Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

RECK is a target of Epstein–Barr virus latent membrane protein 1

Oncogene volume 22, pages 8263–8270 (2003)Cite this article

Abstract

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 p38HOG 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • D'Errico A, Garbisa S, Liotta LA, Castronovo V, Stetler-Stevenson WG and Grigioni WF . (1991). Mod. Pathol., 4, 239–246.

  • Eliopoulos AG, Gallagher NJ, Blake SM, Dawson CW and Young LS . (1999). J. Biol. Chem., 274, 16085–16096.

  • Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffin M and Hammerschmidt W . (1999). EMBO J., 18, 3064–3073.

  • Hammarskjold ML and Simurda MC . (1992). J. Virol., 66, 6496–6501.

  • Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E and Rickinson A . (1991). Cell, 65, 1107–1115.

  • Himelstein BP, Canete-Soler R, Bernhard EJ, Dilks DW and Muschel RJ . (1994). Invas. Metast., 14, 246–258.

  • Horikawa T, Yoshizaki T, Sheen TS, Lee SY and Furukawa M . (2000). Cancer, 89, 715–723.

  • Hu LF, Chen F, Zhen QF, Zhang YW, Luo Y, Zheng X, Winberg G, Ernberg I and Klein G . (1995). Eur. J. Cancer, 5, 658–660.

  • Kieff E . (1995). N. Engl. J. Med., 333, 724–726.

  • Kieff E and Liebowitz D . (1990). Virology. Knipe DM and Fields BN (eds). Raven Press: New York, pp. 1889–1920.

    Google Scholar 

  • Kieser A, Kilger E, Gires O, Ueffin M, Kolch W and Hammerschmidt W . (1997). EMBO J., 16, 6478–6485.

  • Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS and Chung J . (2001). FASEB J., 15, 1953–1962.

  • Kim KR, Yoshizaki T, Miyamori H, Hasegawa K, Horikawa T, Furukawa M, Harada S, Seiki M and Sato H . (2000). Oncogene, 19, 1764–1771.

  • Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y and Noda MA . (1989). Cell, 56, 77–84.

  • Lee TH, Chuang LY and Hung WC . (2000). Oncogene, 19, 3766–3773.

  • Lin CT, Chan WY, Chen W, Huang HM, Wu HC, Hsu MM, Chuang SM and Wang CC . (1993). Lab. Invest., 68, 716–727.

  • Lin CT, Wong CI, Chan WY, Tzung KW, Ho JK, Hsu MM and Chuang SM . (1990). Lab. Invest., 62, 713–724.

  • Liu LT, Chang HC, Chiang LC and Hung WC . (2003). Cancer Res., 63, 3069–3072.

  • Miller G . (1990). Virology. Knipe DM and Fields BN (eds). Raven Press: New York, pp. 1921–1958.

    Google Scholar 

  • Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C and Noda M . (2001). Cell, 107, 789–800.

  • Pallesen G, Hamilton-Dutoit SJ, Rowe M, Lisse I, Ralfkiaer E, Sandvej K and Young LS . (1991). J. Pathol., 165, 289–299.

  • Pan MR and Hung WC . (2002). J. Biol. Chem., 277, 32775–32780.

  • Peng M and Lundgren E . (1992). Oncogene, 7, 1775–1782.

  • Roberts ML and Cooper NR . (1998). Virology, 240, 93–99.

  • Sasahara RM, Takahashi C and Noda M . (1999). Biochem. Biophys. Res. Commun., 264, 668–675.

  • Stetler-Stevenson WG, Aznavoorian S and Liotta LA . (1993). Annu. Rev. Cell Biol., 9, 541–573.

  • Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, Kitaura Y, Takai S, Sasahara RM, Horimoto A, Ikawa Y, Ratzkin BJ, Arakawa T and Noda M . (1998). Proc. Natl. Acad. Sci. USA, 95, 13221–13226.

  • Wang D, Liebowitz D and Kieff E . (1985). Cell, 43, 831–840.

  • Weiss LM, Chen YY, Liu XF and Shibata D . (1991). Am. J. Pathol., 139, 1259–1265.

  • Yang X, He Z, Xin B and Cao L . (2000). Oncogene, 19, 2002–2013.

  • Yoshizaki T, Sato H, Furukawa M and Pagano JS . (1998). Proc. Natl. Acad. Sci. USA, 95, 3616–3621.

Download references

Acknowledgements

We deeply thank Dr CT Lin for providing TW04 EBV-negative NPC cell line, and Dr YS Chang and Dr M Noda for providing the plasmids. We also thank Ms CH Fu for technical assistance. This study was supported by Grant NSC92-2314-B037-117 of the National Science Council of Republic of China to Wen-Chun Hung.

Author information

Authors and Affiliations

  1. Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Li-Teh Liu

  2. Department of Otolaryngology, Chang Gung University, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China

    Jyh-Ping Peng

  3. Department of Physiology, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Hui-Chiu Chang

  4. School of Technology for Medical Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Wen-Chun Hung

Authors
  1. Li-Teh Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jyh-Ping Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-Chiu Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Chun Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wen-Chun Hung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, LT., Peng, JP., Chang, HC. et al. RECK is a target of Epstein–Barr virus latent membrane protein 1. Oncogene 22, 8263–8270 (2003). https://doi.org/10.1038/sj.onc.1207157

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207157

Keywords

This article is cited by

Search

Advanced search

Quick links