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1 Journal of Dental Hygiene Science Vol 5, No 3, pp 97~103 (2005) yw w TGF-β1 EGFR x x ûw ew Expression of TGF-β1 and EGFR in Irritation Fibroma and Oral Leukoplakia Mi-Heon Ryu Department of Dental Hygiene, Namseoul University, Cheonan City , Korea "#453"$5 Irritation fibroma (IF) is the most common tumor-like oral lesion that is evolved by proliferation of collagen in response to chronic irritation Oral leukoplakia (OL) is considered as precancerous lesion characterized by proliferation of epithelial cells due to chronic irritation, smoking and drinking TGF-β1 and EGFR are important factors that play an essential role in extracellular matrix remodeling during normal wound healing process The epithelial reaction by chronic irritation may be connected with pathogenesis of IF and OL In the present study, we examined the expression of TGF-β1 and EGFR in the IF and OL using immunohistochemistry We used 88 cases of IF, 44 cases of OL and 9 cases of normal oral mucosa as normal control TGF-β1 was decreased in the epithelium of IF and OL As for EGFR, the epithelial cells revealed the increased positive expression in IF and OL In case of OL, the Spearman correlation coefficient of TGF-β1 and EGFR was -010 (p < 005), which showed weak correlation In the fibrous tissue, TGF-β1 was increased only in IF The expression difference of TGF-β1 and EGFR may be involved in the pathogenesis of IF and OL,FZ XPSET Irritation fibroma, Oral leukoplakia, Wound healing, TGF-β1, EGFR w ü ùkú ƒ w y wù w, e, e w, x Á w w v w š e,, x, x ƒ e w ñ w t (dome) ql ùkü w w w v w xw w v w š v d û»ù d downward growth pattern w s (collagen) ùkü x ƒ1,2) ü w y ü Corresponding author Tel: Fax: apollon@nsuackr š y 1) w e z w š ew š ew 54% rss ww,,, w, ù q e úe w, HIV y EBV, Candida albicans w, rsk y š 1,2) vd w w x z, rete ridge, v s x, v w s e 1,2) ù ƒw v ƒ w w yƒ» v w e» ù s s», w w x ƒ ùš, s y, w s, v, s, x v sy

2 Expression of TGF-β1 and EGFR in Irritation Fibroma and Oral Leukoplakia x ù s ƒ ƒwš, s s procollagen w, s» w w w e» w xw w s s y,» y, me (cytokine) ƒ w w3,4) e» w PDGF(platelet derived growth factor), TGF(transforming growth factor)-β, EGF(epidermal growth factor), bfgf(basic fibroblast growth factor), VEGF(vascular endothelial growth factor), TNF(tumor necrosis factor)-α, lk(interleukin), vk (prostaglandin), w z(collagenase), p w z (elastase), TIMP(tissue inhibitor of metalloproteinase) e»» z ù (repair process) w w3-5) e» ù chronic wound healing, proliferative scar, keloid, submucosal fibrosis, gingival overgrowth, palmar fibromatosis y ú y e» w ³x w ùš š ƒw v w w w ƒ x vd ƒy x ù» w ùkù Ÿw w w 1-2) w v y g y ww ƒw ù y w» w e» w TGF-β1 EGFR(epidermal growth factor receptor) y w e» w TGF-β1 EGFR x w w w v- w y wwš w 1 1) w ew üw û» ƒ w w 9 2) l ¾ w ew w 88 w 3) l ¾ w ew w 44 w v w w š, v x kƒ yw H/E ƒw w 2 1) w m H/E w w w 2) H/E yw w w 9, y 10% s 24 šwš 20 w z p g (ethyl alcohol) kwš xylene w qv sw z 3µm t w t kqvy pg w, H/E(hematoxylin and eosin) ww yw ww» w» qv s t 30 xylene ƒ qv wš 100%, 90%, 70% pg ww 3% H 2 O 2 10 endogenous peroxidase w z, 04% trypsin 20 z w w g z goat serum 30 k z TGFβ1(mö x w w w, Santa Cruz t, 1:50 ) EGFR(mouse x w w w, Bio- Genex t, 1 : 50 ) w w ƒƒ avidin-biotin yw ww ƒ phosphate buffered saline(pbs) þš, DAB(3,3'- diamonobenzidine) w Mayer's hematoxylin wš Ÿw x (Olympus, CX31, Tokyo, Japan) w w PBS g, 3» k w wì w z w z ƒ 10 (v 5, w 5) w digital cameraƒ x (Olympus, BX51T, Tokyo, Japan) w 200 w ƒ v» ew v v s, w» w w ü ew s sƒ w v w TGFβ1 EGFR x sƒw» w ƒ x 4 ù dw semiquantitive manner w6) (a) grade 0 : x (negative), (b) grade 1 : x sƒ 30% w (1+) (c) grade 2 : x sƒ 30~70% (2+) (d) grade 3 : x s ƒ 70% (3+) ƒ w z, ƒ 0~3 w yw 3) m,

Journal of Dental Hygiene Science Vol 5, No 3, pp 97~103 (2005) TGF-β1 EGFR e v, w w ù w z sƒw sƒ ³ s w š, d w ƒ ordinal scale» ww, TGF-β1 EGFR x» w Mann-Whitney U test w w TGF-β1 EGFR v w

w w sd Ì ƒù ƒ ƒ ƒyd Ì ƒ 'JH (a), (b) Irritation fibroma(a : H/E, 10, b : H/E, 200) 'JH Oral leukoplakia 'JH B Normal oral mucosa - Positive staining in the all layers except keratinized layer

case of proliferative epithelium (TGF-β1, 100) E Irritation fibroma - Positive staining of the epithelial cells in the basal cell layer and prickle cell layers in the case of atropic epithelium

3 Journal of Dental Hygiene Science Vol 5, No 3, pp 97~103 (2005) TGF-β1 EGFR e v, w w ù w z sƒw sƒ ³ s w š, d w ƒ ordinal scale» ww, TGF-β1 EGFR x» w Mann-Whitney U test w w TGF-β1 EGFR v w SAS(statistical analysis system) 82 m qj w 4 v w w s e w s ƒ (Fig 2) 3 yw 1) TGF-β1 1 w w w» v xwš s w w s s š y s w p x w s w {» wš k sƒ û (Fig 1-a, b), v w v 46 v 2 w w w» sd Ì ƒ ƒyd Ì ƒ, v x, v w w w sd Ì ƒù ƒ ƒ ƒyd Ì ƒ 'JH (a), (b) Irritation fibroma(a : H/E, 10, b : H/E, 200) 'JH Oral leukoplakia 'JH B Normal oral mucosa - Positive staining in the all layers except keratinized layer (TGF-β1, 100) C Normal oral mucosa - Focal positive staining of the fibroblasts (TGFβ1, 100) D Irritation fibroma - Focal positive staining of the epithelial cells in the prickle cell layer in the case of proliferative epithelium (TGF-β1, 100) E Irritation fibroma - Positive staining of the epithelial cells in the basal cell layer and prickle cell layers in the case of atropic epithelium (TGFβ1, 200) F Irritation fibroma - Positive staining of the fibroblasts in the mass of irritation fibroma (TGF-β1, 100) G Oral leukoplakia - Positive staining of the epithelial cells in the basal cell layer and the prickle cell layer (TGF-β1, 100) H Oral leukoplakia - Focal positive staining of the epithelial cells in the prickle cell layer (TGF-β1, 100) I Oral leukoplakia - Focal positive staining of the fibroblasts in the submucosal connective tissue (TGF-β1, 200)

Expression of TGF-β1 and EGFR in Irritation Fibroma and Oral Leukoplakia 5BCMF Expression of TGF-β1 Epithelium (%) Connective tissue(%) Normal Oral Mucosa Irritation Fibroma Oral leukoplakia No stain

4 Expression of TGF-β1 and EGFR in Irritation Fibroma and Oral Leukoplakia 5BCMF Expression of TGF-β1 Epithelium (%) Connective tissue(%) Normal Oral Mucosa Irritation Fibroma Oral leukoplakia No stain (focal) Basal cell & (diffuse) < 30% ~ 70% > 70% v ƒyd w v d e ùkü(fig 3-a) v w w s ùkü(fig 3-b) w 3» k k s TGF-β1 š, w PBS k v v v d x (Fig 3-c) v»d d TGF-β1 ùkþ(fig 3-d) ü s s, x üv s TGF-β1 x ƒ ùkü (Fig 3-e, Table 1) v»d d TGF-β1 ù(fig 3-f),»d, d s ùkþ(fig 3-g) v w w s x TGF-β1 x ùkü(fig 3-h, Table 1) v TGF-β1 w, TGF-β1 x w m w ùkü ù(p < 005), w m w ƒ w TGF-β1 w, TGF-β1 x, ƒw, m w ùkü (p < 005) 'JH BNormal oral mucosa - Positive staining of the epithelial cells in the basal layer (EGFR, 100) C Irritation fibroma - Positive staining of the epithelial cells in the basal cell layer and the prickle cell layer (EGFR, 200) D Oral leukoplakia - Positive staining of the epithelial cells in the basal cell layer (EGFR, 100) 2) EGFR v»d s w ùkü(fig 4-a) v w w w 3» k k s EGFR š, w PBS k v v»d d»¾ EGFR (Fig 4-b, Table 2) EGFR x ƒ w ùkü v w w EGFR w m w ùkü(p < 005) v»d d w 1/2 s š v w w x üv s v w s EGFR x ùkü(fig 4-c, Table 2) EGFR w m w ùkü, w ùkü(p < 005) 3) TGF-β1 EGFR» w v w v TGF-β1 EGFR v -010(p < 005), v m w 5BCMF Expression of EGFR Basal cell layer Normal Oral Mucosa Irritation Fibroma Oral leukoplakia Lower Middle Upper Basal cell layer Lower Middle Upper Basal cell layer Lower Middle Upper

5 š Journal of Dental Hygiene Science Vol 5, No 3, pp 97~103 (2005) TGF-β ü s» w wš e» w s» w e» w w w7), v y w s w ƒù w ƒ ³w» w s w wù TGF-β1 x w TGF-β s s» v s w w» ùk ü v s w, w s» e remodeling w morphogenesis w TGF-β s 5ƒ ƒ w, TGF-β1 eù f x x š, w x TGF-β1 signaling pathway» ƒ š 8-10) TGF-β1 yw v, m w w ù w m w w v v š»ù 46 v v v š s TGF-β ƒy vs s» G1 S w s» g s w z ùkü Karatsaidis rs k TGF-β/Smad ƒ TGF-βƒ vd û šw11) v s z ùkü TGF-β1 vƒ w 50% w ùkù TGF-β1 v z w ƒ ƒw w vd w TGF-β1 x yw ƒ w TGF-β1 x ƒw w e» s, w w» w TGF-β1 e j w w w TGFβ nw e w s 7), qp, k, TIMP w w w z w I, III, VI, Xx w TGF-β1 w w wš š 12-14) f(keloid)ù w {l(hypertropic scar) xw v s TGF-β1 ƒ v š sü TGF-β1ƒ ƒw procollagen 1x mrna ƒw w e (hereditary gingival fibromatosis)ù e (drug-induced gingival hyperplasia) 15-20) TGF-β ƒ ƒw š w ü w s ƒ TGF-β1 s w ww x TGF-β1 w w w ƒ EGFR(epidermal growth factor receptor, ErbB) v s» w w w w s w» wù s s EGFR 40, ,000 sw21)» s ww yy x, s, x, s (apoptosis), g w ƒ, g e w ƒ, s x, w s» w w w22,23) EGFR x s ü y ƒ yy s e w w w21) EGF(epidermal growth factor) v s vy w w w, ƒ w» x š EGFR yw, m w w ùkü v»d, d w s ùkü v v EGFR d ¾ x, w EGFR x ƒ w ù ƒ EGF v s w š, EGF EGFR 24) v sƒ w wš š keratinocyteƒ TGF-α xwš 23) w EGFR ù Rotaru v TGF-α x ƒw šw, w TGF-α s paracrine effect ùkü vd s z ùkü 23) ww ü v»d EGFR xwù v z ùkù v wš v v w w acanthosisù ƒy ƒ EGFR vd w s paracrine effect ùkü s w ƒ v s w EGF s y wš g e w w Palmar and plantar fibromatosis TGF-β EGF x w EGF Ix procollagen x ƒw w25), w x ƒ fibromatosis early stage xw šw w Irwin ù EGFR x ƒw šw š, Margo palmar fibromatosis TGF-α EGFR x ü w s s x šw26) s transformation» EGFR yy w EGFR x ƒw s» e,

6 Expression of TGF-β1 and EGFR in Irritation Fibroma and Oral Leukoplakia p w EGFR autocrine function paracrine function s w z š e w, k w w EGFR ƒ ƒw TGF-β1 ƒ ùš EGFR TGF-β1 v ƒ -010 ùkù» ew ƒ EGFR rss» w w w, rss y» l x v x ùkù x ƒ 15) w š w v x w rs s y w ù EGFR rs s» l x» w v x w yƒ ù EGFR x ƒw ƒ š ƒ ww ƒw w yƒ» mw š, e» ù w EGFR TGF-β1 x yƒ ù ƒ vd EGFR x ƒ TGF-β1 x w vd w y w w yƒ ùš ƒ vd EGFR x ùk ü w x ƒ w» w š ƒ wwš l ¾ w ew w w e» w TGF-β1 EGFR w w w yw mw 1 TGF-β1 yw, v TGF-β1 x wš ü s TGF-β1 x ƒw 2 EGFR yw, v EGFR x ƒw 3 TGF-β1 EGFR v w v x ùkü ûw w w šx 1 w wz: w 1q, q,, pp , , w w: w 2q, ù q,, pp , , , Ÿ³: Oral biochemistry 1q, q,, pp54-58, , Armstrong DG, Jude EB: The role of matrix metalloproteinases in wound healing J Am Podiatr Med Assoc 92(1): 12-18, Goldman R: Growth factors and chronic wound healing : Past, present, and future Adv Skin Wound Care 17: 24-35, Bankfalvi A, Krabort M, Végh A, Felszeghy E, Piffkó J: Deranged expression of the E-cadherin/-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomas J Oral Pathol Med 31: 457, Yang GP, Lim IJ, Phan TT, Lorenz HP, Longaker MT: From scarless fetal wounds to keloids : Molecular studies in wound healing Wound Rep Reg 11: , Chin D, Boyle GM, Parsons PG, Coman WB: What is transforming growth factor-beta (TGF-β)? Br J Plast Surg 57: , Dennler S, Goumans MJ, Dijke P: Transforming growth factor β signal transduction J Leukoc Biol 71: , Shi Y, Massagué J: Mechanism of TGF-β signaling from cell membrane to the nucleus Cell 113: , Karatsaidis A, Schreurs O, Axéll T, Helgeland K, Schenck K: Inhibition of the transforming factor-β/smad signaling pathway in the epithelium of oral lichen J Invest Dermatol 121: 1-8, Elder MJ, Dart JK, Lightman S: Conjunctival fibrosis in ocular cicatrical pemphigoid-the role of cytokines Exp Eye Res 65: , Kim JH, Kim BK, Moon KC, Hong HK, Lee HS: Activation of the TGF-β/Smad signaling pathway in focal segmental glomerulosclerosis Kidney Int 64(5): , Lee EH, Joo CK: Role of transforming growth factor-β in transdifferentiation and fibrosis of lens epithelial cells Invest Ophthalmol Vis Sci 40: , Andrade CR, Cotrin P, Graner E, Almeida OP, Sauk JJ, Coletta RD: Transforming growth factor-β1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis J Periodontol 72(12): , Bunduneli N, Kütükçüler N, Aksu G, Atilla G: Evaluation of transforming growth factor-β1 level in crevicular fluid of cyclosporin A - treated patients J Periodontol 72(4): , Linden GJ, Haworth SE, Maxwell AP, Poulton KV, Dyer PA, Middleton D, Irwin CR, Marley JJ, McNamee P, Short CD, Hull PS, James JA: The influence of transforming growth factor-β1 gene polymorphism in the severity of gingival overgrowth associated with concomitant use of cyclosporin A and a calcium channel blocker J Periodontol 72(6): , Uzel MI, Kantarci A, Hong HH, Uygur C, Sheff MC, Firatli E, Trackman PC: Connective tissue growth factor in drug-induced gingival overgrowth J Periodontol 72(7): , Wrights HJ, Chapple ILC, Matthews JB: TGF-β isoforms and TGF-β receptors in drug-induced and hereditary gingival overgrowth J Oral Pathol Med 30: , Mills BG, Frausto A, Brien E : Cytokines associated with the pathophysiology of aggressive fibromatosis J Orthop Res 18: , Herbst RS: Review of epidermal growth factor receptor biology Int J Radiation Oncology Biol Phys 59(2): 21-16, Ellis LM: Epidermal growth factor receptor in tumor angiogenesis Hematol Oncol Clin N Am 18: , Rotaru HR, Choi JY, Hong SP, Lee YC, Yun KI, Kim SG: Transforming growth factor-a and oral fibroma : Immunohistochemical and In situ hybridization study J Oral Maxillofac Surg 61: , ½k: rsvs Epidermal

7 Journal of Dental Hygiene Science Vol 5, No 3, pp 97~103 (2005) Growth Factor Transforming Growth Factor-β1 x w w w, Zamora RL, Kraemer BA, Erlich HP, Groner JP: Presence of growth factors in palmar and platar fibromatosis J Hand Surg 19A: , Margo G, Lanteri E, Micali G, Paravizzini G, Travali S, Lanzafame S: Myofibroblasts of palmar fibromatosis co-express transforming growth factor-alpha and epidermal growth factor receptor J Pathol 181: , 1997 (Received June 26, 2005; Accepted August 31, 2005)

50(1)-09.fm

50(1)-09.fm 2006, Vol. 50, No. 1 Printed in the Republic of Korea 언빨래가마르는현상에대한중등학교화학전공교사들의인식조사 ½x Á» Á½ # Á x* w w yw y š w w # w w (2005. 5. 11 ) A Research of Secondary School Chemistry Major Teachers Perceptions