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Differential expression of fatty acid synthase (FAS) and ErbB2 in nonmalignant and malignant oral keratinocytes

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Abstract

The aim of this study was to investigate fatty acid synthase (FAS) and ErbB2 expression in nonmalignant oral epithelium and oral or head and neck squamous cell carcinomas (OSCC/HNSCC). Morphologically normal, hyperkeratotic, and dysplastic oral epithelium as well as well-differentiated and poorly differentiated OSCC were immunohistochemically evaluated for FAS, ErbB2, and Ki-67. These proteins were also analyzed in a tissue microarray with 55 HNSCC. SCC-9 cells were used to study FAS and ErbB2 during differentiation. FAS expression was higher in hyperkeratosis, dysplasias, and OSCC than in normal epithelium. Well-differentiated OSCC/HNSCC were more positive for FAS than the poorly differentiated tumors. ErbB2 was observed at the surface of nonmalignant and well-differentiated OSCC/HNSCC keratinocytes and in the cytoplasm of poorly differentiated cells. Ki-67 index was progressively higher from normal oral epithelium to OSCC, inversely correlated with cell surface ErbB2, and positively correlated with intracytoplasmic ErbB2. Finally, SCC-9 cell cultures were enriched in membrane ErbB2-positive cells after differentiation by anchorage deprivation. In conclusion, FAS is overexpressed in OSCC/HNSCC and hyperkeratotic oral epithelium and ErbB2 is found at the cell surface of differentiating keratinocytes and in the cytoplasm of poorly differentiated tumor cells. Ki-67 index is higher in epithelial dysplasias and OSCC than in morphologically normal oral epithelium.

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References

  1. Agostini M, Silva SD, Zecchin KG, Coletta RD, Jorge J, Loda M, Graner E (2004) Fatty acid synthase is required for the proliferation of human oral squamous carcinoma cells. Oral Oncol 40:728–735

    Article  PubMed  CAS  Google Scholar 

  2. Alo PL, Visca P, Framarino ML, Botti C, Monaco S, Sebastiani V, Serpieri DE, Di Tondo U (2000) Immunohistochemical study of fatty acid synthase in ovarian neoplasms. Oncol Rep 7:1383–1388

    PubMed  CAS  Google Scholar 

  3. Alo PL, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77:474–482

    Article  PubMed  CAS  Google Scholar 

  4. Ansari MN, Nicolaides N, Fu HC (1970) Fatty acid composition of the living layer and stratum corneum lipids of human sole skin epidermis. Lipids 5:838–845

    Article  PubMed  CAS  Google Scholar 

  5. Araujo CS, Graner E, Almeida OP, Sauk JJ, Coletta RD (2003) Histomorphometric characteristics and expression of epidermal growth factor and its receptor by epithelial cells of normal gingiva and hereditary gingival fibromatosis. J Periodontal Res 38:237–241

    Article  PubMed  CAS  Google Scholar 

  6. Baron A, Migita T, Tang D, Loda M (2004) Fatty acid synthase: a metabolic oncogene in prostate cancer? J Cell Biochem 91:47–53

    Article  PubMed  CAS  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W (2002) Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proc Natl Acad Sci U S A 99:138–143

    Article  PubMed  CAS  Google Scholar 

  9. Chirala SS, Chang H, Matzuk M, Abu-Elheiga L, Mao J, Mahon K, Finegold M, Wakil SJ (2003) Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc Natl Acad Sci U S A 100:6358–6363

    Article  PubMed  CAS  Google Scholar 

  10. Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM (2001) Delineation of prognostic biomarkers in prostate cancer. Nature 412:822–826

    Article  PubMed  CAS  Google Scholar 

  11. Furuya Y, Akimoto S, Yasuda K, Ito H (1997) Apoptosis of androgen-independent prostate cell line induced by inhibition of fatty acid synthesis. Anticancer Res 17:4589–4593

    PubMed  CAS  Google Scholar 

  12. Gansler TS, Hardman W, 3rd Hunt DA, Schaffel S, Hennigar RA (1997) Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Human Pathol 28:686–692

    Article  CAS  Google Scholar 

  13. Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, Lechpammer M, Huesken D, Zimmermann J, Signoretti S, Loda M (2004) The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5:253–261

    Article  PubMed  CAS  Google Scholar 

  14. Gray GM, Yardley HJ (1975) Different populations of pig epidermal cells: isolation and lipid composition. J Lipid Res 16:441–447

    PubMed  CAS  Google Scholar 

  15. Guo CB, Cui NH, Yu GY, Liu DX, Meng SC, Song Q (2003) Effects of cerulenin on the endogenous fatty acid synthetic activity in squamous cell carcinoma of the oral cavity. J Oral Maxillofac Surg 61:909–912

    Article  PubMed  Google Scholar 

  16. Heemers H, Maes B, Foufelle F, Heyns W, Verhoeven G, Swinnen JV (2001) Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway. Mol Endocrinol 15:1817–1828

    Article  PubMed  CAS  Google Scholar 

  17. Innocenzi D, Alo PL, Balzani A, Sebastiani V, Silipo V, La Torre G, Ricciardi G, Bosman C, Calvieri S (2003) Fatty acid synthase expression in melanoma. J Cutan Pathol 30:23–28

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. Khan AJ, King BL, Smith BD, Smith GL, DiGiovanna MP, Carter D, Haffty BG (2002) Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. Clin Cancer Res 8:540–548

    PubMed  CAS  Google Scholar 

  20. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW (2004) Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res 64:2070–2075

    Article  PubMed  CAS  Google Scholar 

  21. Krontiras H, Roye GD, Beenken SE, Myers RB, Mayo MS, Peters GE, Grizzle WE (1999) Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue. Head Neck 21:325–329

    Article  PubMed  CAS  Google Scholar 

  22. Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208

    Article  PubMed  CAS  Google Scholar 

  23. Kusakabe T, Nashimoto A, Honma K, Suzuki T (2002) Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach. Histopathology 40:71–79

    Article  PubMed  CAS  Google Scholar 

  24. Lacasa D, Le Liepvre X, Ferre P, Dugail I (2001) Progesterone stimulates adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c gene expression: potential mechanism for the lipogenic effect of progesterone in adipose tissue. J Biol Chem 276:11512–11516

    Article  PubMed  CAS  Google Scholar 

  25. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, Pizer ES (2001) Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res 61:1493–1499

    PubMed  CAS  Google Scholar 

  26. Menendez JA, Mehmi I, Verma VA, Teng PK, Lupu R (2004) Pharmacological inhibition of fatty acid synthase (FAS): a novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation. Mol Carcinog 41:164–178

    Article  PubMed  CAS  Google Scholar 

  27. Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R (2004) Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci U S A 101:10715–10720

    Article  PubMed  CAS  Google Scholar 

  28. Monk SA, Denison MS, Rice RH (2001) Transient expression of CYP1A1 in rat epithelial cells cultured in suspension. Arch Biochem Biophys 393:154–162

    Article  PubMed  CAS  Google Scholar 

  29. Myers RB, Oelschlager DK, Weiss HL, Frost AR, Grizzle WE (2001) Fatty acid synthase: an early molecular marker of progression of prostatic adenocarcinoma to androgen independence. J Urol 165:1027–1032

    Article  PubMed  CAS  Google Scholar 

  30. 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

    Article  PubMed  CAS  Google Scholar 

  31. Oskouian B (2000) Overexpression of fatty acid synthase in SKBR3 breast cancer cell line is mediated via a transcriptional mechanism. Cancer Lett 149:43–51

    Article  PubMed  CAS  Google Scholar 

  32. Piyathilake CJ, Frost AR, Manne U, Bell WC, Weiss H, Heimburger DC, Grizzle WE (2000) The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung. Human Pathol 31:1068–1073

    Article  CAS  Google Scholar 

  33. Pizer ES, Chrest FJ, DiGiuseppe JA, Han WF (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res 58:4611–4615

    PubMed  CAS  Google Scholar 

  34. Pizer ES, Pflug BR, Bova GS, Han WF, Udan MS, Nelson JB (2001) Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. Prostate 47:102–110

    Article  PubMed  CAS  Google Scholar 

  35. Pizer ES, Wood FD, Heine HS, Romantsev FE, Pasternack GR, Kuhajda FP (1996) Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res 56:1189–1193

    PubMed  CAS  Google Scholar 

  36. Rheinwald JG, Beckett MA (1980) Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22:629–632

    Article  PubMed  CAS  Google Scholar 

  37. Ricardo Martinez I Jr, Peters A (1971) Membrane-coating granules and membrane modifications in keratinizing epithelia. Am J Anat 130:93–119

    Article  PubMed  Google Scholar 

  38. Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T, Bubley G, Balk S, Loda M (2003) Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol Cancer Res 1:707–715

    PubMed  CAS  Google Scholar 

  39. Rossi S, Ou W, Tang D, Bhattacharya N, Dei Tos A, Fletcher J, Loda M (2006) Gastrointestinal stromal tumours overexpress fatty acid synthase. J Pathol 209:369–375

    Article  PubMed  CAS  Google Scholar 

  40. Shurbaji MS, Kalbfleisch JH, Thurmond TS (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Human Pathol 27:917–921

    Article  CAS  Google Scholar 

  41. Silva SD, Agostini M, Nishimoto IN, Coletta RD, Alves FA, Lopes MA, Kowalski LP, Graner E (2004) Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell carcinoma. A clinicopathological study. Oral Oncol 40:688–696

    Article  PubMed  CAS  Google Scholar 

  42. Squier CA, Kremer MJ (2001) Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr 29:7–15

    PubMed  Google Scholar 

  43. Swinnen JV, Esquenet M, Goossens K, Heyns W, Verhoeven G (1997) Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. Cancer Res 57:1086–1090

    PubMed  CAS  Google Scholar 

  44. Swinnen JV, Heemers H, Deboel L, Foufelle F, Heyns W, Verhoeven G (2000) Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19:5173–5181

    Article  PubMed  CAS  Google Scholar 

  45. Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L, Heyns W, Verhoeven G (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98:19–22

    Article  PubMed  CAS  Google Scholar 

  46. Takahiro T, Shinichi K, Toshimitsu S (2003) Expression of fatty acid synthase as a prognostic indicator in soft tissue sarcomas. Clin Cancer Res 9:2204–2212

    PubMed  CAS  Google Scholar 

  47. Uchiyama N, Yamamoto A, Kameda K, Yamaguchi H, Ito M (2000) The activity of fatty acid synthase of epidermal keratinocytes is regulated in the lower stratum spinousum and the stratum basale by local inflammation rather than by circulating hormones. J Dermatol Sci 24:134–141

    Article  PubMed  CAS  Google Scholar 

  48. Van de Sande T, De Schrijver E, Heyns W, Verhoeven G, Swinnen JV (2002) Role of the phosphatidylinositol 3¢-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res 62:642–646

    PubMed  Google Scholar 

  49. Visca P, Alo PL, Del Nonno F, Botti C, Trombetta G, Marandino F, Filippi S, Di Tondo U, Donnorso RP (1999) Immunohistochemical expression of fatty acid synthase, apoptotic-regulating genes, proliferating factors, and ras protein product in colorectal adenomas, carcinomas, and adjacent nonneoplastic mucosa. Clin Cancer Res 5:4111–4118

    PubMed  CAS  Google Scholar 

  50. Watanabe R, Fujii H, Yamamoto A, Yamaguchi H, Takenouchi T, Kameda K, Ito M, Ono T (1996) Expression of cutaneous fatty acid-binding protein and its mRNA in rat skin. Arch Dermatol Res 288:481–483

    Article  PubMed  CAS  Google Scholar 

  51. Weiss L, Hoffmann GE, Schreiber R, Andres H, Fuchs E, Korber E, Kolb HJ (1986) Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biol Chem Hoppe Seyler 367:905–912

    PubMed  CAS  Google Scholar 

  52. Werkmeister R, Brandt B, Joos U (2000) Clinical relevance of erbB-1 and -2 oncogenes in oral carcinomas. Oral Oncol 36:100–105

    Article  PubMed  CAS  Google Scholar 

  53. Xia W, Lau YK, Zhang HZ, Liu AR, Li L, Kiyokawa N, Clayman GL, Katz RL, Hung MC (1997) Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res 3:3–9

    PubMed  CAS  Google Scholar 

  54. 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

    PubMed  CAS  Google Scholar 

  55. Zhang Y, Guo C, Yu G (2005) A pilot study of fatty acid metabolism in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 34:78–81

    Article  PubMed  CAS  Google Scholar 

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We declare that we have no conflict of interest.

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Correspondence to Edgard Graner.

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This work was supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grant 02/08030-1 and CEPID/FAPESP grant 9814335). S.D. Silva, A.L.C.A. Rangel, and M. Agostini are supported by FAPESP fellowships (grants 04/06398-7, 04/13904-6, and 04/06397-0).

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Silva, S.D., Cunha, I.W., Rangel, A.L.C.A. et al. Differential expression of fatty acid synthase (FAS) and ErbB2 in nonmalignant and malignant oral keratinocytes. Virchows Arch 453, 57–67 (2008). https://doi.org/10.1007/s00428-008-0626-5

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