An altered keratinocyte phenotype in oral submucous fibrosis: correlation of keratin K17 expression with disease severity
Anand Lalli
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorWanninayake M. Tilakaratne
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Department of Oral Pathology, University of Peradeniya, Peradeniya, Sri Lanka
Search for more papers by this authorAnura Ariyawardana
Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya, Sri Lanka
Search for more papers by this authorCaroline Fitchett
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorIrene M. Leigh
Centre for Cutaneous Research; Barts and The London, Queen Mary’s School of Medicine and Dentistry, Institute of Cell and Molecular Sciences, London, UK
Present address: College of Medicine, Dentistry and Nursing, University of Dundee, Level 10, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
Search for more papers by this authorEleni Hagi-Pavli
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAlan T. Cruchley
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorE. Kenneth Parkinson
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorMuy-Teck Teh
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorFarida Fortune
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAhmad Waseem
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAnand Lalli
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorWanninayake M. Tilakaratne
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Department of Oral Pathology, University of Peradeniya, Peradeniya, Sri Lanka
Search for more papers by this authorAnura Ariyawardana
Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya, Sri Lanka
Search for more papers by this authorCaroline Fitchett
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorIrene M. Leigh
Centre for Cutaneous Research; Barts and The London, Queen Mary’s School of Medicine and Dentistry, Institute of Cell and Molecular Sciences, London, UK
Present address: College of Medicine, Dentistry and Nursing, University of Dundee, Level 10, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
Search for more papers by this authorEleni Hagi-Pavli
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAlan T. Cruchley
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorE. Kenneth Parkinson
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorMuy-Teck Teh
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorFarida Fortune
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAhmad Waseem
Programme in Muco-Cutaneous Oncology, Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Sciences, London, UK
Search for more papers by this authorAbstract
Oral submucous fibrosis (OSF) is characterized by abnormal collagen metabolism in the submucosal connective tissue. Its influence on the overlying epithelium is not known but about 14% of OSF cases undergo malignant transformation to squamous cell carcinoma indicating association with abnormality of the epithelium. Here, we have defined the keratin expression profile, by immunohistochemistry and quantitative image analysis, using a panel of 22 anti-keratin monoclonal antibodies on 28 OSF samples. We observed an increase of K1 and K10 in the suprabasal layers, induction of K6 in the basal layer and complete loss of K19 in the epithelium. Furthermore, there was increased K17 expression in the suprabasal layers, which correlated with disease severity. In a subset of the most severe OSF cases (14%), K17 expression was completely lost in the basal layer which might define them to be at most risk to undergo malignant transformation. There was no detectable expression of K8, K18, K7 and K9 and the expression of K4, K13, K14, K15 and K16 did not change in OSF. We propose that the altered keratin profiles could be useful as histological diagnostic markers and provide important insights into the pathogenesis of the disease and its predisposition to malignancy.
Supporting Information
Table S1: Keratin immunostaining of OSF and normal epithelial samples: correlation between visual assessment and pixel analysis
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References
- 1 Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol 2006; 42: 561–8.
- 2 Petersen PE. Strengthening the prevention of oral cancer: the WHO perspective. Community Dent Oral Epidemiol 2005; 33: 397–9.
- 3 Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr Eval Carcinog Risks Hum 2004; 85: 1–334.
- 4 Utsunomiya H, Tilakaratne WM, Oshiro K, et al. Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization. J Oral Pathol Med 2005; 34: 498–507.
- 5 Kuo MY, Chen HM, Hahn LJ, Hsieh CC, Chiang CP. Collagen biosynthesis in human oral submucous fibrosis fibroblast cultures. J Dent Res 1995; 74: 1783–8.
- 6 Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Mehta FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984; 92: 224–9.
- 7 Canniff JP, Harvey W, Harris M. Oral submucous fibrosis: its pathogenesis and management. Br Dent J 1986; 160: 429–34.
- 8 Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31: 11–24.
- 9 Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol 2006; 174: 169–74.
- 10 Waseem A, Dogan B, Tidman N, et al. Keratin 15 expression in stratified epithelia: downregulation in activated keratinocytes. J Invest Dermatol 1999; 112: 362–9.
- 11 Bloor BK, Tidman N, Leigh IM, et al. Expression of keratin K2e in cutaneous and oral lesions: association with keratinocyte activation, proliferation, and keratinization. Am J Pathol 2003; 162: 963–75.
- 12 Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966; 22: 764–79.
- 13 Elie N, Plancoulaine B, Signolle JP, Herlin P. A simple way of quantifying immunostained cell nuclei on the whole histologic section. Cytometry A 2003; 56: 37–45.
- 14 Mackenzie IC. The role of epithelial-mesenchymal interactions in epithelial migration and differentiation. J Periodontal Res 1984; 19: 656–60.
- 15 Mueller MM, Fusenig NE. Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells. Differentiation 2002; 70: 486–97.
- 16 Chinnathambi S, Tomanek-Chalkley A, Ludwig N, et al. Recapitulation of oral mucosal tissues in long-term organotypic culture. Anat Rec A Discov Mol Cell Evol Biol 2003; 270: 162–74.
- 17 Mackenzie IC, Hill MW. Maintenance of regionally specific patterns of cell proliferation and differentiation in transplanted skin and oral mucosa. Cell Tissue Res 1981; 219: 597–607.
- 18
Andriessen MP,
Niessen FB,
Van de Kerkhof PC,
Schalkwijk J.
Hypertrophic scarring is associated with epidermal abnormalities: an immunohistochemical study.
J Pathol
1998; 186: 192–200.
10.1002/(SICI)1096-9896(1998100)186:2<192::AID-PATH163>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 19 Machesney M, Tidman N, Waseem A, Kirby L, Leigh I. Activated keratinocytes in the epidermis of hypertrophic scars. Am J Pathol 1998; 152: 1133–41.
- 20 Bloor BK, Seddon SV, Morgan PR. Gene expression of differentiation-specific keratins (K4, K13, K1 and K10) in oral non-dysplastic keratoses and lichen planus. J Oral Pathol Med 2000; 29: 376–84.
- 21 Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis – a collagen metabolic disorder. J Oral Pathol Med 2005; 34: 321–8.
- 22 Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5: 828–31.
- 23 Lane EB, Alexander CM. Use of keratin antibodies in tumor diagnosis. Semin Cancer Biol 1990; 1: 165–79.
- 24 Ogden GR, Lunny D, Lane EB. Keratin antigen retrieval in oral mucosal biopsies using microwave processing. Histochem J 1996; 28: 875–82.
- 25 Ranganathan K, Kavitha R, Sawant SS, Vaidya MM. Cytokeratin expression in oral submucous fibrosis–an immunohistochemical study. J Oral Pathol Med 2006; 35: 25–32.
- 26 Van der Velden LA, Manni JJ, Ramaekers FC, Kuijpers W. Expression of intermediate filament proteins in benign lesions of the oral mucosa. Eur Arch Otorhinolaryngol 1999; 256: 514–9.
- 27 Hansson A, Bloor BK, Haig Y, Morgan PR, Ekstrand J, Grafstrom RC. Expression of keratins in normal, immortalized and malignant oral epithelia in organotypic culture. Oral Oncol 2001; 37: 419–30.
- 28 Waseem A, Lane EB, Harrison D, Waseem N. A keratin antibody recognizing a heterotypic complex: epitope mapping to complementary locations on both components of the complex. Exp Cell Res 1996; 223: 203–14.
- 29 Waseem A, Karsten U, Leigh IM, Purkis P, Waseem NH, Lane EB. Conformational changes in the rod domain of human keratin 8 following heterotypic association with keratin 18 and its implication for filament stability. Biochemistry 2004; 43: 1283–95.
- 30
Leers MP,
Kolgen W,
Bjorklund V, et al.
Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis.
J Pathol
1999; 187: 567–72.
10.1002/(SICI)1096-9896(199904)187:5<567::AID-PATH288>3.0.CO;2-J CAS PubMed Web of Science® Google Scholar
- 31 Ditzel HJ, Strik MC, Larsen MK, et al. Cancer-associated cleavage of cytokeratin 8/18 heterotypic complexes exposes a neoepitope in human adenocarcinomas. J Biol Chem 2002; 277: 21712–22.
- 32 Waseem A, White K, Waseem NH. Identification of a novel keratin epitope: evidence for association between non-helical sub-domains L12 during filament assembly. Int J Biochem Cell Biol 1997; 29: 971–83.
- 33 Su L, Morgan PR, Lane EB. Keratin 14 and 19 expression in normal, dysplastic and malignant oral epithelia. A study using in situ hybridization and immunohistochemistry. J Oral Pathol Med 1996; 25: 293–301.
- 34 Lindberg K, Rheinwald JG. Suprabasal 40 kD keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 1989; 134: 89–98.
- 35 Su L, Morgan PR, Lane EB. Protein and mRNA expression of simple epithelial keratins in normal, dysplastic, and malignant oral epithelia. Am J Pathol 1994; 145: 1349–57.
- 36 Bowden PE. Keratins and other epidermal proteins. In: GC Priestley, Ed. Molecular aspects of dermatology. London: John Wiley & Sons Ltd, 1993; 19–54.
- 37 Tomic-canic M, Komine M, Freedberg IM, Blumenberg M. Epidermal signal transduction and transcription factor activation in activated keratinocytes. J Dermatol Sci 1998; 17: 167–81.
- 38 Haque MF, Meghji S, Khitab U, Harris M. Oral submucous fibrosis patients have altered levels of cytokine production. J Oral Pathol Med 2000; 29: 123–8.
- 39 Jiang CK, Flanagan S, Ohtsuki M, Shuai K, Freedberg IM, Blumenberg M. Disease-activated transcription factor: allergic reactions in human skin cause nuclear translocation of Stat-91 and induce synthesis of keratin K17. Mol Cell Biol 1994; 14: 4759–69.
- 40 Bonnekoh B, Huerkamp C, Wevers A, et al. Up-regulation of keratin 17 expression in human hacat keratinocytes by interferon-gamma. J Invest Dermatol 1995; 104: 58–61.
- 41 Radoja N, Stojadinovic O, Waseem A, et al. Thyroid hormones and gamma interferon specifically increase K15 keratin gene transcription. Mol Cell Biol 2004; 24: 3168–79.
- 42 Ogden GR, Chisholm DM, Leigh IM, Lane EB. Cytokeratin profiles in dyskeratosis congenita: an immunocytochemical investigation of lingual hyperkeratosis. J Oral Pathol Med 1992; 21: 353–7.