Tumor Biology

, Volume 35, Issue 9, pp 9185–9194 | Cite as

High expression of CASK correlates with progression and poor prognosis of colorectal cancer

  • Jin-Lai Wei
  • Zhong-Xue Fu
  • Min Fang
  • Qiu-Yuan Zhou
  • Qing-Ning Zhao
  • Jin-Bao Guo
  • Wei-Dong Lu
  • Hao Wang
Research Article

Abstract

Calcium/calmodulin-dependent serine protein kinase (CASK), which localizes at cell–cell adhesion sites and binds to the heparan sulfate proteoglycan syndecan-2, is involved in cell proliferation, cytoskeletal remodeling, and cell migration. To demonstrate the role of CASK in colorectal cancer (CRC) carcinogenesis, we examined the expression of CASK and its binding protein syndecan-2 in human CRC tissues. The expression of CASK was measured in CRC specimens and the controls from adenomas and normal mucosae by immunohistochemical staining and Western blot analysis. Syndecan-2 protein level was tested in CRC samples and the controls by Western blot analysis. The correlations between CASK expression and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analyzed. Compared to the controls, both CASK and syndecan-2 expression were enhanced in CRC tissues. Furthermore, high expression of CASK and syndecan-2 was significantly correlated with advanced tumor stage, lymphatic invasion, lymph node metastasis, vascular invasion, liver metastasis, and unresectable metastatic CRC. Survival analysis showed that patients with low CASK staining had a significantly better survival compared to patients with high CASK staining. In multivariate analysis, CASK overexpression, advanced tumor stage, lymph node metastasis, vasvular invasion, and liver metastasis were independent prognostic factors of poor DFS and OS. Our present study indicates that CASK overexpression is associated with an unfavorable prognosis. CASK is an independent prognostic factor for CRC, which suggests that it is a novel and crucial predictor for CRC metastasis.

Keywords

Colorectal cancer CASK Prognosis Survival Syndecan-2 

Notes

Acknowledgments

This work was supported by National Natural Science Foundation Of China (No. 81172295). The authors sincerely thank the patients and their families for their participation in this study.

Reference

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Kraus S, Nabiochtchikov I, Shapira S, Arber N. Recent advances in personalized colorectal cancer research. Cancer Lett. 2014;347:15–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 2012;12:23–38.Google Scholar
  4. 4.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Parsons JT, Horwitz AR, Schwartz MA. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat Rev Mol Cell Biol. 2010;11:633–43.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Wu ZQ, Brabletz T, Fearon E, Willis AL, Hu CY, Li XY, et al. Canonical wnt suppressor, axin2, promotes colon carcinoma oncogenic activity. Proc Natl Acad Sci U S A. 2012;109:11312–7.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Hata Y, Butz S, Sudhof TC. Cask: A novel dlg/psd95 homolog with an n-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci. 1996;16:2488–94.PubMedGoogle Scholar
  9. 9.
    Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, et al. Syncam, a synaptic adhesion molecule that drives synapse assembly. Science. 2002;297:1525–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Cohen AR, Woods DF, Marfatia SM, Walther Z, Chishti AH, Anderson JM. Human cask/lin-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J Cell Biol. 1998;142:129–38.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Kwon MJ, Kim Y, Choi Y, Kim SH, Park S, Han I, et al. The extracellular domain of syndecan-2 regulates the interaction of hct116 human colon carcinoma cells with fibronectin. Biochem Biophys Res Commun. 2013;431:415–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Park H, Kim Y, Lim Y, Han I, Oh ES. Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells. J Biol Chem. 2002;277:29730–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Ryu HY, Lee J, Yang S, Park H, Choi S, Jung KC, et al. Syndecan-2 functions as a docking receptor for pro-matrix metalloproteinase-7 in human colon cancer cells. J Biol Chem. 2009;284:35692–701.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Martinez-Estrada OM, Villa A, Breviario F, Orsenigo F, Dejana E, Bazzoni G. Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (cask/lin-2) in human epithelial caco-2 cells. J Biol Chem. 2001;276:9291–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Coussen F, Normand E, Marchal C, Costet P, Choquet D, Lambert M, et al. Recruitment of the kainate receptor subunit glutamate receptor 6 by cadherin/catenin complexes. J Neurosci. 2002;22:6426–36.PubMedGoogle Scholar
  16. 16.
    Weigand JE, Boeckel JN, Gellert P, Dimmeler S. Hypoxia-induced alternative splicing in endothelial cells. PLoS One. 2012;7:e42697.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Caruana G. Genetic studies define maguk proteins as regulators of epithelial cell polarity. Int J Dev Biol. 2002;46:511–8.PubMedGoogle Scholar
  18. 18.
    Funke L, Dakoji S, Bredt DS. Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem. 2005;74:219–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Qi J, Su Y, Sun R, Zhang F, Luo X, Yang Z. Cask inhibits ecv304 cell growth and interacts with id1. Biochem Biophys Res Commun. 2005;328:517–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Hsueh YP, Wang TF, Yang FC, Sheng M. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase cask/lin-2. Nature. 2000;404:298–302.CrossRefPubMedGoogle Scholar
  21. 21.
    Gold KA, Kim ES, Liu D, Yuan P, Behrens C, Solis Soto LM et al. Prediction of survival in resected non-small cell lung cancer using a protein-expression based risk model: implications for personalized chemoprevention and therapy. Clin Cancer Res. 2014;20:1946–54.Google Scholar
  22. 22.
    Wang Q, Lu J, Yang C, Wang X, Cheng L, Hu G, et al. Cask and its target gene reelin were co-upregulated in human esophageal carcinoma. Cancer Lett. 2002;179:71–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Rohrbeck A, Neukirchen J, Rosskopf M, Pardillos GG, Geddert H, Schwalen A, et al. Gene expression profiling for molecular distinction and characterization of laser captured primary lung cancers. J Transl Med. 2008;6:69.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Au CW, Siu MK, Liao X, Wong ES, Ngan HY, Tam KF, et al. Tyrosine kinase b receptor and bdnf expression in ovarian cancers—effect on cell migration, angiogenesis and clinical outcome. Cancer Lett. 2009;281:151–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76.CrossRefPubMedGoogle Scholar
  26. 26.
    Yilmaz M, Christofori G. Emt, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28:15–33.CrossRefPubMedGoogle Scholar
  27. 27.
    Beauvais DM, Rapraeger AC. Syndecans in tumor cell adhesion and signaling. Reprod Biol Endocrinol. 2004;2:3.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Contreras HR, Fabre M, Granes F, Casaroli-Marano R, Rocamora N, Herreros AG, et al. Syndecan-2 expression in colorectal cancer-derived ht-29 m6 epithelial cells induces a migratory phenotype. Biochem Biophys Res Commun. 2001;286:742–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773:642–52.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Hsueh YP, Yang FC, Kharazia V, Naisbitt S, Cohen AR, Weinberg RJ, et al. Direct interaction of cask/lin-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J Cell Biol. 1998;142:139–51.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Jin-Lai Wei
    • 1
  • Zhong-Xue Fu
    • 1
  • Min Fang
    • 2
  • Qiu-Yuan Zhou
    • 3
  • Qing-Ning Zhao
    • 4
  • Jin-Bao Guo
    • 1
  • Wei-Dong Lu
    • 1
  • Hao Wang
    • 1
  1. 1.Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of Emergency and Intensive Care UnitThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  3. 3.Department of pathologyShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong UniversityShanghaiChina
  4. 4.Department of pathology, Southwest HospitalThird Military Medical UniversityChongqingChina

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