RECK is a target of Epstein-Barr virus latent membrane protein 1.
Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) has been suggested to be involved in tumor metastasis. However, the molecular mechanism of LMP1-induced metastasis is largely unknown. In this study, we investigated the effect of LMP1 on the expression of RECK, a metastasis suppressor gene, in an EBV-negative nasopharyngeal carcinoma (NPC) cell line. Our data demonstrated that LMP1 induced downregulation of RECK via transcription repression in TW04 cells. In addition, we found that LMP1 acted via an Sp1 site to inhibit RECK promoter activity. We next studied the signaling pathway that mediated the effect of LMP1 on RECK expression. Our results showed that LMP1 potently stimulated the activity of extracellular signal-regulated kinases (ERKs) and inhibition of ERK activity by PD98059 antagonized LMP1-induced downregulation of RECK. Conversely, the c-Jun N-terminal kinase inhibitor SP600125 and p38(HOG) kinase inhibitor SB203580 had little effect. We also found that the expression of LMP1 increased the invasive ability of TW04 cells. The importance of RECK in LMP1-induced invasiveness was supported by three observations. First, restoration of RECK expression by PD98059 reduced LMP1-induced release of active MMP-9. Second, suppression of PD98059-induced RECK expression by small interference RNA abolished the inhibitory action of PD98059 on LMP1-induced invasiveness. Third, coexpression of RECK with LMP1 in TW04 cells effectively suppressed cell invasiveness induced by LMP1. Taken together, these results suggest that LMP1 inhibits RECK expression via the ERK/Sp1 signaling pathway and this inhibition is a critical step for LMP1-induced tumor metastasis.
Liu
Li-Teh
LT
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
Peng
Jyh-Ping
JP
Chang
Hui-Chiu
HC
Hung
Wen-Chun
WC
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016329:Sp1 Transcription Factor; D014763:Viral Matrix Proteins; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9