Abstract
During latency, herpesvirus infection results in the establishment of a dormant state in which a restricted set of viral genes are expressed. Together with alterations of the viral genome, several host genes undergo epigenetic silencing during latency. These epigenetic dysregulations of cellular genes might be involved in the development of cancer. In this context, Gallid alphaherpesvirus 2 (GaHV-2), causing Marek’s disease (MD) in susceptible chicken, was shown to impair the expression of several cellular microRNAs (miRNAs). We decided to focus on gga-miR-126, a host miRNA considered a tumor suppressor through signaling pathways controlling cell proliferation. Our objectives were to analyze the cause and the impact of miR-126 silencing during GaHV-2 infection. This cellular miRNA was found to be repressed at crucial steps of the viral infection. In order to determine whether miR-126 low expression level was associated with specific epigenetic signatures, DNA methylation patterns were established in the miR-126 gene promoter. Repression was associated with hypermethylation at a CpG island located in the miR-126 host gene epidermal growth factor like-7 (EGFL-7). A strategy was developed to conditionally overexpress miR-126 and control miRNAs in transformed CD4+ T cells propagated from Marek’s disease (MD) lymphoma. This functional assay showed that miR-126 restoration specifically diminishes cell proliferation. We identified CT10 regulator of kinase (CRK), an adaptor protein dysregulated in several human malignancies, as a candidate target gene. Indeed, CRK protein levels were markedly reduced by the miR-126 restoration.
Highlights
MicroRNAs are a class of endogenous, small non-coding RNAs of about22 nucleotides in length that govern post-transcriptional repression of target genes by binding to the 30 untranslated region (UTR) or gene bodies [1]
MiR-126 expression pattern was measured by qRT-Polymerase Chain Reaction (PCR) in a Gallid alphaherpesvirus 2 (GaHV-2) transformed tumor cell line (MSB-1) and cells derived from eight organs collected from non-infected birds
The highest expression was measured in highly vascularized organs with an expression yield up to 30,000-fold higher than that observed in the GaHV-2 transformed cell line
Summary
MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs of about22 nucleotides (nt) in length that govern post-transcriptional repression of target genes by binding to the 30 untranslated region (UTR) or gene bodies [1]. MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs of about. MiRNAs negatively regulate gene expression by decreasing messenger RNA (mRNA) stability and interfering with translation [2]. They play important roles in several biological processes such as cell proliferation, development, differentiation, and tumorigenesis [3,4]. An increasing number of studies show aberrantly expressed miRNAs in cancers. Misexpression of miRNAs mediates neoplastic transformation [8] and is intimately linked to lymphoma development in hematologic malignancies [9,10,11]. MiRNAs have been reported to be involved in virus-induced, in addition to non-infectious, forms of cancers [12].
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