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Expression of Cell Cycle and Apoptosis-related Proteins in Sporadic Odontogenic Keratocysts and Odontogenic Keratocysts Associated with the Nevoid Basal Cell Carcinoma Syndrome

Department of Oral Medicine and Pathology, University of Naples Federico , Faculty of Medicine, School of Dentistry, Naples, Italy

S. Staibano

Department of Biomorphological and Functional Sciences-Pathology Unit, University of Naples Federico , Faculty of Medicine, Naples, Italy

G. Pannone

Department of Oral Medicine and Pathology, University of Naples Federico , Faculty of Medicine, School of Dentistry, Naples, Italy

P. Bucci

Department of Oral Medicine and Pathology, University of Naples Federico , Faculty of Medicine, School of Dentistry, Naples, Italy

P.F. Nocini

Division of Oral and Maxillofacial Surgery, University of Verona, Faculty of Medicine, Verona, Italy

E. Bucci

Department of Oral Medicine and Pathology, University of Naples Federico , Faculty of Medicine, School of Dentistry, Naples, Italy

G. De Rosa

Department of Biomorphological and Functional Sciences-Pathology Unit, University of Naples Federico , Faculty of Medicine, Naples, Italy

Odontogenic keratocysts are occasionally (4-5%) associated with the nevoid basal cell carcinoma syndrome, a pleiotropic, autosomal disorder presenting a spectrum of developmental abnormalities and a predisposition for the development of different neoplasms. The aim of this study was to establish whether keratocysts showing clinically aggressive behavior associated with nevoid basal cell carcinoma syndrome reflect differences in cellular proliferation rate and/or in the expression of oncoproteins and tumor suppressor genes. For this reason, formalin-fixed paraffin-embedded sections of odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome (16 cases) and sporadic odontogenic keratocysts (16 cases) were compared for expression of proliferating cell nuclear antigen (PCNA) and p53, bcl-2, and bcl-1 (cyclin Dl) onco-proteins. Most of the epithelial lining of odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome showed nuclear immunopositivity for p53 protein and overexpression of cyclin Dl with various degrees of staining intensity. All sporadic odontogenic keratocysts were negative for p53 and cyclin Dl. The expressions of bcl-2 oncoprotein were found to be substantially similar between the two groups of lesions, with a cytoplasmic immunopositivity localized only in the resting reserve basal layer of the epithelium. PCNA expression showed no statistically significant difference between the two groups of lesions. In conclusion, the finding of cyclin Dl and p53 overexpression in odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome could be considered a hallmark of a mutated cellular phenotype, thus leading to the hypothesis that their aggressive clinical behavior could be due to a dysregulation of the expression of cyclin Dl and p53 proteins, involved in a check-point control of cellular proliferation.

Key Words: p53 • PCNA, bcl-2 • bcl-1 • AgNOR • immunocytochemistry • mutation • nevoid basal cell carcinoma syndrome • odontogenic cysts • odontogenic keratocysts

REFERENCES

• Ahlfors E, Larsson A, Sjögren S (1984). The odontogenic keratocyst: a benign cystic tumor? J Oral Maxillofac Surg 42:10-19. Areen RG, McClatchey KD, Baker HL (1981). Squamous cell carcinoma developing in an odontogenic keratocyst. Arch Otolaryngal 107:568-569.
• Arnold A., Kim HG, Gaz RD, Eddy RL, Fukushima Y., Bye MG, et al. (1989). Molecular cloning and chromosomal mapping DNA rearranged with the parathyroid hormone gene in parathyroid adenoma. J Clin Invest 83:2034-2040.[Medline] [Order article via Infotrieve]
• Baker SJ, Markowitz S., Fearon ER, Willson JK, Vogelstein B. (1990). Suppression of human colorectal-carcinoma cell growth by wild-type p53. Science 249:912-915.[Abstract/Free Full Text]
• Bale AE, Gailani MR, Leffel DJ (1995). The Gorlin syndrome gene: a tumor suppressor active in basal cell carcinogenesis and embryonic development. Proc Assoc Am Physicians 107:253-257.[Medline] [Order article via Infotrieve]
• Basler K., Struhl G. (1994). Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368:208-214.[CrossRef][Medline] [Order article via Infotrieve]
• Berenson JR, Yang J., Mickel RA (1989). Frequent amplification of the bd-1 locus in head and neck squamous cell carcinomas. Oncogene-4:1111-1116.[Medline] [Order article via Infotrieve]
• Boldy Dar (1989). Application of the AgNOR method to cell imprints of lymphoid tissue. J Pathol 157:75-79.[Medline] [Order article via Infotrieve]
• Brannon RB (1976). The odontogenic keratocyst. A clinicopathologic study of 312 cases. Part L Clinical features. Oral Surg Oral Med Oral Pathol 42:54-72
• Brannon RB (1977). The odontogenic keratocyst. A clinicopathologic study of 312 cases. Part II. Histologic features. Oral Surg Oral Med 0ral Pathol 43:233-255.
• Bravo R. (1986). Synthesis of the nuclear protein cyclin (PCNA) and its relationship with DNA replication. Exp Cell Res 163:287-293.[CrossRef][Medline] [Order article via Infotrieve]
• Bravo R., Frank R., Blundell PA, MacDonald-Bravo H. (1987). Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature 326:515-517..[CrossRef][Medline] [Order article via Infotrieve]
• Browne RM (1971). The odontogenic keratocysts. Histological features and their correlation with clinical behaviour. Br Dent 1131:249-259.
• Capdevila J., Estrada MP, Sanchez-Herrero E., Guerrero I. (1994). The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. EMBO J 13:71-82.[Medline] [Order article via Infotrieve]
• Chidambaram A., Goldstein AM, Gailani MR, Gerrard B., Bale SJ, DiGiovanna JJ, et al. (1996). Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients. Cancer Res 56:4599-4601.[Abstract/Free Full Text]
• Dean M. ( 1997). Towards a unified model of tumor suppression: lessons learned from the human patched gene. Biochim Biophys Acta 1332:M43-M52.[Medline] [Order article via Infotrieve]
• El Murtadi A., Grehan D., Toner M., McCartan BE (1996). Proliferating cell nuclear antigen staining in syndrome and non-syndrome odontogenic keratocysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:217-220.[CrossRef][Medline] [Order article via Infotrieve]
• Finlay CA, Hinds PW, Tan TH, Eliyahu D., Oren M., Levine AJ (1988). Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol 8:531-539.[Abstract/Free Full Text]
• Foley WL, Terry BC, Jacoway JR (1991). Malignant transformation of an odontogenic keratocyst: report of a case. J Oral Maxillofac Surg 49:768-771.[Medline] [Order article via Infotrieve]
• Gimenez-Conti IB, Collet AM, Lanfranchi H., Itoiz ME, Luna M., Xu H-J., et al. (1996). p53, Rb, and Cyclin Dl expression in human oral verrucous carcinomas. Cancer 78:17-23.
• Glantz SA (1994). Statistica per Discipline bio-mediche. 2nd ed. Milano: McGraw-Hill Libri Italia.
• Gorlin RJ (1987). Nevoid basal-cell carcinoma syndrome. Medicine 66:98-113.[Medline] [Order article via Infotrieve]
• Gorlin RJ (1995). Nevoid basal-cell carcinoma syndrome. Dermatologic Clinics 13:113-127.[Medline] [Order article via Infotrieve]
• Hahn H., Wicking C., Zaphiropoulos PG, Gailani MR, Shanley S., Chidambaram A., et al. (1996). Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841-851.[CrossRef][Medline] [Order article via Infotrieve]
• Hall PA, Levison DA, Woods AL, Yu CC, Kellock DB, Watkins JA, et al. (1990). Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasm. J Pathol 162:285-294.[CrossRef][Medline] [Order article via Infotrieve]
• Harrington EA, Fanidi A., Evan GI ( 1994). Oncogenes and cell death. Curr Opin Genet Dev 4:120-129.[CrossRef][Medline] [Order article via Infotrieve]
• Hellemans P., van Dam PA, Weyler J., Van Oosterom AT, Buytaert P., Van Marck E. (1995). Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 72:354-360.[Medline] [Order article via Infotrieve]
• High AS, Robinson PA, Klein CE (1993). Discrimination of parakeratinised odontogenic keratocysts from other odontogenic and non-odontogenic cyst types by expression of a 38kd cell-surface glycoprotein. J Oral Pathol Med 22:363-367.[Medline] [Order article via Infotrieve]
• Hockenbery DM, Zutter M., Hickey W., Nahm M., Korsmeyer SJ (1991). Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci USA 88:6961-6965.[Abstract/Free Full Text]
• Hollstein M., Sidransky D., Vogelstein B., Harris CC (1991). p53 mutations in human cancers. Science 253:49-53.[Abstract/Free Full Text]
• Ingham PW, Taylor AM, Nakano Y (1991). Role of the Drosophila patched gene in positional signaling. Nature 353:184-187. Isobe M, Emanuel BS, Givol D, Oren M, Croce CM (1986). Localization of gene for human p53 tumor antigen to band 17pl3. Nature 320:84-85.
• Joensuu H., Pylkkanem L., Toikkanen S. (1994). Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191-1198.[Abstract]
• Johnson RL, Rothman AL, Xie J., Goodrich LV, Bare JW, Bonifas JM, et al. (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668-1671.[Abstract]
• Kondel PA, Wiberg J. (1988). Odontogenic keratocysts: a follow up study of 29 cases. Swed Dent J 12:57-62.[Medline] [Order article via Infotrieve]
• Korsmeyer SJ (1992). bcl-2 initiates a new category of oncogenes:
• regulatory of cell death. Blood 80:879-886.
• Kuerbitz S., Plunkett BS, Walsh WV, Kastan MB (1992). Wild-type p53 is a cell-cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491-7495.[Abstract/Free Full Text]
• Lench NJ, High AS, Markham AF, Hume WJ, Robinson PA (1996). Investigation of chromosome 9q22.3-q31 DNA marker loss in odontogenic keratocysts. Oral Oncol Eur J Cancer 32(B):202-206.
• Levanat S., Gorlin RJ, Fallet S., Johnson DR, Fantasia JE, Bale AE ( 1996). A two-hit model for developmental defects in Gorlin Syndrome. Nature Genet 12:85-87.[CrossRef][Medline] [Order article via Infotrieve]
• Levine AJ, Momad J., Finlay CA (1991). The p53 tumour suppressor gene. Nature 351:453-456.[CrossRef][Medline] [Order article via Infotrieve]
• Li T-J., Browne RM, Matthews JB (1993). Expression of epidermal growth factor receptors by odontogenic jaw cysts. Virch Arch A Pathol Anat 432:137-144.
• Li T-J., Browne RM, Matthews JB (1994). Quantification of PCNA positive cells within odontogenic jaw cyst epithelium. J Oral Pathol Med 23:184-189.[Medline] [Order article via Infotrieve]
• Li T-J., Browne RM, Matthews JB (1995). Epithelial cell proliferation in the odontogenic keratocysts. A comparative immunocytochemical study of Ki-67 in simple, recurrent and basal cell naevus syndrome (BCNS) associated lesions. J Oral Pathol Med 24:221-226.[CrossRef][Medline] [Order article via Infotrieve]
• Li T-J., Browne RM, Prime SS, Paterson IC, Matthews JB (1996). p53 expression in odontogenic keratocyst epithelium. J Oral Pathol 25:249-255.
• Li W., Ohlmeyer JT, Lane ME, Kalderon D. (1995). Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development. Cell 80:553-562.[CrossRef][Medline] [Order article via Infotrieve]
• Lu Q-L., Elia G., Lucas S., Thomas JA (1993a). Bcl-2 protooncogene expression in Epstein-Barr virus-associated nasopharyngeal carcinoma. Int J Cancer 53:29-35.[Medline] [Order article via Infotrieve]
• Lu Q-L., Poulsom R., Wong L., Hanby AM (1993b). Bcl-2 expression in adult and embryonic non-haemopoietic tissues. J Pathol 169:431-437.[CrossRef][Medline] [Order article via Infotrieve]
• Matthews JB, Mason GI, Browne RM (1988). Epithelial cell markers and proliferating cells in odontogenic jaw cysts. J Pathol 156:283-290.[Medline] [Order article via Infotrieve]
• Minic AJ (1992). Primary intraosseous squamous cell carcinoma arising in a mandibular keratocyst. Int J Oral Maxillofac Surg 21:163-165.[Medline] [Order article via Infotrieve]
• Moos KF, Rennie JS (1987). Squamous cell carcinoma arising in a mandibular keratocyst in a patient with Gorlin's syndrome. Br J Oral Maxillofac Surg 25:280-284.[Medline] [Order article via Infotrieve]
• Ogden GR, Chisholm DM, Kiddie RA, Lane DP ( 1992). p53 protein in odontogenic cysts: increased expression in some odontogenic keratocysts. J Clin Pathol 45:1007-1010.[Abstract/Free Full Text]
• Partridge M., Towers JF (1987). The primordial cyst (odontogenic keratocyst): its tumor-like characteristics and behavior. Br J Oral Maxillofac Surg 25:271-279.[CrossRef][Medline] [Order article via Infotrieve]
• Pietenpohl JA, Vogelstein B. (1993). Tumor suppressor genes: no room at the p53 inn. Nature 365:17-18.[CrossRef][Medline] [Order article via Infotrieve]
• Pindborg JJ, Hansen J. (1963). Studies on odontogenic cyst epithelium. Clinical and Roentgenologic aspects of odontogenic keratocysts. Acta Pathol Microbiol Scand 58:283-294.[Medline] [Order article via Infotrieve]
• Robies AI, Conti CJ (1995). Early overexpression of cyclin Dl protein in mouse skin carcinogenesis. Carcinogen 16:781-786.[Abstract/Free Full Text]
• Rud J., Pindborg JJ (1969). Odontogenic keratocysts: a follow-up study of 21 cases. J Oral Surg 27:323-330.[Medline] [Order article via Infotrieve]
• Scharfetter K., Balz-Hermann C., Lagrange W., Koberg W., Mittermayer C. (1989). Proliferation kinetics-study of the growth of keratocysts. J Cran-Max-Fac Surg 17:226-233.
• Shear M. (1992). Cyst of the oral regions. Bristol: Wright.
• Sherr C. (1993). Mammalian Gl cyclins. Cell 73:1059-1065.[Medline] [Order article via Infotrieve]
• Slootweg PJ (1995). p53 protein and Ki-67 reactivity in epithelial odontogenic lesions. An immunohistochemical study. J Oral Pathol Med 24:393-397.[Medline] [Order article via Infotrieve]
• Tabata T., Kornberg TB (1994). Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76:89-102.[CrossRef][Medline] [Order article via Infotrieve]
• Toller PA (1971). Autoradiography of explants from odontogenic cysts. Br Dent J 131:57-61.[Medline] [Order article via Infotrieve]
• Tsuji T., Sasaki K., Kimura Y., Yamada K., Mori M., Shinozaki F. (1992). Measurement of proliferating cell nuclear antigen (PCNA) and its clinical application in oral cancers. Int J Oral Maxillofac Surg 21:369-372.[CrossRef][Medline] [Order article via Infotrieve]
• Van der Waal I., Rauhamaa R., Van der Kwast WA, Snow GB ( 1985). Squamous cell carcinoma arising in the lining of odontogenic cysts. Int J Oral Surg 14:140-152.
• Waseem NH, Lane DP ( 1990). Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA), structural conservation and the detection of a nucleolar form. J Cell Sci 96:121-129.[Abstract/Free Full Text]
• Woolgar JA, Rippin JW, Browne RM (1987a). A comparative study of the clinical and histological features of recurrent and non-recurrent odontogenic keratocysts. J Oral Pathol 16:124-128.[Medline] [Order article via Infotrieve]
• Woolgar JA, Rippin JW, Browne RM (1987b). A comparative histological study of odontogenic keratocysts in basal cell nevus syndrome and control patients. J Oral Pathol 16:75-80.[CrossRef][Medline] [Order article via Infotrieve]
• Yoshida H., Onizawa K., Yusa H. ( 1996). Squamous cell carcinoma arising in association with an orthokeratinized odontogenic keratocyst: report of a case. J Oral Maxillofac Surg 54:647-651.[Medline] [Order article via Infotrieve]
• Zachariades N., Markaki S., Karabela-Bouropoulou V. (1995). Squamous cell carcinoma developing in an odontogenic keratocyst. Arch Anat Cytol Pathol 43:350-353.[Medline] [Order article via Infotrieve]

Journal of Dental Research, Vol. 78, No. 7, 1345-1353 (1999)
DOI: 10.1177/00220345990780070901


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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Lo Muzio, L. Articles by De Rosa, G. Search for Related Content PubMed PubMed Citation Articles by Lo Muzio, L. Articles by De Rosa, G. Pubmed/NCBI databases Substance via MeSH Social Bookmarking                         What's this?