Skip to main content
SpringerLink
Log in

DNA Mismatch Repair Enzyme hMSH2 in Malignant Melanoma: Increased Immunoreactivity as Compared to Acquired Melanocytic Nevi and Strong MRNA Expression in Melanoma Cell Lines

  • Published:
The Histochemical Journal Aims and scope Submit manuscript

Abstract

Mutations in the mismatch DNA repair gene human MutS homologen 2 (hMSH2) are causative for microsatellite instability and carcinogenesis in various human tumours, including hereditary nonpolyposis colorectal cancer. Because microsatellite instability has been detected in malignant melanoma, we have investigated hMSH2 in melanocytic tumours. We found strong nuclear immunoreactivity for hMSH2 that was elevated in malignant melanoma and melanoma metastases as compared to acquired nevi. These findings suggest that increased genomic instability in malignant melanoma is associated with elevated protein levels of this DNA repair enzyme. hMSH2 is not exclusively regulated by proliferative activity in melanocytes, because there was no correlation between staining patterns of hMSH2 and the proliferation marker Ki-67. In contrast, immunoreactivity scores for hMSH2 and p53 were both upregulated in malignant melanocytic tumours. These findings support the concept that hMSH2 gene expression may be regulated in melanocytes by the p53 protein, as has been reported previously in other tissues. Using the reverse transcription-polymerase chain reaction, we detected strong hMSH2 mRNA expression in each of 8 melanoma cell lines analysed (highest amounts in SK-MEL-25 cells, lowest amounts in MML-I cells). In conclusion, our findings indicate that hMSH-2 may be of importance for genetic stability, tumorigenesis and progression of malignant melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Barnhill RL, Castresana JS, Rubio MP, Martin MT, Idoate M, Vazquez JJ, Thor AD (1994) P53 expression in cutaneous malignant melanoma: an immunohistochemical study of 87 cases of primary, recurrent and metastatic melanoma. Mod Pathol 7: 533–535.

    Google Scholar 

  • Bartek J, Bartkova J, Vojtesek B (1991) Aberrant expression of the p53 oncoprotein is a common feature of a wide spectrum of human malignancies. Oncogene 6: 1699–1703.

    Google Scholar 

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106: 761–771.

    Google Scholar 

  • Brüggen J, Macher E, Sorg C (1981) Expression of surface antigens and its relation to parameters of malignancy in human malignant melanoms. Cancer Immunol Immunother 10: 121–127.

    Google Scholar 

  • Brüggen J, Sorg C (1983) Detection of phenotypic differences on human malignant melanoma lines and their variant sublines with monoclonal antibodies. Cancer Immunol Immunother 15: 200–205.

    Google Scholar 

  • Burchill SW, Martin JC, Imai K, Ferrone S, Warner NL (1982) Heterogeneity of HLA-A, B, Ia-like, and melanoma-associated antigen expression by human melanoma cell lines analyzed with monoclonal antibodies and flow cytometry. Cancer Res 42: 4110–4115.

    Google Scholar 

  • Carey TE, Lloyd KO, Takahashi T, Travassos LR, Old LJ (1979) AU cell-surface antigen of human malignant melanoma: solubilization and partial characterization. Proc Natl Acad Sci USA 76: 2898–2902.

    Google Scholar 

  • Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162: 156–159.

    Google Scholar 

  • Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum Nature 218: 652–656.

    Google Scholar 

  • Cleaver JE (1969) Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc Natl Acad Sci USA 63: 428–435.

    Google Scholar 

  • Cristofolini M, Boi S, Girlando S, Zumiani G, Cristofolini P, Dalla Palma P, Doglioni C, Barbareschi M (1993) P53 protein expression in nevi and melanomas. Arch Dermatol 129: 739–743.

    Google Scholar 

  • Donehower LA, Bradley A (1993) The tumor suppressor p53. Biochem Biophys Acta 1155: 181–205.

    Google Scholar 

  • Ercolani L, Florence B, Denaro M, Alexander M (1988) Isolation and complete sequence of a functional human glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 30: 15335–15341.

    Google Scholar 

  • Fears TR, Scotto J, Schneiderman MA (1977) Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. Am J Epidemiol 105: 420–427.

    Google Scholar 

  • Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038.

    Google Scholar 

  • Harlow E, Williamson NM, Ralston R, Helfman DM, Adams TE (1985) Molecular cloning and in vitro expression of a cDNA clone for human cellular tumor antigen p53. Mol Cell Biol 5: 1601–1610.

    Google Scholar 

  • Jass JR, Smyrk TC, Srewart SM, Lane MR, Lanspa SJ, Lynch HT (1994) Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 14: 1631–1634.

    Google Scholar 

  • Katabuchi H, van Rees B, Lambers AR, Ronnett BM, Blazes MS, Leach FS, Cho KR, Hedrick L (1995) Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res 55: 5556–5560.

    Google Scholar 

  • Leach FS, Polyak K, Burrell M, Johnson KA, Hill D, Dunlop MG, Wyllie AH, Peltomaki P, de la Chapelle A, Hamilton SR, Kinzler KW, Vogelstein B (1996) Mutations of the human mismatch repair gene hMSH-2 in normal and neoplastic tissues. Cancer Res 56: 235–240.

    Google Scholar 

  • Lee JH, Welch DR (1997) Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int J Cancer 71: 1035–1044.

    Google Scholar 

  • Loeb LA(1994) Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 54: 5059–5063.

    Google Scholar 

  • Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch RJ, Cavalieri RJ, Boland CR (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104: 1535–1549.

    Google Scholar 

  • Meissauer A, Kramer MD, Hofmann M, Erkell LJ, Jacob E, Schirrmacher V, Brunner G (1991) Urokinase-type and tissue-type plasminogen activators are essential for in vitro invasion of human melanoma cells. Exp Cell Res 192: 453–459.

    Google Scholar 

  • Mellon I, Champe GN (1996) Products of DNA mismatch repair genes mutS and mutL are required for transcription-coupled nucleotideexcision repair of the lactose operon in Escherichia coli. Proc Natl Acad Sci USA 93: 1292–1297.

    Google Scholar 

  • Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN (1996) Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 272: 557–560.

    Google Scholar 

  • Milner J (1995) DNA damage, p53 and anticancer therapies. Nat Med 1: 879–880.

    Google Scholar 

  • Palombo F, Hughes M, Jiricny J, Truong O, Hsuan J (1994) Mismatch repair and cancer. Nature 367: 417.

    Google Scholar 

  • Prolla TA, Abuin A, Bradley A (1996) Mismatch repair deficient mice in cancer research. Semin Cancer Biol 7: 241–247.

    Google Scholar 

  • Quinn AG, Healy E, Rehman I, Sikkink S, Rees JL (1995) Microsatellite instability in human non-melanoma and melanoma skin cancer. J Invest Dermatol 104: 309–312. hMSH2 in malignant melanoma 467

    Google Scholar 

  • Rass K, Gutwein P, Müller SM, Welter C, Tilgen W, Reichrath J (2000) Immunohistochemical analysis of DNA mismatch repair enzyme hMSH-2 in normal human skin and basal cell carcinomas. Histochem J 32: 93–97.

    Google Scholar 

  • Reichrath J, Kamradt J, Zhu XH, Kong XF, Tilgen W, Holick MF (1999) Analysis of 1,25-dihydroxyvitamin D(3) receptors (VDR) in basal cell carcinoma. Am J Pathol 155: 583-589.

    Google Scholar 

  • Remmele W, Hildebrand U, Hienz HA, Klein PJ, Vierbuchen M, Behnken LJ, Heicke B, Scheidt E (1986) Comparative histological, histochemical, immunohistochemical and biochemical studies on oestrogen receptors, lectin receptors, and Barr bodies in human breast cancer. Virchows Arch A Pathol Anat Histopathol 409: 127–147.

    Google Scholar 

  • Runger TM, Emmert S, Schadendorf D, Diem C, Epe B, Hellfritsch D (2000) Alterations of DNA repair in melanoma cell lines resistant to cisplatin, fotemustine, or etoposide. J Invest Dermatol 114(1): 34–39.

    Google Scholar 

  • Sachs L (1997) Der Vergleich unabh¨angiger Stichproben gemessener Werte: Vergleich der Mittelwerte zweier kleiner Stichproben nach Lord. In: Sachs L, ed. Angewandte Statistik. Berlin, Heidelberg, New York, Tokyo: Springer Verlag.

    Google Scholar 

  • Sato M, Nishigori C, Zghal M, Yagi T, Takebe H (1993) Ultravioletspecific mutations in p53 gene in skin tumors in xeroderma pigmentosum patients. Cancer Res 1253: 2944–2946.

    Google Scholar 

  • Scherer SJ, Welter C, Zang KD, Dooley S (1996a) Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. Biochem Biophys Res Commun 221: 722–728.

    Google Scholar 

  • Scherer SJ, Seib T, Seitz G, Dooley S, Welter C (1996b) Isolation and characterization of the human mismatch repair gene hMSH2 promoter region. Hum Genet 97: 114–116.

    Google Scholar 

  • Scherer SJ, Maier SM, Seifert M, Hanselmann RG, Zang KD, Muller-Hermelink HK, Angel P, Welter C, Schartl M (2000) P53 and c-Jun functionally synergize in the regulation of the DNA repair gene hMSH2 in response to UV. J Biol Chem 275(48): 37469–37473.

    Google Scholar 

  • Setlow RB, Grist E, Thompson K, Woodhead AD (1993) Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci USA 90: 6666–6670.

    Google Scholar 

  • Stretch JR, Gatter KC, Ralfkiaer E, Lane DP, Harris AL (1991) Expression of mutant p53 in melanoma. Cancer Res 51: 5976.

    Google Scholar 

  • Suter L, Brüggen J, Bröcker EB, Sorg C (1985) A tumor-associated antigen expressed in melanoma cells with lower malignant potential. Int J Cancer 35: 787–791.

    Google Scholar 

  • Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM, Moslein G, Baker SM, Liskay RM, Burgart LJ, Honchel R, Halling KC (1996) Altered expression of hMSH-2 and hMLH-1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56: 4836–4840.

    Google Scholar 

  • Volkenandt M, Schlegel U, Nanus DM, Albino AP (1991) Mutational analysis of the human p53 gene in malignant melanoma. Pigment Cell Res 4: 35.

    Google Scholar 

  • Wang H, Lawrence CW, Li G-M, Hays JB (1999) Specific binding of human MSH2/MSH6 mismatch-repair protein heterodimers to DNA incorporating thymine-or uracil-containing UV light photoproducts opposite mismatched bases. J Biol Chem 274: 16894–16900.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany

    Knuth Rass, Paul Gutwein & Wolfgang Tilgen

  2. Department of Human Genetics, The Saarland University Hospital, Homburg/Saar, Germany

    Paul Gutwein & Cornelius Welter

  3. Institute of Radiobiology, Sanitätsakademie der Bundeswehr, Munich, Germany

    Viktor Meineke

  4. Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany

    Jörg Reichrath

Authors
  1. Knuth Rass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Gutwein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cornelius Welter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viktor Meineke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wolfgang Tilgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jörg Reichrath
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rass, K., Gutwein, P., Welter, C. et al. DNA Mismatch Repair Enzyme hMSH2 in Malignant Melanoma: Increased Immunoreactivity as Compared to Acquired Melanocytic Nevi and Strong MRNA Expression in Melanoma Cell Lines. Histochem J 33, 459–467 (2001). https://doi.org/10.1023/A:1014472314354

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014472314354

Keywords

Search

Navigation