Tumor Biology

, Volume 33, Issue 4, pp 1209–1214 | Cite as

Evaluation and prognostic significance of human tissue kallikrein-related peptidase 10 (KLK10) in colorectal cancer

  • Constantina Petraki
  • Youssef M. Youssef
  • William Dubinski
  • Zsuzsanna Lichner
  • Andreas Scorilas
  • Maria D. Pasic
  • Vassilios Komborozos
  • Bishoy Khalil
  • Catherine Streutker
  • Eleftherios P. Diamandis
  • George M. Yousef
Research Article

Abstract

The prognosis of patients with colorectal cancer (CRC) is assessed through conventional clinicopathological parameters, which are not always accurate. Members of the human kallikrein-related peptidases gene family represent potential cancer biomarkers. The aim of this study was to investigate the expression of human tissue kallikrein-related peptidase 10 (KLK10) by immunohistochemistry in CRC, to correlate this expression with various histopathological and clinical variables, and to evaluate its significance as a predictor of disease outcome. KLK10 expression was evaluated by immunohistochemistry and a combined expression score was calculated for each case based on intensity and percentage of positivity. A statistically significant positive association was observed between KLK10 and tumor stage and liver metastases (p = 0.015 and p = 0.035, respectively). Paradoxically, a negative association was observed between KLK10 and tumor grade (p = 0.009). Kaplan–Meier survival curves and univariate analysis showed that both KLK10 expression and stage had statistically significant correlations with disease-free survival (DFS) (p = 0.030 and p < 0.001, respectively) and overall survival (p = 0.010 and p = 0.001, respectively). Cox multivariate analysis showed that both KLK10 expression and stage were independent predictors of unfavorable DFS (p = 0.057 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.001, respectively). In conclusion, KLK10 immunostaining is an independent prognostic marker in patients with CRC.

Keywords

KLK Kallikreins KLK10 Colorectal cancer Prognosis 

Non-standard abbreviations

CRC

Colorectal cancer

PS

Proportion score

IS

Intensity score

TS

Total score

IHC

Immunohistochemistry

Notes

Acknowledgements

This work was supported by grants from the Canadian Cancer Society (CCS grant # 20185), the Ministry of Research and Innovation of the Government of Ontario, the Kidney Foundation of Canada, Prostate Cancer Canada (grant # 2010-555), and the Cancer Research Society.

Conflicts of interest

None.

References

  1. 1.
    Schultz RM, Liebman MN. Structure–function relationship in protein families. In: Devlin TM, editor. Textbook of biochemistry with clinical correlations. New York: Wiley-liss, Inc; 1997. p. 1–2.Google Scholar
  2. 2.
    Yousef GM, Elliott MB, Kopolovic AD, Serry E, Diamandis EP. Sequence and evolutionary analysis of the human trypsin subfamily of serine peptidases. Biochim Biophys Acta. 2004;1698:77–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev. 2001;22:184–204.PubMedCrossRefGoogle Scholar
  4. 4.
    Clements JA, Willemsen NM, Myers SA, Dong Y. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit Rev Clin Lab Sci. 2004;41:265–312.PubMedCrossRefGoogle Scholar
  5. 5.
    Emami N, Diamandis EP. Utility of kallikrein-related peptidases (KLKs) as cancer biomarkers. Clin Chem. 2008;54:1600–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Mavridis K, Scorilas A. Prognostic value and biological role of the kallikrein-related peptidases in human malignancies. Future Oncol. 2010;6:269–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Tan OL, Whitbread AK, Clements JA, Dong Y. Kallikrein-related peptidase (KLK) family mRNA variants and protein isoforms in hormone-related cancers: do they have a function? Biol Chem. 2006;387:697–705.PubMedCrossRefGoogle Scholar
  8. 8.
    Yousef GM, Borgono CA, Popalis C, Yacoub GM, Polymeris ME, Soosaipillai A, et al. In-silico analysis of kallikrein gene expression in pancreatic and colon cancers. Anticancer Res. 2004;24:43–51.PubMedGoogle Scholar
  9. 9.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  10. 10.
    Midgley R, Kerr D. Colorectal cancer. Lancet. 1999;353:391–9.PubMedCrossRefGoogle Scholar
  11. 11.
    McLeod HL, Murray GI. Tumour markers of prognosis in colorectal cancer. Br J Cancer. 1999;79:191–203.PubMedCrossRefGoogle Scholar
  12. 12.
    Diamandis M, White NM, Yousef GM. Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res. 2010;8:1175–87.PubMedCrossRefGoogle Scholar
  13. 13.
    Yousef GM. Personalized Cancer Genomics: The Road Map to Clinical Implementation. Clin Chem. 2012. doi: 10.1373/clinchem.2011.181073.
  14. 14.
    Talieri M, Li L, Zheng Y, Alexopoulou DK, Soosaipillai A, Scorilas A, et al. The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer. Br J Cancer. 2009;100:1659–65.PubMedCrossRefGoogle Scholar
  15. 15.
    Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V. The role for NES1 serine protease as a novel tumor suppressor. Cancer Res. 1998;58:4782–6.PubMedGoogle Scholar
  16. 16.
    Liu XL, Wazer DE, Watanabe K, Band V. Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res. 1996;56:3371–9.PubMedGoogle Scholar
  17. 17.
    Luo LY. Rajpert-De Meyts ER, Jung K, Diamandis EP: Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Br J Cancer. 2001;85:220–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Yousef GM, Polymeris ME, Yacoub GM, Scorilas A, Soosaipillai A, Popalis C, et al. Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res. 2003;63:2223–7.PubMedGoogle Scholar
  19. 19.
    Kioulafa M, Kaklamanis L, Stathopoulos E, Mavroudis D, Georgoulias V, Lianidou ES. Kallikrein 10 (KLK10) methylation as a novel prognostic biomarker in early breast cancer. Ann Oncol. 2009;20:1020–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Li B, Goyal J, Dhar S, Dimri G, Evron E, Sukumar S, et al. CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Cancer Res. 2001;61:8014–21.PubMedGoogle Scholar
  21. 21.
    White NM, Chow TF, Mejia-Guerrero S, Diamandis M, Rofael Y, Faragalla H, et al. Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer. Br J Cancer. 2010;102:1244–53.PubMedCrossRefGoogle Scholar
  22. 22.
    Talieri M, Alexopoulou DK, Scorilas A, Kypraios D, Arnogiannaki N, Devetzi M, et al. Expression analysis and clinical evaluation of kallikrein-related peptidase 10 (KLK10) in colorectal cancer. Tumour Biol. 2011;32:737–44.PubMedCrossRefGoogle Scholar
  23. 23.
    Feng B, Xu WB, Zheng MH, Ma JJ, Cai Q, Zhang Y, et al. Clinical significance of human kallikrein 10 gene expression in colorectal cancer and gastric cancer. J Gastroenterol Hepatol. 2006;21:1596–603.PubMedCrossRefGoogle Scholar
  24. 24.
    Feng B, Zheng MH, Ma JJ, Cai Q, Zhang Y, Ji J, et al. Expression and single nucleotide polymorphisms of kallikrein 10 in colorectal cancer. Zhonghua Wai Ke Za Zhi. 2006;44:623–7.PubMedGoogle Scholar
  25. 25.
    Pettus JR, Johnson JJ, Shi Z, Davis JW, Koblinski J, Ghosh S, et al. Multiple kallikrein (KLK 5, 7, 8, and 10) expression in squamous cell carcinoma of the oral cavity. Histol Histopathol. 2009;24:197–207.PubMedGoogle Scholar
  26. 26.
    Ruckert F, Hennig M, Petraki CD, Wehrum D, Distler M, Denz A, et al. Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma. Br J Cancer. 2008;99:1484–92.PubMedCrossRefGoogle Scholar
  27. 27.
    White NM, Bui A, Mejia-Guerrero S, Chao J, Soosaipillai A, Youssef Y, et al. Dysregulation of kallikrein-related peptidases in renal cell carcinoma: potential targets of miRNAs. Biol Chem. 2010;391:411–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Yousef GM, Diamandis EP. The human kallikrein gene family: new biomarkers for ovarian cancer. Cancer Treat Res. 2009;149:165–87.PubMedCrossRefGoogle Scholar
  29. 29.
    Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70:968–78.PubMedCrossRefGoogle Scholar
  30. 30.
    Ogawa K, Utsunomiya T, Mimori K, Tanaka F, Inoue H, Nagahara H, et al. Clinical significance of human kallikrein gene 6 messenger RNA expression in colorectal cancer. Clin Cancer Res. 2005;11:2889–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Yousef GM, Diamandis EP. Human tissue kallikreins: a new enzymatic cascade pathway? Biol Chem. 2002;383:1045–57.PubMedCrossRefGoogle Scholar
  32. 32.
    Yousef GM, Diamandis EP. Tissue kallikreins: new players in normal and abnormal cell growth? Thromb Haemost. 2003;90:7–16.PubMedGoogle Scholar
  33. 33.
    Idikio HA. Immunohistochemistry in diagnostic surgical pathology: contributions of protein life-cycle, use of evidence-based methods and data normalization on interpretation of immunohistochemical stains. Int J Clin Exp Pathol. 2009;3:169–76.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Constantina Petraki
    • 1
  • Youssef M. Youssef
    • 2
    • 3
  • William Dubinski
    • 2
    • 3
  • Zsuzsanna Lichner
    • 2
    • 3
  • Andreas Scorilas
    • 4
  • Maria D. Pasic
    • 2
  • Vassilios Komborozos
    • 5
  • Bishoy Khalil
    • 3
  • Catherine Streutker
    • 2
    • 3
  • Eleftherios P. Diamandis
    • 2
  • George M. Yousef
    • 2
    • 3
  1. 1.Departments of PathologyMetropolitan HospitalAthensGreece
  2. 2.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  3. 3.Department of Laboratory Medicine, and the Keenan Research Centre in the Li Ka Shing Knowledge InstituteSt. Michael’s Hospital TorontoTorontoCanada
  4. 4.Department of Biochemistry and Molecular BiologyFaculty of Biology, University of AthensAthensGreece
  5. 5.Department of General SurgeryEvangelismos HospitalAthensGreece

Personalised recommendations