Cellular oncomiR orthologue in EBV oncogenesis Sunil G. Babu n , Sanket Singh Ponia 1 , Dinesh Kumar 2 , Sangeeta Saxena 3 Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow 226 025, Uttar Pradesh, India article info Article history: Received 20 April 2011 Accepted 30 July 2011 Keywords: MicroRNA (miRNA) Virally encoded miRNA (vmiRNA) Epstein–Barr virus (EBV) EBV-associated gastric carcinoma (EBVaGC) 3 0 Untranslated region (3 0 UTR) OncomiRs (oncogenic miRNAs) abstract MicroRNAs are small non-coding RNAs that regulate gene expression at multiple levels. The discovery of virally encoded miRNAs attracted immense attention towards their role in viral replication and pathogenesis. Kaposi’s-sarcoma-associated herpes virus encodes miRNA that functions as an orthologue of human cellular miRNA, i.e., hsa-miR-155. Keeping the same view we extended the miRNA-homology search between the miRNAs of humans and Epstein–Barr virus. The In silico analyses shows that EBV encoded miR-BART-5 has a significant ‘seed’ sequence homology to hsa-miR-18 of humans. Further, the mRNA transcripts of the human genes involved in cellular growth could potentially be targeted by both viral as well as human miRNAs. The known etiological role of hsa-miR-18 as an oncomiR suggests that miR-BART-5 may function as viral oncomiR as observed in EBV-positive gastric carcinoma patients. & 2011 Elsevier Ltd. All rights reserved. 1. Introduction MicroRNAs are small non-coding functional RNAs of 21–25 nucleotides. These molecules mediate regulatory roles at both the posttranscriptional and transcriptional level. According to the degree of complementarity with their target in the 3 0 untranslated region (3 0 UTR), they inhibit translation of mRNA to proteins or initiate their degradation and may also result in gene silencing through RNA- directed DNA methylation (Chromatin Remodeling) [1]. It is known that miRNAs play a role in the regulation of genes involved in diverse processes such as development, differentiation, apoptosis and pro- liferation [2]. The miRNA alterations are also reported to be involved in the initiation and progression of human cancer. The miRNAs deemed to play a crucial role in the initiation and progression of human cancer, and those with a role in cancer are designated as oncogenic miRNAs (oncomiRs). Cellular miRNA genes have been identified that might represent downstream targets of activated oncogenic pathways, or that target protein coding genes involved in cancer [3]. The participation of several oncomiRs in tumorigenesis has been proved [4] (Table 1). Deregulation of oncomiRs is associated with genetic or epigenetic alterations, including deletion, amplifica- tion, point mutation and aberrant DNA methylation [3].The discovery of vmiRNAs, especially from a family of oncogenic herpes viruses, has raised the intriguing possibility of their role as critical modulators of viral oncogenesis. The advantages of a viral miRNA-based mechanism are multiple, as these miRNA molecules are small, non-immunogenic, and specific [5]. It is therefore not surprising that DNA viruses have been found to express several viral miRNAs [6]. Also from an evolutionary point of view, it is simpler to develop a regulatory antisense molecule rather than a regulatory protein. Lastly, the combination of a protein-mediated and miRNA-mediated posttran- scriptional regulation provides a tighter evasion strategy, which is more resistant to the host immune response. Herpes viruses can be classified into three subfamilies (a, b, or g) based on the sequence relatedness and virus biology. Till date, the microRNA Registry [7] contains miRNA sequences from only three members of the g (lymphotropic) subfamily – EBV and KSHV of humans and MHV68 of mice – and one from b- herpesvirus subfamily(HCMV or HHV5). EBV, causative agent of infectious mononucleosis and etiologically related to several types of malignancies like Burkitt’s lymphoma and gastric carci- noma (GC) [8], was the first virus known to encode miRNAs [9]. It expresses 39 different miRNAs [10,11] located in two clusters of the viral genome, near genes BART and BHRF, which are known to be activated during latent phase of the viral infection (Fig. 1a). As EBV encoded miRNAs reported to be differentially expressed in the different phases of viral life [12], it was suggested that they can target critical genes involved in apoptosis and cell growth control [13]. It is reported that in EBV-induced epithelial cell transformation the well-known oncogenes, such as those coding for LMP1, EBNA2, and EBNA3s, are not expressed [14]. The functions of the most of these vmiRNAs have yet to be established. Analysis of the closely related rhesus lymphocrypto- virus shows that seven of EBV miRNAs have been conserved with Simian virus across 413 million years of divergent evolu- tion, demonstrating evolutionary conservation of vmiRNAs [12]. Gottwein et al. [15] recently identified a viral miRNA functioning Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/cbm Computers in Biology and Medicine 0010-4825/$ - see front matter & 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.compbiomed.2011.07.007 n Corresponding author. Tel.: þ91 9455036926; fax: þ91 522 2441888. E-mail addresses: sunil_gos@yahoo.com (S.G. Babu), scholar20@gmail.com (S.S. Ponia), dinesh_biotech80@yahoo.co.in (D. Kumar), dr_sangeeta_saxena@yahoo.com (S. Saxena). 1 Tel.: þ91 9311849227. 2 Tel.: þ91 9990589644. 3 Tel.: þ91 9450645342. Computers in Biology and Medicine 41 (2011) 891–898