Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;95(9):741–744. doi: 10.1111/j.1349-7006.2004.tb03255.x

Methylation‐associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers

Toshio Takada 1,2, Yukiko Yagi 1, Takao Maekita 1, Masayoshi Imura 1,2, Shunsuke Nakagawa 2, Sai‐Wah Tsao 3, Kazuaki Miyamoto 1, Osamu Yoshino 2, Toshiharu Yasugi 2, Yuji Taketani 2, Toshikazu Ushijima 1,✉
PMCID: PMC11160044  PMID: 15471560

Abstract

The SFRP1 gene on chromosome 8p11.2 encodes a Wnt signaling antagonist, and was recently demonstrated to be a new tumor suppressor that is inactivated by promoter methylation in human colon cancers. Here, we analyzed promoter methylation of the SFRP1 gene in human ovarian cancers, in which loss of heterozygosity in 8p is frequently observed and involvement of the Wnt signaling pathway has been suggested. Methylation‐specific PCR (MSP) analysis showed that four of 13 ovarian cancer cell lines and two of 17 primary ovarian cancers had methylated SFRP1, while an immortalized ovarian epithelial cell line, HOSE, and seven ovarian endometrial cyst samples did not. In the four ovarian cancer cell lines with the methylation, SFRP1 was not expressed at all as determined by quantitative RT‐PCR analysis. A cell line with SFRP1 methylation, MCAS, was treated with a demethylating agent, 5‐aza‐2′‐deoxycytidine, and demethylation of the promoter and re‐expression of SFRP1 were observed. These results show that SFRP1 is inactivated by promoter methylation in human ovarian cancers, as well as colon cancers.

Abbreviations:

SFRP1

secreted frizzled‐related protein 1

References

  • 1. Guthrie D, Davy ML, Philips PR. A study of 656 patients with “early” ovarian cancer. Gynecol Oncol 1984; 17: 363–9. [DOI] [PubMed] [Google Scholar]
  • 2. Kanazawa K. Annual report on the incidence of ovarian cancers in 2001. Acta Obst Gynaecol Jpn 2004; 56: 91–114 (in Japanese). [Google Scholar]
  • 3. Duggan BD, Dubeau L. Genetics and biology of gynecologic cancer. Curr Opin Oncol 1998; 10: 439–46. [DOI] [PubMed] [Google Scholar]
  • 4. Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta‐catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res 2001; 61: 8247–55. [PubMed] [Google Scholar]
  • 5. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1–24. [DOI] [PubMed] [Google Scholar]
  • 6. Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Isola J, Butzow R. ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. Gynecol Oncol 2004; 92: 31–9. [DOI] [PubMed] [Google Scholar]
  • 7. Rathi A, Virmani AK, Schorge JO, Elias KJ, Maruyama R, Minna JD, Mok SC, Girard L, Fishman DA, Gazdar AF. Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high‐risk women. Clin Cancer Res 2002; 8: 3324–31. [PubMed] [Google Scholar]
  • 8. Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene 1999; 18: 2335–41. [DOI] [PubMed] [Google Scholar]
  • 9. Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER, Latif F. Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene 2001; 20: 1509–18. [DOI] [PubMed] [Google Scholar]
  • 10. Yoon JH, Dammann R, Pfeifer GP. Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int J Cancer 2001; 94: 212–7. [DOI] [PubMed] [Google Scholar]
  • 11. Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS. Purification and molecular cloning of a secreted, Frizzled‐related antagonist of Wnt action. Proc Natl Acad Sci USA 1997; 94: 6770–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Melkonyan HS, Chang WC, Shapiro JP, Mahadevappa M, Fitzpatrick PA, Kiefer MC, Tomei LD, Umansky SR. SARPs: a family of secreted apoptosis‐related proteins. Proc Natl Acad Sci USA 1997; 94: 13636–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002; 31: 141–9. [DOI] [PubMed] [Google Scholar]
  • 14. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Dong Chen W, Pretlow TP, Yang B, Akiyama Y, van Engeland M, Toyota M, Tokino T, Hinoda Y, Imai K, Herman JG, Baylin SB. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 2004; 36: 417–22. [DOI] [PubMed] [Google Scholar]
  • 15. Caldwell GM, Jones C, Gensberg K, Jan S, Hardy RG, Byrd P, Chughtai S, Wallis Y, Matthews GM, Morton DG. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res 2004; 64: 883–8. [DOI] [PubMed] [Google Scholar]
  • 16. Rask K, Nilsson A, Brannstrom M, Carlsson P, Hellberg P, Janson PO, Hedin L, Sundfeldt K. Wnt‐signalling pathway in ovarian epithelial tumours: increased expression of beta‐catenin and GSK3beta. Br J Cancer 2003; 89: 1298–304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Ueda M, Gemmill RM, West J, Winn R, Sugita M, Tanaka N, Ueki M, Drabkin HA. Mutations of the beta‐ and gamma‐catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. Br J Cancer 2001; 85: 64–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Okada S, Tsuda H, Takarabe T, Yoshikawa H, Taketani Y, Hirohashi S. Allelotype analysis of common epithelial ovarian cancers with special reference to comparison between clear cell adenocarcinoma with other histological types. Jpn J Cancer Res 2002; 93: 798–806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Gray JW, Suzuki S, Kuo WL, Polikoff D, Deavers M, Smith‐McCune K, Berchuck A, Pinkel D, Albertson D, Mills GB. Specific keynote: genome copy number abnormalities in ovarian cancer. Gynecol Oncol 2003; 88: S16–21; discussion S22–14. [DOI] [PubMed] [Google Scholar]
  • 20. Tsao SW, Mok SC, Fey EG, Fletcher JA, Wan TS, Chew EC, Muto MG, Knapp RC, Berkowitz RS. Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV‐E6E7 ORFs). Exp Cell Res 1995; 218: 499–507. [DOI] [PubMed] [Google Scholar]
  • 21. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation‐specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Miyamoto K, Asada K, Fukutomi T, Okochi E, Yagi Y, Hasegawa T, Asahara T, Sugimura T, Ushijima T. Methylation‐associated silencing of heparan sulfate D‐glucosaminyl 3‐O‐sulfotransferase‐2 (3‐OST‐2) in human breast, colon, lung and pancreatic cancers. Oncogene 2003; 22: 274–80. [DOI] [PubMed] [Google Scholar]
  • 23. Hess V, A'Hern R, Nasiri N, King DM, Blake PR, Barton DP, Shepherd JH, Ind T, Bridges J, Harrington K, Kaye SB, Gore ME. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004; 22: 1040–4. [DOI] [PubMed] [Google Scholar]
  • 24. Szyllo K, Tchorzewski H, Banasik M, Glowacka E, Lewkowicz P, Kamer‐Bartosinska A. The involvement of T lymphocytes in the pathogenesis of endometriotic tissues overgrowth in women with endometriosis. Mediators Inflamm 2003; 12: 131–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age‐related CpG island methylation in ulcerative colitis. Cancer Res 2001; 61: 3573–7. [PubMed] [Google Scholar]
  • 26. Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, Seki S, Fukushima S, Tsao M‐S, Sugimura T, Ushijima T. Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene in press. [DOI] [PubMed] [Google Scholar]
  • 27. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancers. Cancer Res 2002; 62: 6645–50. [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES