Skip to main content
SpringerLink
Log in

Expression and clinical significance of Notch signaling genes in colorectal cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

The objective of this study was to explore the expression and clinical significance of Notch signaling genes in colorectal cancer. Colorectal cancer samples were prospectively collected from patients post-surgery at the 3rd Affiliated Hospital, Nanjing University of Traditional Chinese Medicine. Immunohistochemistry of tissue arrays was used to analyze the samples and genes involved in the Notch signaling pathway. Microsatellite instability (MSI) was detected by fluorescence multiplex polymerase chain reaction. A total of 146 colorectal cancer samples were collected, including 84 men (57.7%) and 62 women (42.5%). The average age of the study population was 60.8 ± 10.5 years. Notch1 and Notch2 gene expression correlated with tumor pathology type and degree of differentiation. In addition, Jagged 1 (JAG1) and hairy enhancer of split 1 gene expression correlated with the degree of tumor differentiation. Delta-like 1 gene expression varied significantly with tumor location. There was a significant difference between gene expression and MSI. Of the 138 patients, 134 (91.8%) participated in on-site visits, and the average follow-up time was 42.3 ± 13.3 months. During this period, 86 patients (71.6%) were tumor-free. At 1 year post-surgery, 93% of patients were alive, 74% of patients lived for 3 years, and 67% of patients lived for 5 years. The log-rank test was used to perform univariate analysis, and the COX proportional hazards model was used for the multivariate analysis. Based on these analyses, tumor prognosis correlated with the TNM stage, pathological type, microsatellite status as well as Notch2 and JAG1 gene expression. Patients expressing high levels of Notch2 and JAG1 presented with a significantly better prognosis compared to patients expressing negative or weak levels of Notch2 and JAG1. The expression levels of genes associated with the Notch signaling pathway correlated with tumor pathology and the degree of differentiation. In addition, Notch2 and JAG1 expression levels correlated with survival; however, the underlying mechanism for these correlations remains unclear.

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

Similar content being viewed by others

References

  1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics. CA Cancer J Clin. 2002;52:23–47.

    Article  PubMed  Google Scholar 

  2. Radtke F, Raj K. The role of NOTCH in tumorigenesis: oncogene or tumor suppressor? Nature Rev. 2003;3:756–67.

    Article  CAS  Google Scholar 

  3. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.

    Article  PubMed  CAS  Google Scholar 

  4. Qiao L, Wong B. Role of Notch signaling in colorectal cancer. Carcinogenesis. 2009;30:1979–86.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang Y, Li B, Ji ZZ, Zheng PS. Notch1 regulates the growth of human colon cancers. Cancer. 2010;116:5207–18.

    Article  PubMed  CAS  Google Scholar 

  6. Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science. 2005;307:1904–9.

    Article  PubMed  CAS  Google Scholar 

  7. Sikandar SS, Pate KT, Anderson S, et al. Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 2008;33:1223–9.

    Google Scholar 

  8. Jin HY, Liu X, Li VK, Ding Y, Yang B, Geng J, Lai R, Ding S, Ni M, Zhao R. Detection of mismatch repair gene germline mutation carrier among Chinese population with colorectal cancer. BMC Cancer. 2008;8:44.

    Article  PubMed  Google Scholar 

  9. Wang J. Current and future situation of colorectal carcinoma screening. J Dig Surg. 2006;5:303–5.

    Google Scholar 

  10. Subramaniam D, Ramalingam S, Houchen CW, Anant S. Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem. 2010;10:359–71.

    Article  PubMed  CAS  Google Scholar 

  11. Koch U, Radtke F. Notch and cancer: a double-edged sword. Cell Mol Life Sci. 2007;64:2746–62.

    Article  PubMed  CAS  Google Scholar 

  12. Sang L, Coller HA, Roberts JM. Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science. 2008;321:1095–100.

    Article  PubMed  CAS  Google Scholar 

  13. Katoh M, Katoh M. Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Int J Oncol. 2007;31:461–6.

    PubMed  CAS  Google Scholar 

  14. Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle L, Reboldi A, Favaro E, Mecarozzi M, Di Mario G, Screpanti I, Ponzoni M, Doglioni C, Amadori A. Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy. Cancer Res. 2009;69:1314–23. 15.

    Article  PubMed  CAS  Google Scholar 

  15. Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernández-Majada V, Grilli A, López-Bigas N, Bellora N, Albà MM, Torres F, Duñach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A, Espinosa L. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci U S A. 2009;106:6315–20.

    Article  PubMed  CAS  Google Scholar 

  16. Peignon G, Durand A, Cacheux W, Ayrault O, Terris B, Laurent-Puig P, Shroyer N, Van Seuningen I, Honjo T, Perret C, Romagnolo B. Complex interplay between b-catenin signaling and Notch effectors in intestinal tumorigenesis. Gut. 2011;60:166–76.

    Article  PubMed  CAS  Google Scholar 

  17. Chu D, Zhang Z, Zhou Y, Wang W, Li Y, Zhang H, Dong G, Zhao Q, Ji G. Notch1 and Notch2 have opposite prognostic effects on patients with colorectal cancer. Ann Oncol. 2011;22:2440–7.

    Article  PubMed  CAS  Google Scholar 

  18. Ungerbäck J, Elander N, Grünberg J, Sigvardsson M, Söderkvist P. The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells. PLoS One. 2011;6(3):e17957. 18.

    Article  PubMed  Google Scholar 

  19. Schreck KC, Taylor P, Marchionni L, Gopalakrishnan V, Bar EE, Gaiano N, Eberhart CG. The Notch target Hes1 directly modulates Gli1 expression and Hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res. 2010;16:6060–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by the National Nature Science Foundation of China (nos. 30572447 and 30973837).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. National Center of Colorectal Surgery, The 3rd affiliated Hospital of Nanjing University of Traditional Chinese Medicine, 1 Jinling Road, Nanjing, 210001, China

    Hei-Ying Jin, Xiaofeng Wang, Junhua Xu & Yijing Ding

  2. Nanjing Center for Disease Control and Prevention, 2 Zizhulin Road, Nanjing, 210003, China

    Hong-Ying Zhang

Authors
  1. Hei-Ying Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaofeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junhua Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yijing Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hei-Ying Jin.

Additional information

Hei-Ying Jin and Hong-Ying Zhang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jin, HY., Zhang, HY., Wang, X. et al. Expression and clinical significance of Notch signaling genes in colorectal cancer. Tumor Biol. 33, 817–824 (2012). https://doi.org/10.1007/s13277-011-0301-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-011-0301-3

Keywords

Search

Navigation