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Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas

Oncogene volume 25, pages 2666–2673 (2006)Cite this article

Abstract

Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2′-deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P=0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P=0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.

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References

  • Abrams KL, Xu J, Nativelle-Serpentini C, Dabirshahsahebi S, Rogers MB . (2004). J Biol Chem 279: 15916–15928.

  • Akiyama Y, Watkins N, Suzuki H, Jair KW, van Engeland M, Esteller M et al. (2003). Mol Cell Biol 23: 8429–8439.

  • Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP . (1998). Adv Cancer Res 72: 141–196.

  • Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR et al. (1994). Cancer Res 54: 3845–3852.

  • Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB . (1999a). Nat Genet 21: 103–107.

  • Cameron EE, Baylin SB, Herman JG . (1999b). Blood 94: 2445–2451.

  • Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X et al. (2000). Nat Genet 24: 132–138.

  • Dai Z, Popkie AP, Zhu WG, Timmers CD, Raval A, Tannehill-Gregg S et al. (2004). Oncogene 23: 3521–3529.

  • Ghosh-Choudhury N, Choudhury GG, Harris MA, Wozney J, Mundy GR, Abboud SL et al. (2001). Biochem Biophys Res Commun 286: 101–108.

  • Ghosh-Choudhury N, Ghosh-Choudhury G, Celeste A, Ghosh PM, Moyer M, Abboud SL et al. (2000). Biochim Biophys Acta 1497: 186–196.

  • Hardwick JC, van den Brink GR, Bleuming SA, Ballester I, van den Brande JM, Keller JJ et al. (2004). Gasroenterology 126: 111–121.

  • Hay E, Lemonnier J, Modrowski D, Lomri A, Lasmoles F, Marie PJ . (2000). J Cell Physiol 183: 117–128.

  • Helvering LM, Sharp RL, Ou X, Geiser AG . (2000). Gene 256: 123–138.

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

  • Hogan BL . (1996). Genes Dev 10: 1580–1594.

  • Horvath LG, Henshall SM, Kench JG, Turner JJ, Golovsky D, Brenner PC et al. (2004). Prostate 59: 234–242.

  • Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM et al. (2001). Nat Genet 28: 184–187.

  • Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P et al. (1998). Science 28: 1036–1037.

  • Ide H, Yoshida T, Matsumoto N, Aoki K, Osada Y, Sugimura T et al. (1997). Cancer Res 57: 5022–5027.

  • Japanese Gastric Cancer Association (1998). Gastric Cancer 1: 10–24.

  • Jeffery TK, Upton PD, Trembath RC, Morrell NW . (2005). Am J Physiol Lung Cell Mol Physiol 288: L370–L378.

  • Jones PA, Baylin SB . (2002). Nat Rev Genet 3: 415–428.

  • Lauren P . (1965). Acta Pathol Microbiol Scand 64: 31–49.

  • Leung WK, Yu J, Ng EK, To KF, Ma PK, Lee TL et al. (2001). Cancer 91: 2294–2301.

  • Miyazaki H, Watabe T, Kitamura T, Miyazono K . (2004). Oncogene 23: 9326–9335.

  • Narita T, Saitoh K, Kamada T, Kuroiwa A, Mizutani M, Koike C et al. (2000). Development 127: 981–988.

  • Oda T, Kanai Y, Oyama T, Yoshiura K, Shimoyama Y, Birchmeier W et al. (1994). Proc Natl Acad Sci USA 91: 1858–1862.

  • Pouliot F, Labrie C . (2002). J Endocrinol 172: 187–198.

  • Pu H, Gao C, Yuasa T, Namba M, Kondo A, Inada K et al. (1999). In vitro Cell Dev Biol Anim 35: 488–490.

  • Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE et al. (2002). Nature 416: 552–556.

  • Smiraglia DJ, Plass C . (2002). Oncogene 21: 5414–5426.

  • Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP et al. (2002). Nat Genet 31: 141–149.

  • Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K et al. (1999). Cancer Res 59: 5438–5442.

  • van den Brink GR, Hardwick JC, Tytgat GN, Brink MA, Ten Kate FJ, van Deventer SJ et al. (2001). Gastroenterology 121: 317–328.

  • von Bubnoff A, Cho KW . (2001). Dev Biol 239: 1–14.

  • Wen XZ, Miyake S, Akiyama Y, Yuasa Y . (2004). Biochem Biophys Res Commun 316: 100–106.

  • Wong GA, Tang V, El-Sabeawy F, Weiss RH . (2003). Am J Physiol Endocrinol Metab 284: E972–E979.

  • Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW et al. (1988). Science 242: 1528–1534.

  • Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S . (1995). Proc Natl Acad Sci USA 92: 7416–7419.

  • Zimmerman LB, De Jesus-Escobar JM, Harland RM . (1996). Cell 86: 599–606.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (YY and YA). We also thank the Rotary-Yoneyama Scholarship, Japan, for the valuable support, and Astellas Pharma Inc. for generously providing the rhBMP-2.

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  1. X-Z Wen and Y Akiyama: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    X-Z Wen, Y Akiyama & Y Yuasa

  2. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    S B Baylin

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  1. X-Z Wen
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  2. Y Akiyama
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Correspondence to Y Yuasa.

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Wen, XZ., Akiyama, Y., Baylin, S. et al. Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas. Oncogene 25, 2666–2673 (2006). https://doi.org/10.1038/sj.onc.1209297

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