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Published in: Journal of Cancer Research and Clinical Oncology 4/2019

Open Access 01-04-2019 | Ovarian Cancer | Original Article – Cancer Research

Expression of Syk and MAP4 proteins in ovarian cancer

Authors: Siwei Zhang, Suha Deen, Sarah J. Storr, Anqi Yao, Stewart G. Martin

Published in: Journal of Cancer Research and Clinical Oncology | Issue 4/2019

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Abstract

Purpose

We have previously reported on the prognostic importance of the calpain family of proteins in ovarian cancer, especially calpain-2. Spleen tyrosine kinase (Syk) phosphorylates a variety of cytoskeletal proteins with studies suggesting potential interactions between Syk and conventional calpains. Microtubule-associated protein 4 (MAP4) has been reported to be regulated by Syk.

Methods

The current study assessed Syk and MAP4 protein expression, by immunohistochemistry on a tissue microarray comprised of cores from primary ovarian carcinomas (n = 575), to evaluate associations with patient clinical outcomes and other clinicopathological factors and sought to determine whether there were any correlations between the expression of Syk, MAP4 and the calpain system.

Results

MAP4 expression was significantly associated with ovarian cancer histological subtype (P < 0.001), stage (P = 0.001), grade (P < 0.001) and residual tumour (P = 0.005). Despite this finding, we found no significant association existing between MAP4 expression and overall survival. Syk expression was also found significantly associated with histological subtype (P < 0.001). Syk seems to play a contradictory role with respect to tumour progression: low cytoplasmic Syk expression was significantly associated with low stage (P = 0.013), and low nuclear Syk expression with chemo-resistance in patients treated with taxane-containing therapy (P = 0.006). Interestingly, despite the lack of association in the whole cohort, high nuclear Syk expression was significantly associated with better overall survival in certain subgroups (P = 0.001).

Conclusions

The current study indicates a lack of correlation between calpain-2 expression and Syk and MAP4. Syk, MAP4 and calpain-1 appeared to significantly correlate with each other in the whole cohort, with calpain-1 being more highly associated with MAP4 and Syk in mucinous carcinomas. Overall, the current results suggest that Syk, MAP4, and calpain-1 expression are correlated with each other and these proteins may be involved in early stages of tumour spread.
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Literature
go back to reference Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K (2000) Purification and characterization of human Syk produced using a baculovirus expression system. Protein Expr Purif 18(1):86–94CrossRefPubMed Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K (2000) Purification and characterization of human Syk produced using a baculovirus expression system. Protein Expr Purif 18(1):86–94CrossRefPubMed
go back to reference Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259CrossRef Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259CrossRef
go back to reference Coopman PJ, Mueller SC (2006) The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett 241(2):159–173 (Epub 2006 Jan 27) CrossRefPubMed Coopman PJ, Mueller SC (2006) The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett 241(2):159–173 (Epub 2006 Jan 27) CrossRefPubMed
go back to reference Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH, Mueller SC (2000) The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406(6797):742–747CrossRefPubMed Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH, Mueller SC (2000) The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406(6797):742–747CrossRefPubMed
go back to reference Divaris K, Vann WF Jr, Baker AD, Lee JY (2012) Examining the accuracy of caregivers’ assessments of young children’s oral health status. J Am Dent Assoc 143(11):1237–1247CrossRefPubMedPubMedCentral Divaris K, Vann WF Jr, Baker AD, Lee JY (2012) Examining the accuracy of caregivers’ assessments of young children’s oral health status. J Am Dent Assoc 143(11):1237–1247CrossRefPubMedPubMedCentral
go back to reference Gonscherowski V, Becker BF, Moroder L, Motrescu E, Gil-Parrado S, Gloe T, Keller M, Zahler S (2006) Calpains: a physiological regulator of the endothelial barrier? Am J Physiol Heart Circ Physiol 290(5):H2035–H2042CrossRefPubMed Gonscherowski V, Becker BF, Moroder L, Motrescu E, Gil-Parrado S, Gloe T, Keller M, Zahler S (2006) Calpains: a physiological regulator of the endothelial barrier? Am J Physiol Heart Circ Physiol 290(5):H2035–H2042CrossRefPubMed
go back to reference Jiang YY, Shang L, Shi ZZ, Zhang TT, Ma S, Lu CC, Zhang Y, Hao JJ, Shi C, Shi F et al (2016) Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma. Oncogene 35(37):4846–4856. https://doi.org/10.1038/onc.2016.17 CrossRefPubMed Jiang YY, Shang L, Shi ZZ, Zhang TT, Ma S, Lu CC, Zhang Y, Hao JJ, Shi C, Shi F et al (2016) Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma. Oncogene 35(37):4846–4856. https://​doi.​org/​10.​1038/​onc.​2016.​17 CrossRefPubMed
go back to reference Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR, Monroe JG (2005) MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J Exp Med 201(3):431–439CrossRefPubMedPubMedCentral Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR, Monroe JG (2005) MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J Exp Med 201(3):431–439CrossRefPubMedPubMedCentral
go back to reference Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, Rhŷs-Evans P, O-charoenrat P, Eccles S (2007) Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res 67(16):7907–7916CrossRefPubMed Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, Rhŷs-Evans P, O-charoenrat P, Eccles S (2007) Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res 67(16):7907–7916CrossRefPubMed
go back to reference McShane LM, Altman DG, Sauerbrei W. Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93:387–391CrossRefPubMedPubMedCentral McShane LM, Altman DG, Sauerbrei W. Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93:387–391CrossRefPubMedPubMedCentral
go back to reference Moroni M, Soldatenkov V, Zhang L, Zhang Y, Stoica G, Gehan E, Rashidi B, Singh B, Ozdemirli M, Mueller SC (2004) Progressive loss of Syk and abnormal proliferation in breast cancer cells. Cancer Res 64(20):7346–7354CrossRefPubMed Moroni M, Soldatenkov V, Zhang L, Zhang Y, Stoica G, Gehan E, Rashidi B, Singh B, Ozdemirli M, Mueller SC (2004) Progressive loss of Syk and abnormal proliferation in breast cancer cells. Cancer Res 64(20):7346–7354CrossRefPubMed
go back to reference Nakashima H, Natsugoe S, Ishigami S, Okumura H, Matsumoto M, Hokita S, Aikou T (2006) Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer. Cancer Lett 236(1):89–94CrossRefPubMed Nakashima H, Natsugoe S, Ishigami S, Okumura H, Matsumoto M, Hokita S, Aikou T (2006) Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer. Cancer Lett 236(1):89–94CrossRefPubMed
go back to reference Peng CL, Zhang Y, Sun QF, Zhao YP, Hao YT, Zhao XG, Cong B (2013) Inhibitory effects of syk transfection on lung cancer cell invasion. Asian Pac J Cancer Prev 14(5):3001–3003CrossRefPubMed Peng CL, Zhang Y, Sun QF, Zhao YP, Hao YT, Zhao XG, Cong B (2013) Inhibitory effects of syk transfection on lung cancer cell invasion. Asian Pac J Cancer Prev 14(5):3001–3003CrossRefPubMed
go back to reference Poruchynsky MS, Giannakakou P, Ward Y, Bulinski JC, Telford WG, Robey RW, Fojo T (2001) Accompanying protein alterations in malignant cells with a microtubule-polymerizing drug-resistance phenotype and a primary resistance mechanism. Biochem Pharmacol 62(11):1469–1480CrossRefPubMed Poruchynsky MS, Giannakakou P, Ward Y, Bulinski JC, Telford WG, Robey RW, Fojo T (2001) Accompanying protein alterations in malignant cells with a microtubule-polymerizing drug-resistance phenotype and a primary resistance mechanism. Biochem Pharmacol 62(11):1469–1480CrossRefPubMed
go back to reference Wang L, Duke L, Zhang PS, Arlinghaus RB, Symmans WF, Sahin A, Mendez R, Dai JL (2003) Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res 63(15):4724–4730PubMed Wang L, Duke L, Zhang PS, Arlinghaus RB, Symmans WF, Sahin A, Mendez R, Dai JL (2003) Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res 63(15):4724–4730PubMed
go back to reference Wang L, Devarajan E, He J, Reddy SP, Dai JL (2005) Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression. Cancer Res 65(22):10289–10297CrossRefPubMedPubMedCentral Wang L, Devarajan E, He J, Reddy SP, Dai JL (2005) Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression. Cancer Res 65(22):10289–10297CrossRefPubMedPubMedCentral
go back to reference Yanagi S, Inatome R, Takano T, Yamamura H (2001) Syk expression and novel function in a wide variety of tissues. Biochem Biophys Res Commun 288(3):495–498CrossRefPubMed Yanagi S, Inatome R, Takano T, Yamamura H (2001) Syk expression and novel function in a wide variety of tissues. Biochem Biophys Res Commun 288(3):495–498CrossRefPubMed
go back to reference Yu Y, Gaillard S, Phillip JM, Huang TC, Pinto SM, Tessarollo NG, Zhang Z, Pandey A, Wirtz D, Ayhan A et al (2015) Inhibition of spleen tyrosine kinase potentiates paclitaxel-induced cytotoxicity in ovarian cancer cells by stabilizing microtubules. Cancer Cell 28(1):82–96CrossRefPubMedPubMedCentral Yu Y, Gaillard S, Phillip JM, Huang TC, Pinto SM, Tessarollo NG, Zhang Z, Pandey A, Wirtz D, Ayhan A et al (2015) Inhibition of spleen tyrosine kinase potentiates paclitaxel-induced cytotoxicity in ovarian cancer cells by stabilizing microtubules. Cancer Cell 28(1):82–96CrossRefPubMedPubMedCentral
go back to reference Yuan Y, Wang J, Li J, Wang L, Li M, Yang Z, Zhang C, Dai JL (2006) Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin Cancer Res 12(22):6687–6695CrossRefPubMedPubMedCentral Yuan Y, Wang J, Li J, Wang L, Li M, Yang Z, Zhang C, Dai JL (2006) Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin Cancer Res 12(22):6687–6695CrossRefPubMedPubMedCentral
go back to reference Zhang X, Shrikhande U, Alicie BM, Zhou Q, Geahlen RL (2009) Role of the protein tyrosine kinase Syk in regulating cell-cell adhesion and motility in breast cancer cells. Mol Cancer Res 7(5):634–644CrossRefPubMedPubMedCentral Zhang X, Shrikhande U, Alicie BM, Zhou Q, Geahlen RL (2009) Role of the protein tyrosine kinase Syk in regulating cell-cell adhesion and motility in breast cancer cells. Mol Cancer Res 7(5):634–644CrossRefPubMedPubMedCentral
Metadata
Title
Expression of Syk and MAP4 proteins in ovarian cancer
Authors
Siwei Zhang
Suha Deen
Sarah J. Storr
Anqi Yao
Stewart G. Martin
Publication date
01-04-2019
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 4/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-019-02856-9

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