Modulation of LMP1 protein expression by EBV-encoded microRNAs.
Epstein-Barr virus (EBV) was the first human virus found to encode microRNAs (miRNAs), but the function of these miRNAs has been obscure. Nasopharyngeal carcinoma (NPC) is associated with EBV infection, and the EBV-encoded LMP1 is believed to be a key factor in NPC development. However, detection of LMP1 protein in NPC is variable. Here, we report that EBV-encoded BART miRNAs target the 3' UTR of the LMP1 gene and negatively regulate LMP1 protein expression. These miRNAs also modulate LMP1-induced NF-kappaB signaling and alleviate the cisplatin sensitivity of LMP1-expressing NPC cells. Consistent with a previous study on the NPC C666-1 cell line and C15 xenograft, we found abundant expression of BART miRNAs in NPC tissues. Furthermore, DNA sequencing revealed that the 3' UTR of LMP1 is highly conserved in NPC-derived EBV isolates. The data provide insight into the discrepancy between LMP1 transcript and protein detection in NPC and highlight the role of the EBV miRNAs in regulating LMP1 downstream signaling to promote cancer development.
Lo
Angela Kwok Fung
AK
Viral Oncology Program, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
To
Ka Fai
KF
Lo
Kwok Wai
KW
Lung
Raymond Wai Ming
RW
Hui
Jan Wai Ying
JW
Liao
Gangling
G
Hayward
S Diane
SD
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015870:Gene Expression; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012334:RNA, Neoplasm / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics*
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D035683:MicroRNAs; D016328:NF-kappa B; D012334:RNA, Neoplasm; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D002945:Cisplatin