Skip to main content

Advertisement

SpringerLink
Log in

Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Aims

The aim of this study was to compare the clinical and demographic features of 62 patients presenting sporadic odontogenic keratocysts (OKCs) or OKCs associated with nevoid basal cell carcinoma syndrome (NBCCS). In conjunction with this, we also evaluated the immunohistochemical expression of Shh, Ptch1, Ptch2, Smo, Gli1, Gli2 and Gli3 proteins in 86 OKCs. By doing this, we add to the understanding of the biology of this type of lesion, providing tools that will help facilitate the early diagnosis of NBCCS in those patients where the first manifestation is that of OKCs.

Methods

This is a retrospective study; patients were classified into two groups: group 1 which consisted of those who were not affected by NBCCS (49 patients and 57 OKCs) and group 2 which consisted of those who were diagnosed with NBCCS (13 patients and 29 OKCs). The clinical and demographic features were studied and the immunohistochemical expression of Sonic Hedgehog proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) was analyzed in all samples.

Results

There was an increase in the expression of three proteins in the syndromic OKC, when compared to that of sporadic cysts. Shh and Gli1 showed higher cytoplasmic expression, while Smo revealed stronger nuclear and cytoplasmic expressions.

Conclusion and clinical relevance

Our findings suggest that the expression patterns of important Shh pathway proteins can represent valuable markers for early diagnosis of NBCCS-associated OKCs, as the major criterion for the diagnosis of NBCCS is currently based on the late appearance of basal cellular carcinomas. Thus, standardizing a new diagnostic tool for diagnosis of NBCCS could be of great importance in the identification of therapeutic targets. We therefore suggest, as based on our findings, that OKCs showing high expression of Shh, Smo, and Gli1 are potentially associated with NBCCS.

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

Similar content being viewed by others

References

  1. Boffano P, Ruga E, Gallesio C (2010) Keratocystic odontogenic tumor (odontogenic keratocyst): preliminary retrospective review of epidemiologic, clinical, and radiologic features of 261 lesions from University of Turin. J Oral Maxillofac Surg 68:2994–2999

    Article  PubMed  Google Scholar 

  2. Barnes L, Eveson JW, Reichart P, Sidransky D (2005) Pathology and genetics of head and neck Tumours. WHO Classif Tumour. IARC PRESS, Lyon

  3. Wright JM, Vered M (2017) Update from the 4th edition of the World Health Organization classification of head and neck tumours: odontogenic and maxillofacial bone tumors. Head Neck Pathol 11:68–77

    Article  PubMed  PubMed Central  Google Scholar 

  4. Friedrich RE (2007) Diagnosis and treatment of patients with nevoid basal cell carcinoma syndrome [Gorlin-Goltz syndrome (GGS)]. Anticancer Res 27:1783–1787

    PubMed  Google Scholar 

  5. Manfredi M, Vescovi P, Bonanini M, Porter S (2004) Nevoid basal cell carcinoma syndrome: a review of the literature. Int J Oral Maxillofac Surg 33:117–124

    Article  PubMed  Google Scholar 

  6. Yagyuu T, Kirita T, Sasahira T, Moriwaka Y, Yamamoto K, Kuniyasu H (2008) Recurrence of keratocystic odontogenic tumor: clinicopathological features and immunohistochemical study of the Hedgehog signaling pathway. Pathobiology 75:171–176

    Article  PubMed  Google Scholar 

  7. Bitar GJ, Herman CK, Dahman MI, Hoard MA (2002) Basal cell nevus syndrome: guidelines for early detection. Am Fam Physician 65:2501–2504

    PubMed  Google Scholar 

  8. Ortega Garcia De Amezaga A, Gracia Arregui O, Zepeda Nuño S, Acha Sagredo A, Aguirre Urizar JM (2008) Gorlin-Goltz syndrome: clinicopathologic aspects. Med Oral Patol Oral Cir Bucal 13:E338–E343

    PubMed  Google Scholar 

  9. Bree AF, Shah MR (2011) Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet A 155A:2091–2097

    Article  PubMed  Google Scholar 

  10. Hardcastle Z, Mo R, Hui CC, Sharpe PT (1998) The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development 125:2803–2811

    PubMed  Google Scholar 

  11. Adolphe C, Narang M, Ellis T, Wicking C, Kaur P, Wainwright B (2004) An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131:5009–5019

    Article  PubMed  Google Scholar 

  12. Evangelista M, Tian H, de Sauvage FJ (2006) The hedgehog signaling pathway in cancer. Clin Cancer Res 12:5924–5928

    Article  PubMed  Google Scholar 

  13. Chari NS, McDonnell TJ (2007) The sonic hedgehog signalling network in development and neoplasia. Adv Anat Pathol 14:344–352

    Article  PubMed  Google Scholar 

  14. Riobo NA, Lu K, Emerson CP Jr (2006) Hedgehog signal transduction: signal integration and cross talk in development and cancer. Cell Cycle 5:1612–1615

    Article  PubMed  Google Scholar 

  15. Lo Muzio L (2008) Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 3:32

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bhargava D, Deshpande A, Pogrel MA (2012) Keratocystic odontogenic tumour (KCOT)—a cyst to a tumour. Oral Maxillofac Surg 16:163–170

    Article  PubMed  Google Scholar 

  17. Zhang H, Ping XL, Lee PK, Wu XL, Yao YJ, Zhang MJ, Silvers DN, Ratner D, Malhotra R, Peacocke M, Tsou HC (2001) Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol 158:381–385

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vered M, Peleg O, Taicher SBA (2009) The immunoprofile of odontogenic keratocyst (keratocystic odontogenic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts. J Oral Pathol Med 38:597–604

    Article  PubMed  Google Scholar 

  19. Gonzáles-Alva P, Tanaka A, Oku Y, Yoshizawa D, Itoh S, Sakashita H, Ide F, Tajima Y, Kusama K (2008) Keratocystic odontogenic tumours: a retrospective study of 183 cases. J Oral Sci 50:205–212

    Article  Google Scholar 

  20. Ge X, Lyu P, Gu Y, Li L, Li J, Wang Y, Zhang L, Fu C, Cao Z (2015) Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: modulation of PFKFB3 activation. Biochem Biophys Res Commun 464:862–868

    Article  PubMed  Google Scholar 

  21. Ohki K, Kumamoto H, Ichinohasama R, Sato T, Takahashi N, Ooya K (2004) PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. Int J Oral Maxillofac Surg 33:584–592

    Article  PubMed  Google Scholar 

  22. Rui Z, Li-Ying P, Jia-Fei Q, Ying-Ying H, Feng C, Tie-Jun L (2014) Smoothened gene alterations in keratocystic odontogenic tumors. Head Face Med 10:36

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ruiz I, Altaba A, Sánchez P, Dahmane N, Altaba AI, Sánchez P, Dahmane N (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2:361–372

    Article  Google Scholar 

  24. Myoung H, Hong SP, Hong SD, Lee JI, Lim CY, Choung PH, Lee JH, Choi JY, Seo BM, Kim MJ (2001) Odontogenic keratocyst: review of 256 cases for recurrence and clinicopathologic parameters. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 91:328–333

    Article  PubMed  Google Scholar 

  25. MacDonald-Jankowski DS (2011) Keratocystic odontogenis tumour: systematic review. Dentomaxillofac Radiol 40:1–23

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gurgel CA, Buim ME, Carvalho KC, Sales CB, Reis MG, de Suoza RO, de Faro Valverde L, de Azevedo RA, Dos Santos JN, Soares FARE (2014) Transcriptional profiles of SHH pathway genes in keratocystic odontogenic tumour and ameloblastoma. J Oral Pathol Med 43:619–626

    Article  PubMed  Google Scholar 

  27. Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (1991) The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64:959–961

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wicking C, Smyth I, Bale A (1999) The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18:7844–7851

    Article  PubMed  Google Scholar 

  29. Daya-Grosjean L, Couvé-Privat S (2005) Sonic hedgehog signalling in basal cell carcinomas. Cancer Lett 225:181–192

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the São Paulo State Research Foundation (FAPESP) and the Organization for the Improvement of People in Higher Education (CAPES).

Funding

This study was funded by the São Paulo Research Foundation (FAPESP))and the Organization for the Improvement of People in Higher Education (CAPES).

Author information

Authors and Affiliations

  1. Department of Stomatology, School of Dentistry, University of Sao Paulo, Av. Prof. Lineu Prestes 2227 (Butantã), São Paulo, 03178-200, Brazil

    Ana Maria Hoyos Cadavid, M. F. S. D. Rodrigues, T. H. N. Teshima & F. A. Alves

  2. Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, Paulista State University “Julio de Mesquita Filho” – UNESP, São José dos Campos, São Paulo, Brazil

    E. Kaminagakura

  3. Biophotonics Applied to Health Science, Nove de Julho University, São Paulo, Brazil

    M. F. S. D. Rodrigues

  4. Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil

    C. A. L. Pinto

  5. Department of Stomatology, A. C. Camargo Cancer Center, São Paulo, Brazil

    F. A. Alves

Authors
  1. Ana Maria Hoyos Cadavid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Kaminagakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. F. S. D. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. A. L. Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. H. N. Teshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. A. Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Maria Hoyos Cadavid.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hoyos Cadavid, A.M., Kaminagakura, E., Rodrigues, M.F.S.D. et al. Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clin Oral Invest 23, 153–159 (2019). https://doi.org/10.1007/s00784-018-2421-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-018-2421-2

Keywords

Search

Navigation