Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Jul;80(10):1665–1671. doi: 10.1038/sj.bjc.6690579

hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer

A Ercoli 1, G Ferrandina 1, G Raspaglio 1, M Marone 1, N Maggiano 2, P Del Mastro 3, P Benedetti Panici 1, S Mancuso 1, G Scambia 1
PMCID: PMC2363099  PMID: 10408416

Abstract

Defects in DNA mismatch repair have been associated with both hereditary and sporadic forms of human cancer. Most of the attention has been focused on the incidence and genetics of mismatch repair defects, while little is known about the expression levels of the mismatch repair proteins and their significance in cancer cell biology. In this study, both the expression levels of hMSH2 and GTBP proteins were investigated by Western blotting in 20 untreated epithelial ovarian cancers. For these analyses, a commercial anti-hMSH2 monoclonal antibody and a newly generated mouse monoclonal anti-GTBP antibody were used. hMSH2 and GTBP proteins were detected by Western blotting in 19 out of 20 (95%) samples analysed and were found to be directly correlated (r = +0.51, P = 0.025). hMSH2 expression was significantly higher in ovarian cancer cells originating from solid tumours than from ascites (H = 4.5, P = 0.033), whereas GTBP content did not significantly differ according to the origin of cancer cells. No statistically significant differences were found in the distribution of hMSH2 and GTBP levels according to the age of the patients, grade of differentiation, histotype and extent of surgical debulking. The amount of hMSH2 protein was demonstrated to be significantly lower in stage IV than in stage III patients (H = 7.35, P = 0.007). Moreover, significantly lower hMSH2 levels were observed in non-responding patients compared to patients who achieved complete or partial response to cisplatin-based chemotherapy (H = 4.88, P = 0.027). Conversely, GTBP levels were not distributed differently according to stage of disease and chemotherapy response. Our study suggests a possible involvement of hMSH2 in ovarian cancer cell biology and susceptibility to chemotherapy. The possible biological and/or clinical role of GTBP expression in ovarian cancer patients remains to be elucidated. © 1999 Cancer Research Campaign

Keywords: hMSH2, GTBP, ovarian cancer, cisplatin

Full Text

The Full Text of this article is available as a PDF (512.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acharya S., Wilson T., Gradia S., Kane M. F., Guerrette S., Marsischky G. T., Kolodner R., Fishel R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13629–13634. doi: 10.1073/pnas.93.24.13629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aebi S., Kurdi-Haidar B., Gordon R., Cenni B., Zheng H., Fink D., Christen R. D., Boland C. R., Koi M., Fishel R. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. 1996 Jul 1;56(13):3087–3090. [PubMed] [Google Scholar]
  3. Arzimanoglou I. I., Lallas T., Osborne M., Barber H., Gilbert F. Microsatellite instability differences between familial and sporadic ovarian cancers. Carcinogenesis. 1996 Sep;17(9):1799–1804. doi: 10.1093/carcin/17.9.1799. [DOI] [PubMed] [Google Scholar]
  4. Boyer J. C., Umar A., Risinger J. I., Lipford J. R., Kane M., Yin S., Barrett J. C., Kolodner R. D., Kunkel T. A. Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res. 1995 Dec 15;55(24):6063–6070. [PubMed] [Google Scholar]
  5. Branch P., Hampson R., Karran P. DNA mismatch binding defects, DNA damage tolerance, and mutator phenotypes in human colorectal carcinoma cell lines. Cancer Res. 1995 Jun 1;55(11):2304–2309. [PubMed] [Google Scholar]
  6. Brown R., Hirst G. L., Gallagher W. M., McIlwrath A. J., Margison G. P., van der Zee A. G., Anthoney D. A. hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene. 1997 Jul 3;15(1):45–52. doi: 10.1038/sj.onc.1201167. [DOI] [PubMed] [Google Scholar]
  7. Dosch J., Christmann M., Kaina B. Mismatch G-T binding activity and MSH2 expression is quantitatively related to sensitivity of cells to methylating agents. Carcinogenesis. 1998 Apr;19(4):567–573. doi: 10.1093/carcin/19.4.567. [DOI] [PubMed] [Google Scholar]
  8. Duckett D. R., Drummond J. T., Murchie A. I., Reardon J. T., Sancar A., Lilley D. M., Modrich P. Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6443–6447. doi: 10.1073/pnas.93.13.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eshleman J. R., Markowitz S. D. Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol. 1995 Jan;7(1):83–89. [PubMed] [Google Scholar]
  10. Fink D., Nebel S., Aebi S., Zheng H., Cenni B., Nehmé A., Christen R. D., Howell S. B. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996 Nov 1;56(21):4881–4886. [PubMed] [Google Scholar]
  11. Glaab W. E., Tindall K. R. Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. Carcinogenesis. 1997 Jan;18(1):1–8. doi: 10.1093/carcin/18.1.1. [DOI] [PubMed] [Google Scholar]
  12. Hawn M. T., Umar A., Carethers J. M., Marra G., Kunkel T. A., Boland C. R., Koi M. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 1995 Sep 1;55(17):3721–3725. [PubMed] [Google Scholar]
  13. King B. L., Carcangiu M. L., Carter D., Kiechle M., Pfisterer J., Pfleiderer A., Kacinski B. M. Microsatellite instability in ovarian neoplasms. Br J Cancer. 1995 Aug;72(2):376–382. doi: 10.1038/bjc.1995.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kutteh W. H., Kutteh C. C. Quantitation of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 in the effusions of ovarian epithelial neoplasms. Am J Obstet Gynecol. 1992 Dec;167(6):1864–1869. doi: 10.1016/0002-9378(92)91788-c. [DOI] [PubMed] [Google Scholar]
  15. Leach F. S., Polyak K., Burrell M., Johnson K. A., Hill D., Dunlop M. G., Wyllie A. H., Peltomaki P., de la Chapelle A., Hamilton S. R. Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues. Cancer Res. 1996 Jan 15;56(2):235–240. [PubMed] [Google Scholar]
  16. Marra G., Chang C. L., Laghi L. A., Chauhan D. P., Young D., Boland C. R. Expression of human MutS homolog 2 (hMSH2) protein in resting and proliferating cells. Oncogene. 1996 Nov 21;13(10):2189–2196. [PubMed] [Google Scholar]
  17. Mello J. A., Acharya S., Fishel R., Essigmann J. M. The mismatch-repair protein hMSH2 binds selectively to DNA adducts of the anticancer drug cisplatin. Chem Biol. 1996 Jul;3(7):579–589. doi: 10.1016/s1074-5521(96)90149-0. [DOI] [PubMed] [Google Scholar]
  18. Modrich P., Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101–133. doi: 10.1146/annurev.bi.65.070196.000533. [DOI] [PubMed] [Google Scholar]
  19. Palombo F., Gallinari P., Iaccarino I., Lettieri T., Hughes M., D'Arrigo A., Truong O., Hsuan J. J., Jiricny J. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science. 1995 Jun 30;268(5219):1912–1914. doi: 10.1126/science.7604265. [DOI] [PubMed] [Google Scholar]
  20. Papadopoulos N., Nicolaides N. C., Liu B., Parsons R., Lengauer C., Palombo F., D'Arrigo A., Markowitz S., Willson J. K., Kinzler K. W. Mutations of GTBP in genetically unstable cells. Science. 1995 Jun 30;268(5219):1915–1917. doi: 10.1126/science.7604266. [DOI] [PubMed] [Google Scholar]
  21. Scambia G., Ranelletti F. O., Benedetti Panici P., Piantelli M., De Vincenzo R., Bonanno G., Ferrandina G., Isola G., Mancuso S. Synergistic antiproliferative activity of tamoxifen and cisplatin on primary ovarian tumours. Eur J Cancer. 1992;28A(11):1885–1889. doi: 10.1016/0959-8049(92)90029-2. [DOI] [PubMed] [Google Scholar]
  22. Umar A., Boyer J. C., Thomas D. C., Nguyen D. C., Risinger J. I., Boyd J., Ionov Y., Perucho M., Kunkel T. A. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J Biol Chem. 1994 May 20;269(20):14367–14370. [PubMed] [Google Scholar]
  23. Wilson T. M., Ewel A., Duguid J. R., Eble J. N., Lescoe M. K., Fishel R., Kelley M. R. Differential cellular expression of the human MSH2 repair enzyme in small and large intestine. Cancer Res. 1995 Nov 15;55(22):5146–5150. [PubMed] [Google Scholar]
  24. Yamada M., O'Regan E., Brown R., Karran P. Selective recognition of a cisplatin-DNA adduct by human mismatch repair proteins. Nucleic Acids Res. 1997 Feb 1;25(3):491–496. doi: 10.1093/nar/25.3.491. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES