Modulation of LMP2A expression by a newly identified Epstein-Barr virus-encoded microRNA miR-BART22.
Infection with the Epstein-Barr virus (EBV) is a strong predisposing factor in the development of nasopharyngeal carcinoma (NPC). Many viral gene products including EBNA1, LMP1, and LMP2 have been implicated in NPC tumorigenesis, although the de novo control of these viral oncoproteins remains largely unclear. The recent discovery of EBV-encoded viral microRNA (miRNA) in lymphoid malignancies has prompted us to examine the NPC-associated EBV miRNA. Using large-scale cloning analysis on EBV-positive NPC cells, two novel EBV miRNA, now named miR-BART21 and miR-BART22, were identified. These two EBV-encoded miRNA are abundantly expressed in most NPC samples. We found two nucleotide variations in the primary transcript of miR-BART22, which we experimentally confirmed to augment its biogenesis in vitro and thus may underline the high and consistent expression of miR-BART22 in NPC tumors. More importantly, we determined that the EBV latent membrane protein 2A (LMP2A) is the putative target of miR-BART22. LMP2A is a potent immunogenic viral antigen that is recognized by the cytotoxic T cells; down-modulation of LMP2A expression by miR-BART22 may permit escape of EBV-infected cells from host immune surveillance. Taken together, we demonstrated that two newly identified EBV-encoded miRNA are highly expressed in NPC. Specific sequence variations on the prevalent EBV strain in our locality might contribute to the higher miR-BART22 expression level in our NPC samples. Our findings emphasize the role of miR-BART22 in modulating LMP2A expression, which may facilitate NPC carcinogenesis by evading the host immune response.
Lung
Raymond Wai-Ming
RW
Department of Anatomical and Cellular Pathology at Li Ka-Shing Institute of Health Science, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Tong
Joanna Hung-Man
JH
Sung
Ying-Man
YM
Leung
Pak-Sing
PS
Ng
David Chi-Heng
DC
Chau
Shuk-Ling
SL
Chan
Anthony Wing-Hung
AW
Ng
Enders Kai-On
EK
Lo
Kwok-Wai
KW
To
Ka-Fai
KF
D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009303:Nasopharyngeal Neoplasms / Q000821:virology*; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D019139:Tumor Escape; D014763:Viral Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D035683:MicroRNAs; D014763:Viral Matrix Proteins