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  • Original Paper
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Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1

Oncogene volume 24, pages 6617–6625 (2005)Cite this article

Abstract

E-cadherin is a key cell adhesion molecule implicated as a tumor suppressor, which is frequently altered in hepatocellular carcinoma, especially in hepatitis B virus (HBV)-related tumors. Here, we report that HBV X protein (HBx) represses E-cadherin expression at the transcription level. Based on the differential effects of HBx natural variants, we determined that Lys-130 in the transactivation domain of HBx is critical for the E-cadherin repression. The repression effect of HBx was abolished after treatment with DNA methyltransferase inhibitor, 5′-Aza-2′dC. In addition, methylation-specific PCR analysis revealed that the CpG island 1 of E-cadherin promoter is hypermethylated by HBx. Furthermore, HBx induces DNA methyltransferase 1 expression by stimulating its transcription. Therefore, we conclude that HBx represses E-cadherin expression by inducing methylation-mediated promoter inactivation. The reduced E-cadherin expression results in dramatic morphological changes of the HBx-expressing cells. In addition, HBx-expressing cells aggregate poorly in suspension culture, reflecting their altered intercellular interactions. The biological significance was further demonstrated by the increased collagen invasion ability of HBx-expressing cells. Therefore, the present study suggests that HBx plays a role during hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

HBV:

hepatitis B virus

HBx:

HBV X protein

DNMT:

DNA methylatransferase

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

HBSS:

Hank's balanced salt solution

HCC:

hepatocellular carcinoma

MMP:

matrix metalloproteinase

MSP:

methylation-specific PCR

SDS:

sodium dodecyl sulfate

References

  • Anzola M . (2004). J. Viral. Hepat., 11, 383–393.

  • Baptista M, Kramvis A and Kew MC . (1999). Hepatology, 29, 946–953.

  • Benn J, Su F, Doria M and Schneider RJ . (1996). J. Virol., 70, 4978–4985.

  • Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F and Cornelisse C . (1996). Oncogene, 13, 1919–1925.

  • Bigey P, Ramchandani S, Theberge J, Araujo FD and Szyf M . (2000). Gene, 242, 407–418.

  • Block TM, Mehta AS, Fimmel CJ and Jordan R . (2003). Oncogene, 22, 5093–5107.

  • Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA . (2000). Nat. Cell Biol., 2, 76–83.

  • Chan CF, Yau TO, Jin DY, Wong CM, Fan ST and Ng IO . (2004). Clin. Cancer Res., 10, 4140–4149.

  • Chung TW, Lee YC and Kim CH . (2004). FASEB J., 18, 1123–1125.

  • Diao J, Garces R and Richardson CD . (2001). Cytokine Growth Factor Rev., 12, 189–205.

  • Feitelson MA and Duan LX . (1997). Am. J. Pathol., 150, 1141–1157.

  • Foty RA and Steinberg MS . (2004). Int. J. Dev. Biol., 48, 397–409.

  • Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D and Birchmeier W . (1991). J. Cell Biol., 113, 173–185.

  • Gorman CM, Merlino GT, Willingham MC, Pastan I and Howard BH . (1982). Proc. Natl. Acad. Sci. USA, 79, 6777–6781.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Hirohashi S . (1998). Am. J. Pathol., 153, 333–339.

  • Hirohashi S and Kanai Y . (2003). Cancer Sci., 94, 575–581.

  • Hsia CC, Yuwen H and Tabor E . (1996). Lancet, 348, 625–626.

  • Jia L, Wang XW and Harris CC . (1999). Int. J. Cancer, 80, 875–879.

  • Kanai Y, Ushijima S, Hui AM, Ochiai A, Tsuda H, Sakamoto M and Hirohashi S . (1997). Int. J. Cancer, 71, 355–359.

  • Kawanishi J, Kato J, Sasaki K, Fujii S, Watanabe N and Niitsu Y . (1995). Mol. Cell. Biol., 15, 1175–1181.

  • Kim CM, Koike K, Saito I, Miyamura T and Jay G . (1991). Nature, 351, 317–320.

  • Kwun HJ and Jang KL . (2004). Nucleic Acids Res., 32, 2202–2213.

  • Lara-Pezzi E, Gomez-Gaviro MV, Galvez BG, Mira E, Iniguez MA, Fresno M, Martinez-A C, Arroyo AG and Lopez-Cabrera M . (2002). J. Clin. Invest., 110, 1831–1838.

  • Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzalo M, Carretero M, Moreno-Otero R, Sanchez-Madrid F and Lopez-Cabrera M . (2001a). J. Hepatol., 34, 409–415.

  • Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F and Lopez-Cabrera M . (2001b). Oncogene, 20, 3323–3331.

  • Lara-Pezzi E, Serrador JM, Montoya MC, Zamora D, Yanez-Mo M, Carretero M, Furthmayr H, Sanxhez-Madrid F and Lopez-Cabrera M . (2001c). Hepatology, 33, 1270–1281.

  • Lee CW, Sorensen TS, Shikama N and La Thangue NB . (1998). Oncogene, 16, 2695–2710.

  • Matsumura T, Makino R and Mitamura K . (2001). Clin. Cancer Res., 7, 594–599.

  • Melki JR, Vincent PC, Brown RD and Clark SJ . (2000). Blood, 95, 3208–3213.

  • Miyasaka M . (1995). Clin. Orthop., 312, 10–18.

  • Nabi IR . (1999). J. Cell Sci., 112, 1803–1811.

  • Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB and Schuebel KE . (2000). Nature, 404, 1003–1007.

  • Sanders DS, Blessing K, Hassan GA, Bruton R, Marsden JR and Jankowski J . (1999). Mol. Pathol., 52, 151–157.

  • Santi D, Norment A and Garrett CE . (1984). Proc. Natl. Acad. Sci. USA, 81, 6996–6997.

  • Shih WL, Kuo ML, Chuang SE, Cheng AL and Doong SL . (2000). J. Biol. Chem., 275, 25858–25864.

  • Silye R, Karayiannakis AJ, Syrigos KN, Poole S, van Noorden S, Batchelor W, Regele H, Sega W, Boesmueller H, Krausz T and Pignatelli M . (1998). J. Pathol., 186, 350–355.

  • Takahashi K, Akahane Y, Hino K, Ohta Y and Mishiro S . (1998). Arch. Virol., 143, 2313–2326.

  • Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P and Buendia MA . (1997). Oncogene, 14, 395–404.

  • Tsai CN, Tsai CL, Tse KP, Chang HY and Chang YS . (2002). Proc. Natl. Acad. Sci. USA, 99, 10084–10089.

  • Venard V, Corsaro D, Kajzer C, Bronowicki JP and Le Faou A . (2000). J. Med. Virol., 62, 177–184.

  • Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR and Harris CC . (1994). Proc. Natl. Acad. Sci. USA, 91, 2230–2234.

  • Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Sturzbecher HW, Hoeijmakers JH and Harris CC . (1995). Cancer Res., 55, 6012–6016.

  • Watabe M, Nagafuchi A, Tsukita S and Takeichi M . (1994). J. Cell Biol., 127, 247–256.

  • Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P and Buendia MA . (2002). Hepatology, 36, 692–701.

  • Wheelock MJ and Johnson KR . (2003). Annu. Rev. Cell Dev. Biol., 19, 207–235.

  • Yoo YG, Oh SH, Park ES, Cho H, Lee N, Park H, Kim DK, Yu DY, Seong JK and Lee MO . (2003). J. Biol. Chem., 278, 39076–39084.

  • Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T and Hirohashi S . (1995). Proc. Natl. Acad. Sci. USA, 92, 7416–9419.

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Acknowledgements

This work was supported by a grant from Pusan National University. HJK was supported by a postdoctoral training fellowship from Pusan National University.

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  1. Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 609-735, Korea

    Jung-Ok Lee, Hyun Jin Kwun, Jin Kyu Jung, Kyung Hee Choi, Do Sik Min & Kyung Lib Jang

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Correspondence to Kyung Lib Jang.

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Lee, JO., Kwun, H., Jung, J. et al. Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24, 6617–6625 (2005). https://doi.org/10.1038/sj.onc.1208827

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