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.
Colorectal cancer CASK Prognosis Survival Syndecan-2
This is a preview of subscription content, log in to check access.
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.
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
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
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
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
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
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
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
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
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
Caruana G. Genetic studies define maguk proteins as regulators of epithelial cell polarity. Int J Dev Biol. 2002;46:511–8.PubMedGoogle Scholar
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
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
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
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
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
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
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
Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76.CrossRefPubMedGoogle Scholar
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