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Published in: Medical Oncology 2/2013

01-06-2013 | Original Paper

Hypermethylation and prognostic implication of Syk gene in human colorectal cancer

Authors: Zuli Yang, Lijun Huo, Hao Chen, Beibei Ni, Jun Xiang, Liang Kang, Lei Wang, Junsheng Peng, Yunfei Yuan, Jianping Wang

Published in: Medical Oncology | Issue 2/2013

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Abstract

The study was aimed to investigate the relationship between hypermethylation of Syk gene and clinicopathological characteristics and long-term outcomes in colorectal cancer. The effect of Syk on cell proliferation and invasion ability was also assessed. Methylation and expression status of Syk were explored in CRC tissues and cell lines by MSP, qRT-PCR and western blot assay. The effects of Syk overexpression on tumorigenesis were studied by in vitro assay. The correlation between Syk methylation and clinical relevance in CRC patients was also analyzed. Syk methylation was found 48.6 % in CRC tissue samples and 57.1 % in cell lines, respectively. The loss of Syk expression could be restored by demethylation agent. Overexpression of Syk in CRC cell inhibited cell proliferation (p < 0.01) and invasion (p < 0.01). The methylation of Syk was significantly associated with histological grade (p = 0.002), lymph node status (p < 0.001) and TNM stage (p < 0.001). Five-year overall survival in methylated Syk group was significantly lower than that in unmethylated Syk group (59 vs. 80 %, p < 0.001). Multivariate analysis demonstrated that Syk methylation was an independent prognostic factor for overall survival. Syk is identified as a potential tumor suppressor in CRC progression. Syk methylation is correlated with poor overall survival, which acts as an independent prognostic indicator of CRC.
Literature
1.
go back to reference Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics. CA Cancer J Clin. 2005;55(1):10–30.PubMedCrossRef Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics. CA Cancer J Clin. 2005;55(1):10–30.PubMedCrossRef
2.
go back to reference Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686–92.PubMedCrossRef Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686–92.PubMedCrossRef
3.
go back to reference 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer. Adopted on November 7, 1997 by the American Society of Clinical Oncology. J Clin Oncol. 1998; 16(2):793–5. 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer. Adopted on November 7, 1997 by the American Society of Clinical Oncology. J Clin Oncol. 1998; 16(2):793–5.
4.
go back to reference Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57(5):808–11.PubMed Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57(5):808–11.PubMed
5.
go back to reference Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA. 1998;95(15):8698–702.PubMedCrossRef Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA. 1998;95(15):8698–702.PubMedCrossRef
6.
go back to reference Shin SK, Nagasaka T, Jung BH, Matsubara N, Kim WH, Carethers JM, Boland CR, Goel A. Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer. Gastroenterology. 2007;133(6):1849–57.PubMedCrossRef Shin SK, Nagasaka T, Jung BH, Matsubara N, Kim WH, Carethers JM, Boland CR, Goel A. Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer. Gastroenterology. 2007;133(6):1849–57.PubMedCrossRef
7.
go back to reference Hibi K, Mizukami H, Shirahata A, Goto T, Sakata M, Sanada Y. Aberrant methylation of the netrin-1 receptor genes UNC5C and DCC detected in advanced colorectal cancer. World J Surg. 2009;33(5):1053–7.PubMedCrossRef Hibi K, Mizukami H, Shirahata A, Goto T, Sakata M, Sanada Y. Aberrant methylation of the netrin-1 receptor genes UNC5C and DCC detected in advanced colorectal cancer. World J Surg. 2009;33(5):1053–7.PubMedCrossRef
8.
go back to reference Flück M, Zürcher G, Andres AC, Ziemiecki A. Molecular characterization of the murine syk protein tyrosine kinase cDNA, transcripts and protein. Biochem Biophys Res Commun. 1995;213(1):273–81.PubMedCrossRef Flück M, Zürcher G, Andres AC, Ziemiecki A. Molecular characterization of the murine syk protein tyrosine kinase cDNA, transcripts and protein. Biochem Biophys Res Commun. 1995;213(1):273–81.PubMedCrossRef
9.
go back to reference Tsuchida S, Yanagi S, Inatome R, Ding J, Hermann P, Tsujimura T, Matsui N, Yamamura H. Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes. J Biochem. 2000;127(2):321–7.PubMedCrossRef Tsuchida S, Yanagi S, Inatome R, Ding J, Hermann P, Tsujimura T, Matsui N, Yamamura H. Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes. J Biochem. 2000;127(2):321–7.PubMedCrossRef
10.
go back to reference Dejmek J, Leandersson K, Manjer J, Bjartell A, Emdin SO, Vogel WF, Landberg G, Andersson T. Expression and signalling of Wnt05a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. Clin Cancer Res. 2005;11:520–8.PubMed Dejmek J, Leandersson K, Manjer J, Bjartell A, Emdin SO, Vogel WF, Landberg G, Andersson T. Expression and signalling of Wnt05a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. Clin Cancer Res. 2005;11:520–8.PubMed
11.
go back to reference Okamura S, Ng CC, Koyama K, Takei Y, Arakawa H, Monden M, Nakamura Y. Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system. Oncol Res. 1999;11(6):281–5.PubMed Okamura S, Ng CC, Koyama K, Takei Y, Arakawa H, Monden M, Nakamura Y. Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system. Oncol Res. 1999;11(6):281–5.PubMed
12.
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. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature. 2000;406:742–7.PubMedCrossRef Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH, Mueller SC. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature. 2000;406:742–7.PubMedCrossRef
13.
go back to reference Stewart Z, Pietenpol J. Syk: a new player in the field of breast cancer. Breast Cancer Res. 2001;3:5–7.PubMedCrossRef Stewart Z, Pietenpol J. Syk: a new player in the field of breast cancer. Breast Cancer Res. 2001;3:5–7.PubMedCrossRef
14.
go back to reference Yuan Y, Mendez R, Sahin A, Dai JL. Hypermethylation leads to silencing of the SYK gene in human breast cancer. Cancer Res. 2001;61(14):5558–61.PubMed Yuan Y, Mendez R, Sahin A, Dai JL. Hypermethylation leads to silencing of the SYK gene in human breast cancer. Cancer Res. 2001;61(14):5558–61.PubMed
15.
go back to reference Wang S, Ding YB, Chen GY, Xia JG, Wu ZY. Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma. World J Gastroenterol. 2004;10(12):1815–8.PubMed Wang S, Ding YB, Chen GY, Xia JG, Wu ZY. Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma. World J Gastroenterol. 2004;10(12):1815–8.PubMed
16.
go back to reference Muthusamy V, Duraisamy S, Bradbury CM, Hobbs C, Curley DP, Nelson B, Bosenberg M. Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006;66(23):11187–93.PubMedCrossRef Muthusamy V, Duraisamy S, Bradbury CM, Hobbs C, Curley DP, Nelson B, Bosenberg M. Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006;66(23):11187–93.PubMedCrossRef
17.
go back to reference Ogane S, Onda T, Takano N, Yajima T, Uchiyama T, Shibahara T. Spleen tyrosine kinase as a novel candidate tumor suppressor gene for human oral squamous cell carcinoma. Int J Cancer. 2009;124(11):2651–7.PubMedCrossRef Ogane S, Onda T, Takano N, Yajima T, Uchiyama T, Shibahara T. Spleen tyrosine kinase as a novel candidate tumor suppressor gene for human oral squamous cell carcinoma. Int J Cancer. 2009;124(11):2651–7.PubMedCrossRef
18.
go back to reference Yuan Y, Wang J, Li J, Wang L, Li M, Yang Z, Zhang C, Dai JL. Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin Cancer Res. 2006;12(22):6687–95.PubMedCrossRef Yuan Y, Wang J, Li J, Wang L, Li M, Yang Z, Zhang C, Dai JL. Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin Cancer Res. 2006;12(22):6687–95.PubMedCrossRef
19.
go back to reference Li J, Sidell N. Growth-related oncogene produced in human breast cancer cells and regulated by Syk protein-tyrosine kinase. Int J Cancer. 2005;117(1):14–20.PubMedCrossRef Li J, Sidell N. Growth-related oncogene produced in human breast cancer cells and regulated by Syk protein-tyrosine kinase. Int J Cancer. 2005;117(1):14–20.PubMedCrossRef
20.
go back to reference Bailet O, Fenouille N, Abbe P, Robert G, Rocchi S, Gonthier N, Denoyelle C, Ticchioni M, Ortonne JP, Ballotti R, Deckert M, Tartare-Deckert S. Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest. Cancer Res. 2009;69(7):2748–56.PubMedCrossRef Bailet O, Fenouille N, Abbe P, Robert G, Rocchi S, Gonthier N, Denoyelle C, Ticchioni M, Ortonne JP, Ballotti R, Deckert M, Tartare-Deckert S. Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest. Cancer Res. 2009;69(7):2748–56.PubMedCrossRef
21.
go back to reference Dong SW, Ma L, Xu N, Yan HQ, Liu HY, Li YW, Zhang P. Research on the reactivation of Syk expression caused by the inhibition of DNA promoter methylation in the lung cancer. Neoplasma. 2011;58(1):89–95.PubMedCrossRef Dong SW, Ma L, Xu N, Yan HQ, Liu HY, Li YW, Zhang P. Research on the reactivation of Syk expression caused by the inhibition of DNA promoter methylation in the lung cancer. Neoplasma. 2011;58(1):89–95.PubMedCrossRef
22.
go back to reference Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, Rhŷs-Evans P, O-charoenrat P, Eccles S. Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res. 2007;67:7907–16.PubMedCrossRef Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, Rhŷs-Evans P, O-charoenrat P, Eccles S. Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res. 2007;67:7907–16.PubMedCrossRef
Metadata
Title
Hypermethylation and prognostic implication of Syk gene in human colorectal cancer
Authors
Zuli Yang
Lijun Huo
Hao Chen
Beibei Ni
Jun Xiang
Liang Kang
Lei Wang
Junsheng Peng
Yunfei Yuan
Jianping Wang
Publication date
01-06-2013
Publisher
Springer US
Published in
Medical Oncology / Issue 2/2013
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-013-0586-8

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