波西氏肉瘤相关疱疹病毒（KSHV）miR-M4-5p，由MDV-1编码的细胞microRNA-155（miR-155）直向同源物也参与了MD致癌作用。在源自MDV诱导的T细胞淋巴瘤的淋巴母细胞系中，已显示miR-M4-5p高表达并通过调节多种信号途径参与诱导MD淋巴瘤的发生。在此，我们报告了含有宿主WW域的氧化还原酶（（WWOX）作为miR-M4-5p的生物学靶标。进一步的实验表明，miR-M4-5p作为一种重要的oncomiRNA，可通过靶向WWOX（一种众所周知的肿瘤抑制因子）抑制细胞凋亡来促进鸡胚成纤维细胞（CEF）和MSB-1细胞的增殖。我们的数据在阐明由miR-155病毒类似物介导的调节机制中可能会导致MD肿瘤发生的过程中提供了新颖的见解。