Abstract
E-cadherin plays an important role in maintaining tissue architecture. Loss of E-cadherin expression has often been associated with cancer metastasis. This study assessed the immuno-expression of E-cadherin and methylation of CDH1 and correlated them with clinical features in primary epithelial ovarian cancer. Moreover, epithelial ovarian cancer cell SKOV3 was used to explore the mechanism how the demethylating agent 5-Aza inhibited cancer metastasis. Of 80 patients with primary ovarian cancer, we found that decreased immunoexpression pattern of E-cadherin was associated with clinical stage, lymph node metastasis, and degree of differentiation. Methylation of CDH1 detected by MSP occurred frequently and was correlated with reduced expression of E-cadherin protein. 5-Aza treatment could lead to re-expression of functional E-cadherin, followed by decreased MMP-2 and MMP-9 activity and inhibition of cell invasion in SKOV3 cells. Therefore, we conclude that assessment of E-cadherin immunoreactivity or methylation of CDH1 may be a useful prognostic indicator in ovarian cancer, complementary to established prognostic factors. The mechanism underlying 5-Aza’s anti-metastasis activity is associated with restored functional expression of E-cadherin and decreased MMPs activity. Correction of aberrant DNA methylation by 5-Aza may provide a new strategy for ovarian cancer prevention and therapy.
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Abbreviations
- E-cadherin:
-
epithelial cadherin
- LCM:
-
laser capture microdissection
- WHO:
-
World Health Organization
- FIGO:
-
International Federation of Gynecology and Obstetrics system
- MMPs:
-
matrix metalloproteinases
References
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al (2006) Cancer statistics, 2006. CA Cancer J Clin 56(2):106–130
Berkenblit A, Cannistra SA (2005) Advances in the management of epithelial ovarian cancer. J Reprod Med 50(6):426–438
Naora H, Montell DJ (2005) Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer 5(5):355–366
Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198(1):11–26
Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251(5000):1451–1455
Kemler R (1993) From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 9(9):317–321
Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM et al (2000) E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst 92(7):569–573
Brinck U, Jacobs S, Neuss M, Tory K, Rath W, Kulle B et al (2004) Diffuse growth pattern affects E-cadherin expression in invasive breast cancer. Anticancer Res 24(4):2237–2242
Kallakury BV, Sheehan CE, Winn-Deen E, Oliver J, Fisher HA, Kaufman RP, Jr et al (2001) Decreased expression of catenins (alpha and beta), p120 CTN, and E-cadherin cell adhesion proteins and E-cadherin gene promoter methylation in prostatic adenocarcinomas. Cancer 92(11):2786–2795
Behrens J, Mareel MM, Van Roy FM, Birchmeier W (1989) Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol 108(6):2435–2447
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A et al (1991) E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113(1):173–185
Machado JC, Oliveira C, Carvalho R, Soares P, Berx G, Caldas C et al (2001) E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene 20(12):1525–1528
Cleton-Jansen AM (2002) E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Breast Cancer Res 4(1):5–8
Ji X, Woodard AS, Rimm DL, Fearon ER (1997) Transcriptional defects underlie loss of E-cadherin expression in breast cancer. Cell Growth Differ 8(7):773–778
Hennig G, Behrens J, Truss M, Frisch S, Reichmann E, Birchmeier W (1995) Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene 11(3):475–484
Yeh KT, Shih MC, Lin TH, Chen JC, Chang JY, Kao CF et al (2002) The correlation between CpG methylation on promoter and protein expression of E-cadherin in oral squamous cell carcinoma. Anticancer Res 22(6C):3971–3975
Kudo Y, Kitajima S, Ogawa I, Hiraoka M, Sargolzaei S, Keikhaee MR et al (2004) Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin Cancer Res 10(16):5455–5463
Kwon GY, Yoo BC, Koh KC, Cho JW, Park WS, Park CK (2005) Promoter methylation of E-cadherin in hepatocellular carcinomas and dysplastic nodules. J Korean Med Sci 20(2):242–247
Kanai Y, Ushijima S, Hui AM, Ochiai A, Tsuda H, Sakamoto M et al (1997) The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J Cancer 71(3):355–359
Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG (2000) Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem 275(4):2727–2732
Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF et al (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55(22):5195–5199
Li LC, Zhao H, Nakajima K, Oh BR, Ribeiro Filho LA, Carroll P et al (2001) Methylation of the E-cadherin gene promoter correlates with progression of prostate cancer. J Urol 166(2):705–709
Fujioka T, Takebayashi Y, Kihana T, Kusanagi Y, Hamada K, Ochi H et al (2001) Expression of E-cadherin and beta-catenin in primary and peritoneal metastatic ovarian carcinoma. Oncol Rep 8(2):249–255
Faleiro-Rodrigues C, Macedo-Pinto IM, Maia SS, Vieira RH, Lopes CS (2005) Biological relevance of E-cadherin–catenin complex proteins in primary epithelial ovarian tumours. Gynecol Obstet Invest 60(2):75–83
Patel IS, Madan P, Getsios S, Bertrand MA, MacCalman CD (2003) Cadherin switching in ovarian cancer progression. Int J Cancer 106(2):172–177
Sundfeldt K, Piontkewitz Y, Ivarsson K, Nilsson O, Hellberg P, Brannstrom M et al (1997) E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int J Cancer 74(3):275–280
Imai T, Horiuchi A, Shiozawa T, Osada R, Kikuchi N, Ohira S et al (2004) Elevated expression of E-cadherin and alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas. Hum Pathol 35(12):1469–1476
Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Ferreira VM, Lopes CS (2004) Association of E-cadherin and beta-catenin immunoexpression with clinicopathologic features in primary ovarian carcinomas. Hum Pathol 35(6):663–669
Risinger JI, Berchuck A, Kohler MF, Boyd J (1994) Mutations of the E-cadherin gene in human gynecologic cancers. Nat Genet 7(1):98–102
Rathi A, Virmani AK, Schorge JO, Elias KJ, Maruyama R, Minna JD et al (2002) Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res 8(11):3324–3331
Makarla PB, Saboorian MH, Ashfaq R, Toyooka KO, Toyooka S, Minna JD et al (2005) Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin Cancer Res 11(15):5365–5369
Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR et al (1996) Laser capture microdissection. Science 274(5289):998–1001
Scully R (ed) (1999) Histological typing of ovarian tumors. WHO international classification of tumours, 2nd edn. Springer, Berlin
Pecorelli S, Benedet JL, Creasman WT, Shepherd JH (1999) FIGO staging of gynecologic cancer. 1994–1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet 65(3):243–249
Hensley ML (2002) Epithelial ovarian cancer. Curr Treat Options Oncol 3(2):131–141
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826
Sheng S (2001) The urokinase-type plasminogen activator system in prostate cancer metastasis. Cancer Metastasis Rev 20(3–4):287–296
Graff JR, Greenberg VE, Herman JG, Westra WH, Boghaert ER, Ain KB et al (1998) Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle’s cell, and poorly differentiated human thyroid carcinoma. Cancer Res 58(10):2063–2066
Wong AS, Maines-Bandiera SL, Rosen B, Wheelock MJ, Johnson KR, Leung PC et al (1999) Constitutive and conditional cadherin expression in cultured human ovarian surface epithelium: influence of family history of ovarian cancer. Int J Cancer 81(2):180–188
Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J et al (1999) Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 59(5):1090–1095
Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feldmann G, Madelenat P et al (1997) Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. Hum Pathol 28(8):922–928
Hoffman AG, Burghardt RC, Tilley R, Auersperg N (1993) An in vitro model of ovarian epithelial carcinogenesis: changes in cell-cell communication and adhesion occurring during neoplastic progression. Int J Cancer 54(5):828–838
Veatch AL, Carson LF, Ramakrishnan S (1994) Differential expression of the cell–cell adhesion molecule E-cadherin in ascites and solid human ovarian tumor cells. Int J Cancer 58(3):393–399
Auersperg N, Pan J, Grove BD, Peterson T, Fisher J, Maines-Bandiera S et al (1999) E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci USA 96(11):6249–6254
Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16(4):168–174
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Yuecheng, Y., Hongmei, L. & Xiaoyan, X. Clinical Evaluation of E-cadherin Expression and its Regulation Mechanism in Epithelial Ovarian Cancer. Clin Exp Metastasis 23, 65–74 (2006). https://doi.org/10.1007/s10585-006-9020-3
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DOI: https://doi.org/10.1007/s10585-006-9020-3