Skip to main content

Advertisement

SpringerLink
Log in

Human kallikrein-related peptidase 12 (KLK12) splice variants expression in breast cancer and their clinical impact

  • Research Article
  • Published:
Tumor Biology

Abstract

Kallikrein-related peptidases (KLKs) are a group of 15 serine proteases, hormonally regulated, and localized on chromosome 19q13.4. Alternative splicing is a process that plays significant role in the development, physiology, and different diseases, like cancer. Kallikrein family numbers more than 82 alternative transcripts. Understanding the role that those gene transcripts play in various cancer types, could lead to the discovery of diagnostic markers or drug targets. The present study was designed to analyze the expression profile of the splice variants of kallikrein-related peptidase 12 (KLK12) in breast cancer patients and to evaluate their clinical significance. KLK12 splice variants (KLK12sv3 and KLK12sv1/KLK12sv2) were examined in 69 tissue samples of breast cancer using quantitative real-time PCR as well as semi-quantitative PCR. Relative quantitative expression of KLK12 was statistically associated to clinicopathological parameters. From the splice variants examined, statistical associations with clinicopathological parameters were obtained only from KLK12sv3 variant. KLK12sv3 is more frequently expressed in tumors of lower grade (p = 0.040), early patient TNM stage (p = 0.024), and smaller tumor size (p = 0.023). Positive KLK12sv3 expression is associated with longer patient disease-free survival (DFS) (p = 0.042) and higher progesterone receptor concentration (p = 0.008). KLK12sv1/KLK12sv2 expression is statistically associated with KLK12sv3 expression (p = 0.001). KLK12sv3 can be regarded as a marker of good prognosis in breast cancer.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Smith RA, Cokkinides V, Brooks D, Saslow D, Shah M, Brawley OW. Cancer Screening in the United States, 2010: A Review of Current American. Cancer Society Guidelines and Issues in Cancer Screening. CA Cancer J Clin. 2010;60:99–119.

    PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    PubMed  Google Scholar 

  3. Lopez-Otin C, Lynn MM. Emerging roles of proteases in tumor suppression. Nat Rev Cancer. 2007;7:800–8.

    CAS  PubMed  Google Scholar 

  4. Lawrence MG, Lai J, Clements JA. Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocrine Rev. 2010;31:407–46.

    CAS  Google Scholar 

  5. Eissa A, Diamandis EP. Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions. Biol Chem. 2008;389:669–80.

    CAS  PubMed  Google Scholar 

  6. Borgono CA, Diamandis EP. The emerging roles of human kallikreins in cancer. Nat Rev Cancer. 2004;4:876–90.

    CAS  PubMed  Google Scholar 

  7. Pampalakis G, Sotiropoulou G. Tissue kallikrein proteolytic cascade pathways in normal physiology and cancer. Biochim Biophys Acta. 2007;1776:22–31.

    CAS  PubMed  Google Scholar 

  8. Lu Y, Papagerakis P, Yamakoshi Y, Hu JCC, Bartlett JD, Simmer JP. Functions of KLK4 and MMP-20 in dental enamel formation. Biol Chem. 2008;389:695–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Scarisbrick IA, Limbo R, Vandell AG, Keegan M, Blaber SI, Blaber M, et al. Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration. Biol Chem. 2008;389:739–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Oikonomopoulou K, Hansen KK, Chapman K, Vergnolle N, Diamandis EP, Hollenberg MD. Kallikrein-mediated activation of PARs in inflammation and nociception. Inflamm Res 2007;56, Suppl 3:s499–s502.

    CAS  Google Scholar 

  11. Shaw JLV, Diamandis EP. A potential role for tissue kallikrein-related peptidases in human cervico-vaginal physiology. Biol Chem. 2008;389:681–8.

    CAS  PubMed  Google Scholar 

  12. Smith Jr RS, Gao L, Chao L, Chao J. Tissue kallikrein and kinin infusion promotes neovascularization in limb ischemia. Biol Chem. 2008;389:725–30.

    CAS  PubMed  Google Scholar 

  13. Sotiropoulou G, Pampalakis G, Diamandis EP. Functional roles of human kallikrein-related peptidases. J Biol Chem. 2009;284:32989–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Sotiropoulou G, Pampalakis G. Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation. Biol Chem. 2010;391:321–31.

    CAS  PubMed  Google Scholar 

  15. Υoon H, Blaber S, Evans DM, Trim J, Juliano MA, Scaristrick IA, et al. Activation profiles of human kallikrein-related peptidases by proteinases of thrombostasis axis. Protein Sci. 2008;11:1998–2007.

    Google Scholar 

  16. Blaber M, Yoon H, Juliano MA, Scarisbrick IA, Blaber SI. Functional intersection of the kallirein-related peptidases (KLKs) and thrombostasis axis. Biol Chem. 2010;391:311–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Oikonomopoulou K, Diamandis EP, Hollenberg MD. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier. Biol Chem. 2010;391:299–310.

    CAS  PubMed  Google Scholar 

  18. Michael IP, Kurlender L, Memari N, Yousef GM, Du D, Grass L, et al. Intron retention: a common splicing event within the human kallikrein gene family. Clin Chem. 2005;51:506–15.

    CAS  PubMed  Google Scholar 

  19. Kurlender L, Borgono C, Michael I, Obiezu Ch, Elliott MB, Yousef GM, et al. A survey of alternative transcripts of human tissue kallikrein genes. Biochim Biophys Acta. 2005;1755:1–14.

    CAS  PubMed  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. Yousef GM, Magklara A, Diamandis EP. KLK12 is a novel serine protease and a new member of the human kallikrein gene family: differential expression in breast cancer. Genomics. 2000;69:331–41.

    CAS  PubMed  Google Scholar 

  22. Lundwall A, Band V, Blaber M, Clements J, Courty Y, Diamandis E, et al. A comprehensive nomenclature for serine proteases with homology to the tissue kallikrein. Biol Chem. 2006;387:637–41.

    CAS  PubMed  Google Scholar 

  23. Komatsu N, Takata M, Otsuki N, Toyama T, Ohka R, Takehara K, et al. Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. J Invest Dermatol. 2003;121:542–9.

    CAS  PubMed  Google Scholar 

  24. Memari N, Weiping J, Diamandis EP, Luo LY. Enzymatic properties of human kallikrein-related peptidase 12 (KLK12). Biol Chem. 2007;388:427–35.

    CAS  PubMed  Google Scholar 

  25. Yoon H, Laxmikanthan G, Lee J, Blaber SI, Rodriquez A, Kogot JM, et al. Activation profiles and regulatory cascades of the human kallikrein-related peptidases. J Biol Chem. 2007;282:31852–64.

    CAS  PubMed  Google Scholar 

  26. Giusti B, Serrati S, Margheri F, Papucci L, Rossi L, Poggi F, et al. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum. 2005;52:3618–28.

    CAS  PubMed  Google Scholar 

  27. Scorilas A, Talieri M, Ardavanis A, Courtis N, Dimitriadis E, Yotis J, et al. Polyadenylate polymerase enzymatic activity in mammary tumor cytosols: a new independent prognostic marker in primary breast cancer. Cancer Res. 2000;60:5427–33.

    CAS  PubMed  Google Scholar 

  28. Talieri M, Mathioudaki K, Prezas P, Alexopoulou DK, Diamandis EP, Xynopoulos D, et al. Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer. Thromb Haemost. 2009;101:741–7.

    CAS  PubMed  Google Scholar 

  29. 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. Tumor Biol. 2011;32:737–44.

    CAS  Google Scholar 

  30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2 (−Delta Delta C(T)) method. Methods. 2001;5:402–8.

    Google Scholar 

  31. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10:7252–9.

    CAS  PubMed  Google Scholar 

  32. Black DL. Protein diversity from alternative splicing: a challenge for bioinformatics and post-genome biology. Cell. 2000;103:367–70.

    CAS  PubMed  Google Scholar 

  33. Thorsen K, Sorensen KD, Brems-Eskilden AS, Modin Ch, Gaustadnes M, Hein A-MK, et al. Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis. Mol Cel Proteomics. 2008;7:1214–24.

    CAS  Google Scholar 

  34. Blair ChA, Xiaolin Z. Potential molecular targeting of splice variants for cancer treatment. Indian J Exp Biol. 2011;49:836–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Dong Y, Kaushal A, Brattsand M, Nicklin J, Clements JA. Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers. Clin Cancer Res. 2003;1719:1710–20.

    Google Scholar 

  36. Dong Y, Bui LT, Odorico DM, Tan OL, Myers SA, Samaratunga H, et al. Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms. Endocrine-Relat Cancer. 2005;12:875–89.

    CAS  Google Scholar 

  37. Planque Ch, Choi Y-H, Guyetant S, Heuze-Vourc’h N, Briollais L, Courty Y. Alternative splicing variant of kallikrein-related peptidase 8 as an independent predictor of unfavorable prognosis in lung cancer. Clin Chem. 2010;56:987–97.

    CAS  PubMed  Google Scholar 

  38. Heuze-Vourc’h N, Leblond V, Courty Y. Complex alternative splicing of the hKLK3 gene coding for the tumor marker PSA (prostate-specific-antigen). Eur J Biochem. 2003;270:706–14.

    PubMed  Google Scholar 

  39. Memari N, Diamandis EP, Earle T, Campbell A, Van Dekken H, Van der Kwast TH. Human kallikrein-related peptidase 12 antibody generation and immunohistochemical localization in prostatic tissues. Prostate. 2007;67:1465–74.

    CAS  PubMed  Google Scholar 

  40. Mitsui S, Yamada T, Okui A, Kominami K, Uemura H, Yamaguchi N. A novel isoform of a kallikrein-like protease, TLSP/hippostasin, (PRSS20), is expressed in the human brain and prostate. Biochem Biophys Res Commun. 2000;272:205–11.

    CAS  PubMed  Google Scholar 

  41. Mauridis K, Avgeris M, Koutalellis G, Stravodimos K, Scorilas A. Expression analysis and study of the KLK15 mRNA splice variants in prostate cancer and benign prostatic hyperplasia. Cancer Scie. 2010;101:693–9.

    Google Scholar 

  42. Slawin KM, Shariat Sh, Nguyen C, Leventis AK, Song W, Kattan MW, et al. Detection of metastatic prostate cancer using a splice variant-specific reverse transcriptase-polymerase chain reaction assay for grandular kallikrein. Cancer Res. 2000;60:7142–8.

    CAS  PubMed  Google Scholar 

  43. David A, Mabjeesh N, Azar I, Biton Sh, Engel Sh, Bernstein J, et al. Unusual alternative splicing within the human kallikrein genes KLK2 and KLK3 give rise to novel prostate-specific proteins. J Biol Chem. 2002;277:18084–90.

    CAS  PubMed  Google Scholar 

  44. Nakamura T, Mitsui Sh, Okui A, Miki T, Yamagushi N. Molecular cloning and expression of a variant form of hippostasin/KLK11 in prostate. Prostate. 2003;54:299–305.

    CAS  PubMed  Google Scholar 

  45. Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem. 2007;53:1423–32.

    CAS  PubMed  Google Scholar 

  46. Kim JT, Song EY, Chung K-S, Kang MA, Kim JW, Kim SJ, et al. Up-regulation and clinical significance of serine protease kallikrein 6 in colon cancer. Cancer. 2011;177:2608–19.

    Google Scholar 

  47. Harvey TJ, Hooper JD, Myers SA, Stephenson SA, Ashworth LK, Clements JA. Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J Biol Chem. 2000;275:37397–406.

    CAS  PubMed  Google Scholar 

  48. 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.

    CAS  PubMed  Google Scholar 

  49. Borgono CA, Michael IP, Komatsu N, Jayakumar A, Kapadia R, Clayman GL, et al. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem. 2007;282:3640–52.

    CAS  PubMed  Google Scholar 

  50. Shaw JLV, Petraki C, Watson C, Bocking A, Diamandis EP. Role of tissue kallikrein-related peptidases in cervical mucus remodeling and host defense. Biol Chem. 2008;389:1513–22.

    CAS  PubMed  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Cellular Physiology, G. Papanicolaou Research Center of Oncology, Saint Savvas Cancer Hospital, 171 Alexandras Avenue, Athens, 11522, Greece

    Maroulio Talieri, Marina Devetzi & Eleana Pappa

  2. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece

    Andreas Scorilas

  3. Department of Breast Cancer Surgery, Saint Savvas Cancer Hospital, 171 Alexandras Ave., Athens, 11522, Greece

    Nikolaos Tsapralis & Ioannis Missitzis

  4. Department of Medical Oncology, Saint Savvas Cancer Hospital, 171 Alexandras Ave., Athens, 11522, Greece

    Alexandros Ardavanis

Authors
  1. Maroulio Talieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina Devetzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Scorilas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eleana Pappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nikolaos Tsapralis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ioannis Missitzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandros Ardavanis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maroulio Talieri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Talieri, M., Devetzi, M., Scorilas, A. et al. Human kallikrein-related peptidase 12 (KLK12) splice variants expression in breast cancer and their clinical impact. Tumor Biol. 33, 1075–1084 (2012). https://doi.org/10.1007/s13277-012-0347-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-012-0347-x

Keywords

Search

Navigation