The Oncogenic MicroRNA OncomiR-21 Overexpressed during Marek's Disease Lymphomagenesis Is Transactivated by the Viral Oncoprotein Meq

Abstract

cGallid herpesvirus 2 (GaHV-2) is an oncogenic herpesvirus that causes T lymphoma in chicken. GaHV-2 encodes a basic leucine zipper (bZIP) protein of the AP-1 family, Meq. Upon formation of homo-or heterodimers with c-Jun, Meq may modulate the expression of viral and cellular genes involved in lymphomagenesis. GaHV-2 also encodes viral microRNAs (miRNAs) involved in latency and apoptosis escape. However, little is known about cellular miRNA deregulation during the development of GaHV-2-associated lymphoma. We determined the cellular miRNA expression profiles of chickens infected with a very virulent strain (RB-1B) or a vaccine strain (CVI988) or noninfected. Among the most deregulated cellular miRNAs, we focused our efforts on gga-miR-21, which is upregulated during GaHV-2 infection. We mapped the gga-miR-21 promoter to the 10th intron of the TMEM49 gene and found it to be driven by AP-1-and Ets-responsive elements. We show here that the viral oncoprotein Meq binds to this promoter, thereby transactivating gga-miR-21 expression. We confirmed that this miRNA targets chicken programmed death cell 4 (PDCD4) and promotes tumor cell growth and apoptosis escape. Finally, gga-miR-21 was overexpressed only during infection with a very virulent strain (RB-1B) and not during infection with a nononcogenic strain (CVI988), providing further evidence for its role in GaHV-2 lymphomagenesis. Our data therefore suggest an additional role for Meq in GaHV-2-mediated lymphomagenesis through the induction of miR-21 expression.

Identification of differentially expressed miRNAs through high-throughput sequencing in the chicken lung in response to Mycoplasma gallisepticum HS

“…miRNAs are involved in immune processes, the immune response and inflammation modulation (Baltimore et al, 2008;Lindsay, 2008) and certainly participate in various diseases of poultry, including avian influenza (Y et al, 2009), Marek's disease (X. Li et al, 2014;Stik et al, 2013), avian leucosis (H. Li et al, 2014;Q. Wang et al, 2013), infectious bursal disease (Y.-s. Wang et al, 2013), and ovarian carcinoma (Lee et al, 2012).…”

MicroRNAs in the Host Response to Viral Infections of Veterinary Importance

“…These miRNAs were found to target genes that are related to lymphomagenesis ( 134 ) (Table S1 in Supplementary Material). Stik et al ( 137 ) used white leghorn chicken experimentally inoculated with the oncogenic RB-1B strain as a model to investigate connections between the chicken miRNA response and the oncogenic nature of MDV. This study reported that gga-miR-21 was upregulated in chicken inoculated with the oncogenic strain, as compared to chicken vaccinated with the non-oncogenic strain CVI988 and non-infected chicken.…”

Marek΄s Disease: rapid progress in research with unclear biological implementations

“…Primary studies indicated that these miRNAs flank to the Meq oncogene and/or map to latency-associated transcripts that are antisense to the immediate-early ICP4 gene (Burnside, et al, 2006). Stick et al (2013) proposed that gga-miR-21 is upregulated during MDV-1 infection, indicating that Meq oncoprotein map to the relevant gga-miR-21 promoter of the TMEM49 gene. It was found that gga-miR-21 is overexpressed only upon infection with a very virulent RB1-B strain but not during infection with low pathogenic strain of MDV-1, CVI988/Rispens.…”