The expression of erbB2 and erbB3 receptors was investigated in an experimental model of chemically induced oral carcinogenesis in normal and diabetic (type I) Sprague-Dawley rats.
Thirteen diabetic and twelve normal rats developed precancerous and cancerous lesions after 4-nitroquinoline-N-oxide treatment, while six diabetic and six normal animals were used as controls. Sections of biopsies from all animals were classified histologically in the following categories: normal mucosa, hyperplasia, dysplasia, early invasion, well- and moderately-differentiated squamous cell carcinoma. Each section was studied immunohistochemically using monoclonal antibodies against erbB2 and erbB3 proteins and six representative histological regions in each section were analysed.
The erbB2 was expressed at very low levels in normal rats, while in diabetic animals its expression was significantly increased during early invasion (P = 0.04). The erbB3 expression was significantly elevated in well-differentiated carcinoma in normal animals (P = 0.01), while in diabetic animals it was significantly increased during oral mucosal hyperplasia and dysplasia (P = 0.03 and 0.0007, respectively). The comparison of erbB2 expression between diabetic and normal rats revealed significant differences in all stages except for the tumor stage of moderately differentiated carcinoma (P = 0.01, 0.00001, 0.00001, 0.003, and 0.00001). In regard to erbB3 expression, significant differences between diabetic and normal rats existed only in normal, non-cancerous and precancerous stages (P = 0.007, 0.0001, 0.0003).
It seems that diabetes enhances the expression of both erbB2 and erbB3 in certain stages of oral oncogenesis possibly resulting in promotion of cell proliferation and inhibition of apoptosis.
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Albuquresque RLC Jr, Miguel MCC, Costa ALL, Souza LB (2003) Correlation of c-erbB-2 and S-100 expression with the malignancy grading and anatomical site in oral squamous cell carcinoma. Int J Exp Pathol 84:259–265
Backer JM, Myers MG Jr, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M, Hu P, Margolis B, Skolnik EY, Schlessinger J, White MF (1992) Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J 11:3469–3479
Bei R, Pompa G, Vitolo D, Moriconi E, Ciocci L, Quaranta M, Frati L, Kraus MH, Muraro R (2001) Co-localization of multiple ErbB receptors in stratified epithelium of oral squamous cell carcinoma. J Pathol 195:343–348
Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R et al (1990) Overexpression of Her-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50:4087–4091
Bsoul SA, Huber MA, Terezhalmy GT (2005) Squamous cell carcinoma of the oral tissues: a comprehensive review for oral healthcare providers. J Contemp Dent Pract 6(4):1–16
Carver RS, Mathew PM, Russell WE (1997) Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors. Endocrinology 138(12):5195–5201
Citri A, Skaria KB, Yarden Y (2003) The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 284:54–65
De Vicente JC, Esteban I, Germana P, Germana A, Vega JA (2003) Expression of ErbB3 and ErbB4 protooncogene proteins in oral squamous cell carcinoma: a pilot study. Med Oral 8:374–381
Derka S, Vairaktaris E, Papakosta V, Vassiliou S, Acil Y, Vylliotis A, Spyridonidou S, Lazaris AC, Mourouzis C, Kokkori A, Moulavasili P, Perrea D, Donta I, Yapijakis C, Patsouris E (2006) Cell proliferation and apoptosis culminate in early stages of oral oncogenesis. Oral Oncol 42(5):540–550
Eldar-Finkelman H, Krebs EG (1997) Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci USA 94:9660–9664
Finney LS, Finney MO, Gonzales Campoy JM (1997) What the mouth has to say about diabetes. Careful examinations can avert serious complications. Postgrad Med 102:117–126
Folli F, Saad MJ, Backer JM, Kahn CR (1993) Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. Clin Invest 92:1787–1794
Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M (1995) Enhanced c-erbB3 expression in human pancreatic cancer: correlates with tumor progression. Clin Cancer Res 11:1413–1420
Funayama T, Nakanishi T, Takahashi K, Taniguchi S, Takigawa M, Matsumura T (1998) Overexpression of c-erbB-3 in various stages of human squamous cell carcinomas. Oncology 55:161–167
Goutzanis L, Vairaktaris E, Yapijakis C, Kavantzas N, Nkenke E, Derka S, Vassiliou S, Acil Y, Kessler P, Stavrianeas N, Perrea D, Donta I, Skandalakis P, Patsouris E (2007) Diabetes may increase risk for oral cancer through the insulin receptor substrate-1 and focal adhesion kinase pathway. Oral Oncol 43:165–173
Hemi R, Paz K, Wertheim N, Karasik A, Zick Y, Kanety H (2002) Transactivation of ErbB2 and ErbB3 by tumor necrosis factor-alpha and anisomycin leads to impaired insulin signaling through serine/threonine phosphorylation of IRS proteins. J Biol Chem 277(11):8961–8969
Hetzel DJ, Wilson TO, Keeney GL, Roche PC, Cha SS, Podratz KC (1992) Her-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol 47:179–185
Hou L, Shi D, Tu SM, Zhang HZ, Hung MC, Ling D (1992) Oral cancer progression and c-erbB-2/neu proto-oncogene expression. Cancer Lett 65:215–220
Issing WJ, Heppt WJ, Kastenbauer ER (1993) erbB-3, a third member of the erbB/epidermal growth factor receptor gene family: its expression in head and neck cancer cell lines. Eur Arch Otorhinolaryngol 250:392–395
Kawamura M, Fukuda S, Kawabata K, Iwamoto Y (1998) Comparison of health behaviour and oral/medical conditions in non-insulin-dependent (type 2) diabetics and non diabetics. Austr Dent J 43:315–320
Khademi B, Shirazi FM, Vasei M, Doroudchi M, Gandomi B, Modjtahedi H, Pezeshki AM, Ghaderi A (2002) The expression of p53, c-erbB-1 and c-erbB-2 molecules and their correlation with prognostic markers in patients with head and neck tumors. Cancer Lett 184:223–230
King CR, Kraus MH, Aaronson SA (1985) Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229:974–976
Kraus MH, Popescu NC, Amsbaugh SC, King CR (1987) Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J 6:605–610
Mori S, Mori Y, Mukaiyama T, Yamada Y, Sonobe Y, Matsushita H et al (1990) In vitro and in vivo release of soluble erbB-2 protein from human carcinoma cells. Jpn Cancer Res 81:489–494
Nagler RM, Kerner H, Laufer D, Ben-Eliezer S, Minkov I, Ben-Itzhak O (2002) Squamous cell carcinoma of the tongue: the prevalence and prognostic roles of p53, Bcl-2, c-erbB-2 and apoptotic rate as related to clinical and pathological characteristics in a retrospective study. Cancer Lett 186:137–150
O-Charoenrat P, Rhys-Evans PH, Eccles S (2001) Characterization of ten newly-derived human head and neck squamous carcinoma cell lines with special reference to c-erbB proto-oncogene expression. Anticancer Res 21:1953–1963
Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 98:4640–4645
Peles E, Yarden Y (1993) Neu and its ligands: from an oncogene to neural factors. Bioessays 5:815–824
Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y (1996) Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 15:2452–2467
Pirola L, Zvelebil MJ, Bulgarelli-Leva G, Van Obberghen E, Waterfield MD, Wymann MP (2001) Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase alpha (PI3Kalpha). Functions of lipid kinase-deficient PI3Kalpha in signaling. J Biol Chem 276:21544–21554
Pirola L, Bonnafous S, Johnston AM, Chaussade C, Portis F, Van Obberghen E (2003) Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. J Biol Chem 278(18):15641–15651
Rajkumar T, Gooden CSR, Lemoine NR, Gullick WJ (1993) Expression of the c-erbB3 protein in gastrointestinal tract tumors determined by monoclonal antibody RTJ1. J Pathol 170:271–278
Shintani S, Funayama T, Yoshihama Y, Alcalde RE, Matsumura T (1995) Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma. Cancer Lett 95:79–83
Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL 3rd (1994) Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269:14661–14665
Soltoff SP, Carraway KL, Prigent SA, Gullick WG, Cantley LC (1994) ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 14:3550–3558
Stern DF (2003) ErbBs in mammary development. Exp Cell Res 284:89–98
Tanti JF, Gremeaux T, Van Obberghen E, Le Marchand-Brustel Y (1994) Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase. Biochem J 304:17–21
Tsigris C, Karayiannakis AJ, Syrigos KN, Zbar A, Diamantis T, Kalahanis N, Alexiou D (2002a) Clinical significance of soluble c-erbB-2 levels in the serum and urine of patients with gastric cancer. Anticancer Res 22(5):3061–3065
Tsigris C, Karayiannakis AJ, Zbar A, Syrigos KN, Baibas N, Diamantis T, Alexiou D (2002b) Clinical significance of serum and urinary c-erbB-2 levels in colorectal cancer. Cancer Lett 184(2):215–222
Ujpal M, Matos O, Bibok G, Szabo G (2002) Incidence of diabetes mellitus in patients with malignant tumors of the oral cavity. Orv Hetil 143:2731–2733
Ujpal M, Matos O, Bibok G, Somogyi A, Szabo G, Suba Z (2004) Diabetes and oral tumors in Hungary. Epidemiological correlations. Diabetes Care 27:770–774
Vora HH, Shah NG, Patel DD, Trivedi TI, Chikhlikar PR (2003) Prognostic significance of biomarkers in squamous cell carcinoma of the tongue: multivariate analysis. J Surg Oncol 82(1):34–50
Werkmeister R, Brandt B, Joos U (1996) The erbB oncogenes as prognostic markers in oral squamous cell carcinomas. Am J Surg 172:681–683
Werkmeister R, Brandt B, Joos U (2000) Clinical relevance of erbB-1 and -2 oncogenes in oral carcinomas. Oral Oncol 36:100–105
Wilkman TS, Hietanen JH, Malmstrom MJ, Konttinen YT (1998) Immunohistochemical analysis of the oncoprotein c-erbB-2 expression in oral benign and malignant lesions. Int J Oral Maxillofac Surg 27:209–212
Xia W, Lau YK, Zhang HZ, Xiao FY, Johnston DA, Liu AR, Li L, Katz RL, Hung MC (1999) Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res 5:4164–4174
This work was co-funded by the European Social Fund and National Resources (EPEAEK II “Pythagoras” 70/3/7391) grant to E.V.
Conflict of interest statement:
There are no financial or personal relationships with other people or organisations that could inappropriately influence (bias) our work.
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Vairaktaris, E., Goutzanis, L., Vassiliou, S. et al. Enhancement of erbB2 and erbB3 expression during oral oncogenesis in diabetic rats. J Cancer Res Clin Oncol 134, 337–344 (2008). https://doi.org/10.1007/s00432-007-0289-7
- Oral squamous cell carcinoma
- Histological grade