Advertisement

Tumor Biology

, Volume 34, Issue 2, pp 621–628 | Cite as

Loss of MUC2 expression predicts disease recurrence and poor outcome in colorectal carcinoma

  • Adam Elzagheid
  • Fatma Emaetig
  • Abdelbaset Buhmeida
  • Matti Laato
  • Omran El-Faitori
  • Kari Syrjänen
  • Yrjö Collan
  • Seppo Pyrhönen
Research Article

Abstract

Clinical staging and histological grading after surgery have been the “gold standard” for predicting prognosis and planning for adjuvant therapy of colorectal cancer (CRC). With the recent development of molecular markers, it has become possible to characterize tumors at the molecular level. This is important for stage II and III CRCs, in which clinicopathological features do not accurately predict heterogeneity, e.g., in their tumor response to adjuvant therapy. In the present study, archival samples from 141 patients with stage I, II, III, or IV CRC treated during 1981–1990 at Turku University Hospital (Finland) were used (as microarray blocks) to analyze MUC2 expression by immunohistochemistry. Altogether, 49.7 % of all tumors were positive for MUC2. There was no significant correlation between MUC2 expression and age (P < 0.499), tumor invasion (P < 0.127), tumor staging (P < 0.470), histological grade (P < 0.706), lymph node involvement (P < 0.854), or tumor metastasis (P < 0.586). However, loss of MUC2 expression was significantly associated with disease recurrence (P < 0.031), tumor localization (P < 0.048), and with borderline significance with gender (P < 0.085). In univariate (Kaplan–Meier) survival analysis, positive MUC2 significantly predicted longer disease-free survival (DFS) and disease-specific survival (DSS) as well. However, in multivariate (Cox) survival analysis, MUC2 lost its power as an independent predictor of DFS and DSS. Our results implicate the value of MUC2 expression in predicting disease recurrence and long-term survival in CRC.

Keywords

MUC2 expression Colorectal cancer Prognosis Recurrence Adjuvant therapy 

Notes

Acknowledgments

The authors would like to thank the National Scientific Research Authority, Tripoli, Libya, for supporting and funding this project.

Conflicts of interest

None

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.PubMedCrossRefGoogle Scholar
  2. 2.
    Heinzerling JH, Anthony T, Livingston EH, Huerta S. Predictors of distant metastasis and mortality in patients with stage II colorectal cancer. Am Surg. 2007;73(3):230–8.PubMedGoogle Scholar
  3. 3.
    Huerta S, Goulet EJ, Livingston EH. Colon cancer and apoptosis. Am J Surg. 2006;191(4):517–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Chung DC. Molecular prognostic markers and colorectal cancer: the search goes on. Gastroenterology. 1998;114(6):1330–2.PubMedCrossRefGoogle Scholar
  5. 5.
    Offit K. Genetic prognostic markers for colorectal cancer. N Engl J Med. 2000;342(2):124–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Gum JR, Byrd JC, Hicks JW, Toribara NW, Lamport DT, Kim YS. Molecular cloning of human intestinal mucin cDNAs. Sequence analysis and evidence for genetic polymorphism. J Biol Chem. 1989;264(11):6480–7.PubMedGoogle Scholar
  7. 7.
    Fontenot JD, Tjandra N, Bu D, Ho C, Montelaro RC, Finn OJ. Biophysical characterization of one-, two-, and three-tandem repeats of human mucin (muc-1) protein core. Cancer Res. 1993;53(22):5386–94.PubMedGoogle Scholar
  8. 8.
    Gendler SJ, Spicer AP. Epithelial mucin genes. Annu Rev Physiol. 1995;57:607–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Audie JP, Janin A, Porchet N, Copin MC, Gosselin B, Aubert JP. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem. 1993;41(10):1479–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Audie JP, Tetaert D, Pigny P, Buisine MP, Janin A, Aubert JP, Porchet N, Boersma A. Mucin gene expression in the human endocervix. Human Reproduction (Oxford, England). 1995;10(1):98–102.CrossRefGoogle Scholar
  11. 11.
    Park SY, Roh SJ, Kim YN, Kim SZ, Park HS, Jang KY, Chung MJ, Kang MJ, Lee DG, Moon WS. Expression of MUC1, MUC2, MUC5AC and MUC6 in cholangiocarcinoma: prognostic impact. Oncol Rep. 2009;22(3):649–57.PubMedGoogle Scholar
  12. 12.
    Kwon JA, Lee SY, Ahn EK, Seol SY, Kim MC, Kim SJ, Kim SI, Chu IS, Leem SH. Short rare MUC6 minisatellites-5 alleles influence susceptibility to gastric carcinoma by regulating gene. Hum Mutat. 2010;31(8):942–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bobek LA, Tsai H, Biesbrock AR, Levine MJ. Molecular cloning, sequence, and specificity of expression of the gene encoding the low molecular weight human salivary mucin (MUC7). J Biol Chem. 1993;268(27):20563–9.PubMedGoogle Scholar
  14. 14.
    McGuckin MA, Walsh MD, Hohn BG, Ward BG, Wright RG. Prognostic significance of MUC1 epithelial mucin expression in breast cancer. Hum Pathol. 1995;26(4):432–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Hanski C, Hofmeier M, Schmitt-Graff A, Riede E, Hanski ML, Borchard F, Sieber E, Niedobitek F, Foss HD, Stein H, et al. Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary. J Pathol. 1997;182(4):385–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Dong Y, Walsh MD, Cummings MC, Wright RG, Khoo SK, Parsons PG, McGuckin MA. Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours. J Pathol. 1997;183(3):311–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Blank M, Klussmann E, Kruger-Krasagakes S, Schmitt-Graff A, Stolte M, Bornhoeft G, Stein H, Xing PX, McKenzie IF, Verstijnen CP, et al. Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types. Int J Cancer. 1994;59(3):301–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Elzagheid A, Algars A, Bendardaf R, Lamlum H, Ristamaki R, Collan Y, Syrjanen K, Pyrhonen S. E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome. World J Gastroenterol. 2006;12(27):4304–9.PubMedGoogle Scholar
  19. 19.
    Buhmeida A, Hilska M, Elzagheid A, Laato M, Collan Y, Syrjanen K, Pyrhonen S. DNA image cytometry predicts disease outcome in stage II colorectal carcinoma. Anticancer Res. 2009;29(1):99–106.PubMedGoogle Scholar
  20. 20.
    Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjanen S, Syrjanen K, Collan Y, Pyrhonen S. MMP-9 (gelatinase B) expression is associated with disease-free survival and disease-specific survival in colorectal cancer patients. Cancer Invest. 2010;28(1):38–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Buhmeida A, Bendardaf R, Hilska M, Collan Y, Laato M, Syrjanen S, Syrjanen K, Pyrhonen S. Prognostic significance of matrix metalloproteinase-9 (MMP-9) in stage II colorectal carcinoma. J Gastrointest Cancer. 2009;40(3–4):91–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Haydon A. Adjuvant chemotherapy in colon cancer: what is the evidence? Intern Med J. 2003;33(3):119–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Ajioka Y, Allison LJ, Jass JR. Significance of MUC1 and MUC2 mucin expression in colorectal cancer. J Clin Pathol. 1996;49(7):560–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Yamamoto H, Bai YQ, Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun. 2003;300(4):813–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Mizoshita T, Tsukamoto T, Inada KI, Hirano N, Tajika M, Nakamura T, Ban H, Tatematsu M. Loss of MUC2 expression correlates with progression along the adenoma-carcinoma sequence pathway as well as de novo carcinogenesis in the colon. Histol Histopathol. 2007;22(3):251–60.PubMedGoogle Scholar
  26. 26.
    Hanski C, Riede E, Gratchev A, Foss HD, Bohm C, Klussmann E, Hummel M, Mann B, Buhr HJ, Stein H, et al. MUC2 gene suppression in human colorectal carcinomas and their metastases: in vitro evidence of the modulatory role of DNA methylation. Lab Invest. 1997;77(6):685–95.PubMedGoogle Scholar
  27. 27.
    Ookawa K, Kudo T, Aizawa S, Saito H, Tsuchida S. Transcriptional activation of the MUC2 gene by p53. J Biol Chem. 2002;277(50):48270–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Vincent A, Perrais M, Desseyn JL, Aubert JP, Pigny P, Van Seuningen I. Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells. Oncogene. 2007;26(45):6566–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Okudaira K, Kakar S, Cun L, Choi E, Wu Decamillis R, Miura S, Sleisenger MH, Kim YS, Deng G. MUC2 gene promoter methylation in mucinous and non-mucinous colorectal cancer tissues. Int J Oncol. 2010;36(4):765–75.PubMedGoogle Scholar
  30. 30.
    Yonezawa S, Sato E. Expression of mucin antigens in human cancers and its relationship with malignancy potential. Pathol Int. 1997;47(12):813–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Li A, Goto M, Horinouchi M, Tanaka S, Imai K, Kim YS, Sato E, Yonezawa S. Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia. Pathol Int. 2001;51(11):853–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Bresalier RS, Niv Y, Byrd JC, Duh QY, Toribara NW, Rockwell RW, Dahiya R, Kim YS. Mucin production by human colonic carcinoma cells correlates with their metastatic potential in animal models of colon cancer metastasis. J Clin Invest. 1991;87(3):1037–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Lugli A, Zlobec I, Baker K, Minoo P, Tornillo L, Terracciano L, Jass JR. Prognostic significance of mucins in colorectal cancer with different DNA mismatch-repair status. J Clin Pathol. 2007;60(5):534–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Bendardaf R, Lamlum H, Ristamaki R, Algars A, Collan Y, Pyrhonen S. Response to chemotherapy (irinotecan plus 5-fluorouracil) in colorectal carcinoma can be predicted by tumour DNA content. Oncology. 2004;66(1):46–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Bendardaf R, Lamlum H, Ristamaki R, Korkeila E, Syrjanen K, Pyrhonen S. Thymidylate synthase and microsatellite instability in colorectal cancer: implications for disease free survival, treatment response and survival with metastases. Acta Oncol. 2008;47(6):1046–53.PubMedCrossRefGoogle Scholar
  36. 36.
    Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002;101(5):403–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Carethers J. One colon lumen but two organs. Gastroenterology. 2011;141(2):411–2.PubMedCrossRefGoogle Scholar
  38. 38.
    Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88.PubMedGoogle Scholar
  39. 39.
    Bleeker WA, Hayes VM, Karrenbeld A, Hofstra RM, Hermans J, Buys CC, Plukker JT. Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes' C colon cancer. Am J Gastroenterol. 2000;95(10):2953–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Hilska M, Roberts PJ, Collan YU, Laine VJ, Kossi J, Hirsimaki P, Rahkonen O, Laato M. Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer. 2007;121(4):714–23.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Adam Elzagheid
    • 1
  • Fatma Emaetig
    • 1
  • Abdelbaset Buhmeida
    • 2
  • Matti Laato
    • 3
  • Omran El-Faitori
    • 1
  • Kari Syrjänen
    • 4
    • 5
  • Yrjö Collan
    • 6
  • Seppo Pyrhönen
    • 4
  1. 1.Department of Pathology, Faculty of MedicineBenghazi UniversityBenghaziLibya
  2. 2.Center of Excellence in Genomic Medicine Research (CEGMR)King Abdul-Aziz UniversityJeddahSaudi Arabia
  3. 3.Department of Surgery, Turku University HospitalUniversity of TurkuTurkuFinland
  4. 4.Department of Oncology and Radiotherapy, Turku University HospitalUniversity of TurkuTurkuFinland
  5. 5.Teaching and Research InstituteBarretos Cancer HospitalBarretosBrazil
  6. 6.Department of Pathology, Turku University HospitalUniversity of TurkuTurkuFinland

Personalised recommendations