Skip to main content

Advertisement

SpringerLink
Log in

Desmoglein-3/γ-catenin and E-cadherin/ß-catenin differential expression in oral leukoplakia and squamous cell carcinoma

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

Abstract

Objective

The purpose of this study was to investigate gene/protein expression alterations of intercellular connections’ components in oral leukoplakia (OLs) and squamous-cell carcinoma (OSCCs).

Materials and methods

Expression of desmogleins-2,3 (Dsg2/Dsg3), E-cadherin, and their cytoplasmic ligand, β/γ-catenins were quantitatively assessed in HSC-3 cells growing as monolayer cultures (ML)/multicellular aggregates (MCAs), using RT-PCR/Western blot, whereas their localization was detected by immunofluorescence. Furthermore, their expression was semi-quantitatively investigated in tissues from 25 OLs/25 OSCCs, using automated immunohistochemistry.

Results

The steady-state levels of Dsg3 RNA transcripts increased as HSC-3 cells enter their exponential phase of growth, before a dramatic decrease to be observed as cells reached their plateau phase especially in MCAs. Upon the same period of time, Dsg2 levels have been increased. The expression of γ-catenin but not that of β-catenin was increased after 48 h in both MLs and MCAs. In clinical samples, Dsg3, Ε-cadherin, β/γ-catenin down-regulation was observed to be associated with the grade of OLs-dysplasia and OSCCs. Importantly, a membrane-to-cytoplasmic switch of expression and strong perinuclear aggregation of Dsg3/γ-catenin was seen in both HSC-3 cells and OLs/OSCCs.

Conclusions

The altered expression of Dsg3/γ-catenin and E-cadherin/β-catenin, in vitro and in ODs/OSCC imply their involvement in growth regulation and phenotype of dysplastic/malignant oral epithelial cells, contributing to the better understanding of epithelial dysplasia and OSCCs.

Clinical relevance

The observed alterations of their expression suggest a role of Dsg3 and γ-catenin (additionally to E-cadherin/β-catenin) as biomarkers of malignant transformation risk of oral dysplasia and the biological behavior (aggressiveness) of oral cancer, respectively.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Zhong X, Rescorla FJ (2012) Cell surface adhesion molecules and adhesion-initiated signaling: understanding of anoikis resistance mechanisms and therapeutic opportunities. Cell Signal 24:393–401

    Article  PubMed  Google Scholar 

  2. Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455

    Article  PubMed  Google Scholar 

  3. Ziober BL, Silverman SS Jr, Kramer RH (2001) Adhesive mechanisms regulating invasion and metastasis in oral cancer. Crit Rev Oral Biol Med 12:499–510

    Article  PubMed  Google Scholar 

  4. Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198:11–26

    PubMed  Google Scholar 

  5. Chidgey M, Dawson C (2007) Desmosomes: a role in cancer. Br J Cancer 96:1783–1787

    Article  PubMed Central  PubMed  Google Scholar 

  6. Tian X, Liu Z, Niu B, Zhang J, Tan TK, Lee SR et al (2011) E-cadherin/β-catenin complex and the epithelial barrier. J Biomed Biotechnol 2011:567305

    PubMed Central  PubMed  Google Scholar 

  7. Vizirianakis IS, Chen YQ, Kantak SS, Tsiftsoglou AS, Kramer RH (2002) Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells. Int J Oncol 21:135–144

    PubMed  Google Scholar 

  8. Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ (2012) E-cadherin’s dark side: possible role in tumor progression. Biochim Biophys Acta 1826:23–31

    PubMed Central  PubMed  Google Scholar 

  9. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480

    Article  PubMed  Google Scholar 

  10. Ochiai A, Akimoto S, Kanai Y, Shibata T, Oyama T, Hirohashi S (1994) c-erbB-2 gene product associates with catenins in human cancer cells. Biochem Biophys Res Commun 205:73–78

    Article  PubMed  Google Scholar 

  11. Pece S, Gutkind JS (2000) Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J Biol Chem 275:41227–41233

    Article  PubMed  Google Scholar 

  12. Garrod DR, Merritt AJ, Nie Z (2002) Desmosomal adhesion: structural basis, molecular mechanism and regulation (review). Mol Membr Biol 19:81–94

    Article  PubMed  Google Scholar 

  13. Harada H, Iwatsuki K, Ohtsuka M, Han GW, Kaneko F (1996) Abnormal desmoglein expression by squamous cell carcinoma cells. Acta Derm Venereol 76:417–420

    PubMed  Google Scholar 

  14. Krunic AL, Garrod DR, Madani S, Buchanan MD, Clark RE (1998) Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin. Br J Cancer 77:1275–1279

    Article  PubMed Central  PubMed  Google Scholar 

  15. Imai K, Kumagai S, Nakagawa K, Yamamoto E, Nakanishi I, Okada Y (1995) Immunolocalization of desmoglein and intermediate filaments in human oral squamous cell carcinomas. Head Neck 17:204–212

    Article  PubMed  Google Scholar 

  16. Chen YJ, Chang JT, Lee L, Wang HM, Liao CT, Chiu CC et al (2007) DSG3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of oncogenesis. Oncogene 26:467–476

    Article  PubMed  Google Scholar 

  17. Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D et al (2004) Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5:489–500

    Article  PubMed  Google Scholar 

  18. Kurzen H, Münzing I, Hartschuh W (2003) Expression of desmosomal proteins in squamous cell carcinomas of the skin. J Cutan Pathol 30:621–630

    Article  PubMed  Google Scholar 

  19. Garrod D (2010) Desmosomes in vivo. Dermatol Res Pract 2010:212439

    PubMed Central  PubMed  Google Scholar 

  20. Windoffer R, Borchert-Stuhlträger M, Leube RE (2002) Desmosomes: interconnected calcium-dependent structures of remarkable stability with significant integral membrane protein turnover. J Cell Sci 115:1717–1732

    PubMed  Google Scholar 

  21. Närkiö-Mäkelä M, Pukkila M, Lagerstedt E, Virtaniemi J, Pirinen R, Johansson R et al (2009) Reduced gamma-catenin expression and poor survival in oral squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 135:1035–1040

    Article  PubMed  Google Scholar 

  22. Nagel JM, Kriegl L, Horst D, Engel J, Gautam S, Mantzoros CS et al (2010) γ-Catenin is an independent prognostic marker in early stage colorectal cancer. Int J Colorectal Dis 25:1301–1309

    Article  PubMed  Google Scholar 

  23. Rieger-Christ KM, Ng L, Hanley RS, Durrani O, Ma H, Yee AS et al (2005) Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 92:2153–2159

    Article  PubMed Central  PubMed  Google Scholar 

  24. Miravet S, Piedra J, Miró F, Itarte E, García de Herreros A, Duñach M (2002) The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin. J Biol Chem 277:1884–1891

    Article  PubMed  Google Scholar 

  25. Hakimelahi S, Parker HR, Gilchrist AJ, Barry M, Li Z, Bleackley RC et al (2000) Plakoglobin regulates the expression of the anti-apoptotic protein BCL-2. J Biol Chem 275:10905–10911

    Article  PubMed  Google Scholar 

  26. Dusek RL, Godsel LM, Chen F, Strohecker AM, Getsios S, Harmon R et al (2007) Plakoglobin deficiency protects keratinocytes from apoptosis. J Invest Dermatol 127:792–801

    Article  PubMed  Google Scholar 

  27. Chidgey M, Dawson C (2007) Desmosomes: a role in cancer? Br J Cancer 96:1783–1787

    Article  PubMed Central  PubMed  Google Scholar 

  28. Kantak SS, Kramer RH (1998) E-cadherin regulates anchorage-independent growth and survival in oral squamous cell carcinoma cells. J Biol Chem 273:16953–16961

    Article  PubMed  Google Scholar 

  29. Cirillo N, Boutros S (2008) Fate of desmoglein 3 and E-cadherin in anchorage-independent growth and adhesion to substrates of oral squamous carcinoma cells. J Stomatol Invest 2:41–51

    Google Scholar 

  30. Gornowicz-Porowska J, Bowszyc-Dmochowska M, Seraszek-Jaros A, Kaczmarek E, Dmochowski M (2011) Loss of correlation between intensities of desmoglein 2 and desmoglein 3 expression in basal cell carcinomas. Acta Dermatovenerol Croat 19:150–155

    PubMed  Google Scholar 

  31. Lopes FF, da Costa Miguel MC, Pereira AL, da Cruz MC, de Almeida FR, Pinto LP et al (2009) Changes in immunoexpression of E-cadherin and beta-catenin in oral squamous cell carcinoma with and without nodal metastasis. Ann Diagn Pathol 13:22–29

    Article  PubMed  Google Scholar 

  32. Tanaka N, Odajima T, Ogi K, Ikeda T, Satoh M (2003) Expression of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br J Cancer 89:557–563

    Article  PubMed Central  PubMed  Google Scholar 

  33. Wang L, Liu T, Wang Y, Cao L, Nishioka M, Aguirre RL et al (2007) Altered expression of desmocollin 3, desmoglein 3, and beta-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation. Virchows Arch 451:959–966

    Article  PubMed  Google Scholar 

  34. Lo Muzio L, Lo Russo L, Falaschini S, Ciavarella D, Pentenero M, Arduino P et al (2009) Beta- and gamma-catenin expression in oral dysplasia. Oral Oncol 45:501–504

    Article  PubMed  Google Scholar 

  35. Mahomed F, Altini M, Meer S (2007) Altered E-cadherin/beta-catenin expression in oral squamous carcinoma with and without nodal metastasis. Oral Dis 13:386–392

    Article  PubMed  Google Scholar 

  36. Ishida K, Ito S, Wada N, Deguchi H, Hata T, Hosoda M et al (2007) Nuclear localization of beta-catenin involved in precancerous change in oral leukoplakia. Mol Cancer 6:62

    Article  PubMed Central  PubMed  Google Scholar 

  37. Sato K, Okazaki Y, Tonogi M, Tanaka Y, Yamane GY (2002) Expression of beta-catenin in rat oral epithelial dysplasia induced by 4-nitroquinoline 1-oxide. Oral Oncol 38:772–778

    Article  PubMed  Google Scholar 

  38. Williams HK, Sanders DS, Jankowski JA, Landini G, Brown AM (1998) Expression of cadherins and catenins in oral epithelial dysplasia and squamous cell carcinoma. J Oral Pathol Med 27:308–317

    Article  PubMed  Google Scholar 

  39. Santos-García A, Abad-Hernández MM, Fonseca-Sánchez E, Julián-González R, Galindo-Villardón P, Cruz-Hernández JJ et al (2006) E-cadherin, laminin and collagen IV expression in the evolution from dysplasia to oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal 11:E100–E105

    PubMed  Google Scholar 

  40. Takayama T, Shiozaki H, Shibamoto S, Oka H, Kimura Y, Tamura S et al (1996) Beta-catenin expression in human cancers. Am J Pathol 148:39–46

    PubMed  Google Scholar 

  41. Shinohara M, Hiraki A, Ikebe T, Nakamura S, Kurahara S, Shirasuna K et al (1998) Immunohistochemical study of desmosomes in oral squamous cell carcinoma: correlation with cytokeratin and E-cadherin staining, and with tumour behaviour. J Pathol 184:369–381

    Article  PubMed  Google Scholar 

  42. Hiraki A, Shinohara M, Ikebe T, Nakamura S, Kurahara S, Garrod DR (1996) Immunohistochemical staining of desmosomal components in oral squamous cell carcinomas and its association with tumour behaviour. Br J Cancer 73:1491–1497

    Article  PubMed Central  PubMed  Google Scholar 

  43. Alazawi WO, Morris LS, Stanley MA, Garrod DR, Coleman N (2003) Altered expression of desmosomal components in high-grade squamous intraepithelial lesions of the cervix. Virchows Arch 443:51–56

    Article  PubMed  Google Scholar 

  44. Teh MT, Parkinson EK, Thurlow JK, Liu F, Fortune F, Wan H (2011) A molecular study of desmosomes identifies a desmoglein isoform switch in head and neck squamous cell carcinoma. J Oral Pathol Med 40:67–76

    Article  PubMed  Google Scholar 

  45. Yin T, Green KJ (2004) Regulation of desmosome assembly and adhesion. Semin Cell Dev Biol 15:665–677

    PubMed  Google Scholar 

  46. Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D, Ben-Ze'ev A (1996) Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J Cell Biol 133:19–20

    Article  Google Scholar 

  47. Papagerakis S, Shabana AH, Depondt J, Pibouin L, Blin-Wakkach C, Berdal A (2004) Altered plakoglobin expression at mRNA and protein levels correlates with clinical outcome in patients with oropharynx squamous carcinomas. Hum Pathol 35:75–85

    Article  PubMed  Google Scholar 

  48. Ueda G, Sunakawa H, Nakamori K, Shinya T, Tsuhako W, Tamura Y et al (2006) Aberrant expression of beta- and gamma-catenin is an independent prognostic marker in oral squamous cell carcinoma. Int J Oral Maxillofac Surg Apr 35:356–361

    Article  Google Scholar 

  49. Fillies T, Buerger H, Gaertner C, August C, Brandt B, Joos U et al (2005) Catenin expression in T1/2 carcinomas of the floor of the mouth. Int J Oral Maxillofac Surg 34:907–911

    Article  PubMed  Google Scholar 

  50. Lin YC, Wu MY, Li DR, Wu XY, Zheng RM (2004) Prognostic and clinicopathological features of E-cadherin, alpha-catenin, beta-catenin, gamma-catenin and cyclin D1 expression in human esophageal squamous cell carcinoma. World J Gastroenterol 10:3235–3239

    PubMed  Google Scholar 

  51. Yamada K, Jordan R, Mori M, Speight PM (1997) The relationship between E-cadherin expression, clinical stage and tumour differentiation in oral squamous cell carcinoma. Oral Dis 3:82–85

    Article  PubMed  Google Scholar 

  52. Behrens J (1999) Cadherins and catenins: role in signal transduction and tumor progression. Cancer Metastasis Rev 18:15–30

    Article  PubMed  Google Scholar 

  53. Andreadis D, Epivatianos A, Mireas G, Nomikos A, Poulopoulos A, Yiotakis J et al (2006) Immunohistochemical detection of E-cadherin in certain types of salivary gland tumours. J Laryngol Otol 120:298–304

    Article  PubMed  Google Scholar 

  54. Liu LK, Jiang XY, Zhou XX, Wang DM, Song XL, Jiang HB (2010) Upregulation of vimentin and aberrant expression of E-cadherin/beta-catenin complex in oral squamous cell carcinomas: correlation with the clinicopathological features and patient outcome. Mod Pathol 23:213–224

    Article  PubMed  Google Scholar 

  55. Kurtz KA, Hoffman HT, Zimmerman MB, Robinson RA (2006) Decreased E-cadherin but not beta-catenin expression is associated with vascular invasion and decreased survival in head and neck squamous carcinomas. Otolaryngol Head Neck Surg 134:142–146

    Article  PubMed  Google Scholar 

  56. Schipper JH, Unger A, Jahnke K (1994) E-cadherin as a functional marker of the differentiation and invasiveness of squamous cell carcinoma of the head and neck. Clin Otolaryngol Allied Sci 19:381–384

    Article  PubMed  Google Scholar 

  57. Mattijssen V, Peters HM, Schalkwijk L, Manni JJ, van 't Hof-Grootenboer B, De Mulder PH et al (1993) E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. Int J Cancer 55:580–585

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Prof. Athanasios D. Dinopoulos and Mrs. Giannakopoulou Aggeliki (Department of Anatomy, School of Veterinary Medicine, Aristotle University of Thessaloniki) for help conducting immunofluorescence analysis, and Mrs. M. Kefala and Dr M. Tsopanomichalou (Department of Histopathology, Red Cross Hospital of Athens) for their technical assistance in immunochemistry.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Laboratory of Pharmacology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Marianthi Kyrodimou, Elsa P. Amanatiadou & Ioannis S. Vizirianakis

  2. Department of Oral Medicine/Pathology, School of Dentistry, School of Natural Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Dimitrios Andreadis & Apostolos Epivatianos

  3. Department of Histopathology, Red Cross Hospital of Athens, Athens, Greece

    Angeliki Drougou & Calypso Barbatis

  4. Department of Informatics, School of Natural Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Lefteris Angelis

Authors
  1. Marianthi Kyrodimou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitrios Andreadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angeliki Drougou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elsa P. Amanatiadou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lefteris Angelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Calypso Barbatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Apostolos Epivatianos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ioannis S. Vizirianakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ioannis S. Vizirianakis.

Additional information

Marianthi Kyrodimou and Dimitrios Andreadis have equally contributed as first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 40 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kyrodimou, M., Andreadis, D., Drougou, A. et al. Desmoglein-3/γ-catenin and E-cadherin/ß-catenin differential expression in oral leukoplakia and squamous cell carcinoma. Clin Oral Invest 18, 199–210 (2014). https://doi.org/10.1007/s00784-013-0937-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-013-0937-z

Keywords

Search

Navigation