Skip to main content
SpringerLink
Log in

Hypermethylation and prognostic implication of Syk gene in human colorectal cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

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.

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

Similar content being viewed by others

References

  1. 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.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  CAS  Google Scholar 

  3. 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. 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  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. 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.

    Article  PubMed  CAS  Google Scholar 

  10. 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  CAS  Google Scholar 

  11. 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  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Stewart Z, Pietenpol J. Syk: a new player in the field of breast cancer. Breast Cancer Res. 2001;3:5–7.

    Article  PubMed  CAS  Google Scholar 

  14. 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  CAS  Google Scholar 

  15. 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  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant (no. 81072042) from National Nature Scientific Funds, China.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Zuli Yang, Hao Chen, Jun Xiang & Junsheng Peng

  2. Department of Ophthalmology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Lijun Huo

  3. Gastrointestinal Institute, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Beibei Ni

  4. Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People’s Republic of China

    Liang Kang, Lei Wang & Jianping Wang

  5. Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

    Yunfei Yuan

Authors
  1. Zuli Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lijun Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beibei Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liang Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junsheng Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yunfei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jianping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianping Wang.

Additional information

Zuli Yang and Lijun Huo contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, Z., Huo, L., Chen, H. et al. Hypermethylation and prognostic implication of Syk gene in human colorectal cancer. Med Oncol 30, 586 (2013). https://doi.org/10.1007/s12032-013-0586-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0586-8

Keywords

Search

Navigation