口腔麟狀上皮細胞癌是一侵犯性的口腔癌。主要好發於中東與東南亞地區，與嚼食檳榔、抽菸草飲食習性相關。口腔癌在這高復發與低存活率情形下，深入研究癌症病理機制和設計更有效率藥物治療策略是必須的。我們利用蛋白質體技術來分析，比較癌化細胞與正常細胞之間蛋白質表現型態是否有何差異，進一步做為癌症生物標誌或分子標的。利用蛋白質體技術，初步研究顯示FABP5蛋白質在口腔癌上明顯地大量表現。脂肪酸鍵結蛋白(FABPs)是由結構同源性細胞質蛋白所組成的多基因性家族，其能與多元不飽和長鏈脂肪酸、碳廿酸結合，且能以配體做為運載媒介來傳遞細胞內功能，例如脂肪酸的攝取和所調控的訊息傳送。我們利用反轉錄聚合酶連鎖反應和西方墨點法技術來偵測FABP5於口腔麟狀上皮細胞株與組織表現情形，結果顯示FABP5在口腔癌細胞中表現量明顯增加；探討FABP5在口腔癌所扮演的角色，我們觀察大量口腔麟狀上皮腫瘤組織經由免疫組織染色法和及時定量聚合酶連鎖反應，證實FABP5大量表現在腫瘤細胞初期和中度分化位置。FABP5如何影響口腔癌細胞分化的過程，我們將FABP5構築在腺病毒載體中,感染口腔癌細胞株,研究結果發現FABP5在腫瘤細胞中會增加細胞生長的活性及侵犯能力。進一步探討FABP5於分化中細胞所扮演的角色,經由mammalian two hybrid assay 來研究FABP5是否會與retinoic acid receptor (RAR)進行交互作用，結果發現FABP5會與vitamin D receptor (VDR)進行交互作用而不會與RAR反應，VDR活性會受FABP5 以ligand-independent 方式而增加；綜合以上結果顯示FABP5在口腔癌前期可作為早期診斷指標，且會藉由改變VDR的轉譯活化活性來調控細胞的分化。

Oral squamous cell carcinoma (OSCC) is an aggressive oral cancer which mainly occurs in Central and Southeast Asia. The high recurrence and low survival rates of OSCC require our continued efforts to understand the pathogenesis of the disease for designing better therapeutic strategies. Proteomics is a powerful technology for rapid screening of a large number of biomarkers or molecular targets. In this study, we adopted proteomic approach to compare the protein expression profiles between oral cancer and normal oral mucosa. Epidermal fatty acid binding protein (FABP5) has been found to be significantly over-expressed in OSCC. Fatty acid binding proteins (FABPs) constitute a multigene family of structurally homologous cytosolic proteins capable of binding polyunsaturated long chain fatty acids (PUFAs) and various eicosanoids, and may work as vehicles of their ligands for given cellular functions such as cellular FA uptake and FA-mediated signal transduction.The highly expression of FABP5 in several OSCC cell lines and OSCC specimens was also confirmed by Western blotting and RT-PCR. To investigate the role of FABP5 in oral carcinogenesis, we have evaluated the expression of FABP5 in a large number of OSCC tumors and the paired normal adjacent tissues by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction. We found that FABP5 was over expressed in early stage tumor cells and in moderated differentiated tumor cells. The purpose of this study was to examine changes in FABP5 expression during oral carcinogenesis, and the effects of FABP5 overexpression using an adenoviral vector; OSCC cells were transfected with Ad-FABP5, the effects of FABP5 was increased cell proliferation and invasion in tumor cell line. For further characterized the roles of FABP5 in cell differentiation, a mammalian two hybrid assay was used to evaluate if FABP5 can interact with retinoic acid receptor (RAR), Interestingly, we’ve found that FABP5 was not interacted with RAR but did interact with vitamin D receptor (VDR). FABP5 enhanced the transcriptional activity of VDR in the ligand-dependent manner. Taken together, our results identify that FABP5 is a biomarker for oral cancer early detection and modulates the cell differentiation by altering the VDR transactivation activity.

Allen, G.W., Liu, J., Kirby, M.A. & De Leon, M. Induction and axonal localization of epithelial/epidermal fatty acid-binding protein in retinal ganglion cells are associated with axon development and regeneration. J Neurosci Res 66, 396-405 (2001).
Allen, G.W., Liu, J.W. & De Leon, M. Depletion of a fatty acid-binding protein impairs neurite outgrowth in PC12 cells. in Brain Res Mol Brain Res Vol. 76 315-24 (2000).
Brouard, M.C., Saurat, J.H., Ghanem, G. & Siegenthaler, G. Urinary excretion of epidermal-type fatty acid-binding protein and S100A7 protein in patients with cutaneous melanoma. Melanoma Res 12, 627-31 (2002).
Buhlmann, C., Borchers, T., Pollak, M. & Spener, F. Fatty acid metabolism in human breast cancer cells (MCF7) transfected with heart-type fatty acid binding protein. Mol Cell Biochem 199, 41-8 (1999).
Chmurzynska, A. The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet 47, 39-48 (2006).
Fujii, K. et al. Proteomic study of human hepatocellular carcinoma using two-dimensional difference gel electrophoresis with saturation cysteine dye. Proteomics 5, 1411-22 (2005).
Guthmann, F. et al. Expression of fatty-acid-binding proteins in cells involved in lung-specific lipid metabolism. Eur J Biochem 253, 430-6 (1998).
Gutierrez-Gonzalez, L.H. et al. Solution structure and backbone dynamics of human epidermal-type fatty acid-binding protein. Biochem J 364, 725-37 (2002).
Hagens, G. et al. Calcium-binding protein S100A7 and epidermal-type fatty acid-binding protein are associated in the cytosol of human keratinocytes. Biochem J 339 (Pt 2), 419-27 (1999).
Hagens, G. et al. Probable interaction between S100A7 and in the cytosol of human keratinocytes from psoriatic scales. Mol Cell Biochem 192, 123-8 (1999).
Hohoff, C., Borchers, T., Rustow, B., Spener, F. & van Tilbeurgh, H. Expression, purification, and crystal structure determination of recombinant human epidermal-type fatty acid binding protein. Biochemistry 38, 12229-39 (1999).
Jing C, Beesley C, Foster CS, Chen H, Rudland PS, West DC, et al. Human cutaneous fatty acid-binding protein induces metastasis by up-regulating the expression of vascular endothelial growth factor gene in rat Rama 37 model cells. Cancer Res 2001;61:4357–64.
Kuijpers, A.L. et al. The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin. Br J Dermatol 139, 380-9 (1998).
Lehmann, F. et al. Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg Med Chem Lett 14, 4445-8 (2004).
Liu, Y., Longo, L.D. & De Leon, M. In situ and immunocytochemical localization of mRNA and protein during neuronal migration and differentiation in the rat brain. Brain Res 852, 16-27 (2000).
Munz, M., Zeidler, R. & Gires, O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein. Cancer Lett 225, 151-7 (2005).
M. Balzar, H.A. Bakker, I.H. Briaire-de-Bruijn, G.J. Fleuren, S.O. Warnaar, S.V. Litvinov, Cytoplasmic tail regulates the intercellular adhesion function of the epithelial cell adhesion molecule, Mol. Cell. Biol. 18 (1998) 4833–4843.
Nourani, M.R. et al. Localization of epidermal-type fatty acid binding protein in macrophages in advanced atretic follicles of adult mice. J Mol Histol 36, 391-400 (2005).
Nguan-Soon Tan, Natacha S. Shaw, et al. Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription, Mol. Cell. Biol. 22 (2002) 5114–5127.
O'Shaughnessy, R.F., Seery, J.P., Celis, J.E., Frischauf, A. & Watt, F.M. PA-FABP, a novel marker of human epidermal transit amplifying cells revealed by 2D protein gel electrophoresis and cDNA array hybridisation. FEBS Lett 486, 149-54 (2000).
Owada, Y., Suzuki, R., Iwasa, H., Spener, F. & Kondo, H. Localization of epidermal-type fatty acid binding protein in the thymic epithelial cells of mice. Histochem Cell Biol 117, 55-60 (2002).
Peleg S, Sastry M, Distinct conformational changes induced by 20-epi analogues of 1 alpha,25-dihydroxyvitamin D3 are associated with enhanced activation of the vitamin D receptor. Biochem J 270, 10551-8 (1995).
Rauch, J. et al. Allogenic antibody-mediated identification of head and neck cancer antigens. Biochem Biophys Res Commun 323, 156-62 (2004).
Schachtrup, C., Emmler, T., Bleck, B., Sandqvist, A. & Spener, F. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins. Biochem J 382, 239-45 (2004).
Uma, R.S., Naresh, K.N., D'Cruz, A.K., Mulherkar, R. & Borges, A.M. Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein. Oral Oncol (2006).
Veerkamp, J.H. & Zimmerman, A.W. Fatty acid-binding proteins of nervous tissue. J Mol Neurosci 16, 133-42; discussion 151-7 (2001).
Yun, X. et al. Differential localization of brain-type and epidermal-type fatty acid binding proteins in the adrenal gland of mice. Tohoku J Exp Med 203, 77-86 (2004).
Yasufumi Goto, Yuriko Matsuzaki, et al. New Melanoma Antigen Fatty Acid–Binding Protein 7, Involved in Proliferation and Invasion, Is a Potential Target for Immunotherapy and Molecular Target Therapy. Cancer Res 2006;66:4443–4449.