Skip to main content
Log in

Immunohistochemical evidence of the prognostic value of hedgehog pathway components in primary gallbladder carcinoma

  • Original Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

Purpose

The activation of hedgehog (Hh) pathways has been studied extensively in many malignant tumors to elucidate their clinical diagnostic and prognostic utilities. However, their roles in primary gallbladder carcinoma (GBC) remain poorly understood. This study was conducted to clarify the immunoreactivity and prognostic value of Hh pathway components in GBC.

Methods

Levels of sonic hedgehog (Shh), its receptor, Patched (Ptch1), and its downstream transcription factor, Gli1 protein, were measured by immunohistochemistry in 93 specimens from patients with GBC. We analyzed the correlations between the expression of these factors and clinicopathological features, including prognosis.

Results

Among the 93 GBC specimens, 76 (81.7%), 70 (75.3%) and 66 (70.0%) were positive for Shh, Ptch1 and Gli1 expression, respectively. Expressions were significantly correlated with stage, lymph node metastasis, venous invasion, hepatic infiltration and lymphatic invasion (all P < 0.05). Patients with positive staining for Shh, Ptch1 and Gli1 had significantly lower survival rates than patients with negative staining. The expression patterns of Shh, Ptch1 and Gli1 were all associated with a malignant behavior risk category in GBC.

Conclusions

To our knowledge, this is the first report to define the role of the Hh pathway in GBC. Shh, Ptch1 and Gli1 are frequently expressed in GBC and associated with poorer survival. Thus, high expressions of Shh, Ptch1 and Gli1 proteins could serve as auxiliary parameters for predicting the malignant behavior of GBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol. 2003;4:167–76.

    Article  PubMed  Google Scholar 

  2. Fujikawa T, Tanaka A, Abe T, Yoshimoto H, Tokumitsu Y, Tada S, et al. Undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi: report of a case. Surg Today. 2011;41:579–84.

    Article  PubMed  Google Scholar 

  3. Roa I, De Aretxabala X, Araya JC, Roa J. Preneoplastic lesions in gallbladder cancer. J Surg Oncol. 2006;93:615–23.

    Article  PubMed  Google Scholar 

  4. Berman DM, Karhadkar SS, Maitra A. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846–51.

    Article  PubMed  CAS  Google Scholar 

  5. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3:903–11.

    Article  PubMed  Google Scholar 

  6. Ma X, Chen K, Huang S. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 2005;26:1698–705.

    Article  PubMed  CAS  Google Scholar 

  7. Kameda C, Tanaka H, Yamasaki A. The Hedgehog pathway is a possible therapeutic target for patients with estrogen receptor-negative breast cancer. Anticancer Res. 2009;29:871–9.

    PubMed  CAS  Google Scholar 

  8. Lauth M, Toftgrd R. The Hedgehog pathway as a drug target in cancer therapy. Curr Opin Investig Drugs. 2007;8:457–61.

    PubMed  CAS  Google Scholar 

  9. Walter K, Omura N, Hong SM. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Cancer Res. 2010;16:1781–9.

    Article  PubMed  CAS  Google Scholar 

  10. Laurendeau I, Ferrer M, Garrido D. Gene expression profiling of the Hedgehog signaling pathway in human meningiomas. Mol Med. 2010;16:262–70.

    Article  PubMed  CAS  Google Scholar 

  11. Thayer SP, di Magliano MP, Heiser PW. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851–6.

    Article  PubMed  CAS  Google Scholar 

  12. Han ME, Lee YS, Baek SY, Kim BS, Kim JB, Oh SO. Hedgehog signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2. Int J Mol Sci. 2009;10:3033–43.

    Article  PubMed  CAS  Google Scholar 

  13. Chen G, Goto Y, Sakamoto R, Tanaka K, Matsubara E, Nakamura M, et al. GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor. Biochem Biophys Res Commun. 2011;404:809–15.

    Article  PubMed  CAS  Google Scholar 

  14. Kelleher FC. Hedgehog signalling and therapeutics in pancreatic cancer. Carcinogenesis. 2010 (in press).

  15. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059–87.

    Article  PubMed  CAS  Google Scholar 

  16. Ju B, Spitsbergen J, Eden CJ, Taylor MR, Chen W. Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish. Mol Cancer. 2009;8:40.

    Article  PubMed  Google Scholar 

  17. Saqui-Salces M, Merchant JL. Hedgehog signaling and gastrointestinal cancer. Biochim Biophys Acta. 2010;1803:786–95.

    Article  PubMed  CAS  Google Scholar 

  18. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.

    Article  PubMed  CAS  Google Scholar 

  19. Misra S, Chaturvedi A, Misra NC. Gallbladder cancer. Curr Treat Options Gastroenterol. 2006;9:95–106.

    Article  PubMed  Google Scholar 

  20. Yanai K, Nagai S, Wada J, Yamanaka N, Nakamura M, Torata N, et al. Hedgehog signaling pathway is a possible therapeutic target for gastric cancer. J Surg Oncol. 2007;95:55–62.

    Article  PubMed  CAS  Google Scholar 

  21. Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg. 2010;45:387–92.

    Article  PubMed  Google Scholar 

  22. Wu WK, Cho CH, Lee CW, Fan D, Wu K, Yu J, et al. Dysregulation of cellular signaling in gastric cancer. Cancer Lett. 2010;295:144–53.

    Article  PubMed  CAS  Google Scholar 

  23. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–54.

    Article  PubMed  CAS  Google Scholar 

  24. Yang Y, Tian X, Xie X, Zhuang Y, Wu W, Wang W. Expression and regulation of hedgehog signaling pathway in pancreatic cancer. Langenbecks Arch Surg. 2010;395:515–25.

    Article  PubMed  Google Scholar 

  25. Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP, et al. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis. 2009;30:131–40.

    Article  PubMed  CAS  Google Scholar 

  26. Rush SZ, Abel TW, Valadez JG, Pearson M, Cooper MK. Activation of the Hedgehog pathway in pilocytic astrocytomas. Neuro Oncol. 2010;12:790–8.

    Article  PubMed  CAS  Google Scholar 

  27. Li YC, Deng YH, Guo ZH, Zhang MM, Zhu J, Pu CL, et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. Eur J Med Res. 2010;15:468–74.

    PubMed  CAS  Google Scholar 

  28. Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121:148–60.

    Article  PubMed  CAS  Google Scholar 

  29. Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009;9:873–86.

    Article  PubMed  CAS  Google Scholar 

  30. Morton JP, Mongeau ME, Klimstra DS. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA. 2007;104:5103–8.

    Article  PubMed  CAS  Google Scholar 

  31. Merchant JL, Saqui-Salces M, El-Zaatari M. Hedgehog signaling in gastric physiology and cancer. Prog Mol Biol Transl Sci. 2010;96:133–56.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The research was supported by the National Natural Science Foundation of China (#81172287).

Conflict of interest

Jinmao Li and his co-authors have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xilin Du.

Additional information

J. Li and T. Wu contributed to this work equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Wu, T., Lu, J. et al. Immunohistochemical evidence of the prognostic value of hedgehog pathway components in primary gallbladder carcinoma. Surg Today 42, 770–775 (2012). https://doi.org/10.1007/s00595-012-0157-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-012-0157-1

Keywords

Navigation