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Research for Betel quid Related Oral Cancer

Research for Betel quid Related Oral Cancer . Tien-Yu Shieh D.D.S., Ph.D., DNM., FICD Dean of College of Dental Medicine Kaohsiung Medical University Professor/Specialist of Oral and Maxillo-Facial Surgery. Betel quid chewing associated diseases. OSCC NPC Esophagus cancer Liver cancer

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Research for Betel quid Related Oral Cancer

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  1. Research for Betel quid Related Oral Cancer Tien-Yu Shieh D.D.S., Ph.D., DNM., FICD Dean of College of Dental Medicine Kaohsiung Medical University Professor/Specialist of Oral and Maxillo-Facial Surgery

  2. Betel quid chewing associated diseases • OSCC • NPC • Esophagus cancer • Liver cancer • Central obesity • Prematurity • Blood pressure regulation

  3. Research Scheme Center of Excellence for Environmental Medicine ENT for pharynx and larynx Patients from KMUH,OS Gastroenterology for Endoscope Questionnaire Blood Tissue epidemiology Paraffin block Serum (Protein) DNA / RNA Buffy coat (DNA) ＋ Molecular Epidemiology Stain Lip N2 / -80℃ Already：ACE、TNF-α、MMP-2、VEGF、P53、COX-2、TIMP Further：KLK、SCCA、BIRC5、HOX1、BUB1、CDHP、EPR1、KB20、 MOP9、CLIF…

  4. Table. Plasma KLK6, KLK7, and KLK10 in OSCC, oral premalignant patients , and health control. (P value analysis by Wilcoxon Rank Sum Test.) ELISA-血清中蛋白質 As show in this table, there was no significant between protein concentration and OSCC, oral premalignant, and control. Missing: Protein concentration too low to measurement

  5. Figure1-b. Relationship between different cancer stage of OSCC patients and the protein localization in KLK6, 7, and 10 免疫組織化學染色法—Protein localization Score Stage

  6. Table . Expression of KLK6, 7, and 10 mRNA in cancer lesion and surrounding normal tissues in OSCC patients. (N=12) 1 4.38 RNA濃度

  7. 在抽菸、嚼食檳榔及喝酒習慣下， KLK7與KLK10基因多型性與發展成口腔鱗狀上皮癌之多變項邏輯式回歸分析。 調整年齡、種族、教育程度使用習慣

  8. Global Center of Excellence for Oral Health Research and Development • Gene bank :patient sample size • Oral cancer tissue:158 Oral precancer tissue:22 • Oral cancer blood:534 Oral precancer blood:193 • Normal blood:624 DNA methylation tissue Real time PCR RNA PROTEIN IHC DNA SNP blood ELISA PROTEIN activity

  9. Current and previous studies for genetic susceptibility to oral squamous cell squamous carcinoma • Detoxification: microsomal epoxide hydrolase and MnSOD • DNA repair: OGG1, MUTYH, and MTH1 • Immune surveillance and apoptosis: Fas and FasL • Cell cycle: cyclin D1 and p53 • Inflammation: COX-2 • Cytokines and its signal transduction factor: TGFB1, IL-8, IL-10 and NFKB1 • Angiogenesis: VEGF • Receptor and signal tranduction: Her-2/neu and PPARMatrix degradation: MMP-9 and MMP-2

  10. Center of Excellence for Environmental Medicine

  11. The effects of alcohal drinking（A）, betel quid chewing（B）and cigarette smoking（c）on the incidence of oral cancer or sites of occurrence and mean age at diagnosis were different. Betel quid chewing was considered to be the most important risk factor for oral cancer. By stratified analysis incorporating the three factors simultaneously, relative risks were estimated at 122.8, for A+B+C factor, 89.1 for B+C, 54.0 for A+B and 28.2 for B only, as compared with participants abstaining from all three habits. CI. confidnce interval; A, Alcohal drinking; B, Betel quid chewing; C, Cigarette smoking

  12. Our other study realized that sites of occurrence, habits and mean age at diagnosis of oral cancer were quite different according to the oral habits (Tab.4)

  13. Epidemiological studies Chewing areca for an average 24.4 years (with an average of 17.3±18.5 portions a day) Oral precancerous lesion prevalence OSF :17.6% leukoplakia :24.4% Yang, Lee, Tung, Shieh et al., J Oral Pathol Med 2001; 30: 213-9

  14. After 3 years follow-up we found that the malignant transformation rate （100 person-year）for dysplasia, VH, leukoplakia and OSF are 7.98, 5.91, 3.37, and 2.85 respectively Source：KMUH data

  15. Mechanism of OSF Oral submucosal Fibroblasts Abnormal accumulation of collagen (1) Lysyl oxidase activity ↑ collagens ↑ (I, III, V) (2) Collagenase activity ↓ (3) TIMP-1 ↑ Betel quid chewing (4)(5) Phagocytosis activity ↓ (individual or same person) Influences cytokines production (1) R-H Ma, C-C Tsai, T-Y Shieh: Increased lysyl oxidase activity in fibroblasts cultrues from oral submucous fibrosis associated with betel nut chewing in Taiwan J Oral Pathol Med 24: 407-412, 1995. (2) I-Y Huang, T-Y Shieh: Collagen content and types in oral submucous fibrosis. Kaohsiung J Med Sci 5: 162-171, 1989. (3) D-H Shieh, L-C Chiang, T-Y Shieh: Augmented mRNA expression of tissue inhibitor of metalloproteinase-1(TIMP-1) in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis. Oral Oncology 39:728-735, 2003. (4) D-H Shieh, L-C Chiang, C-H Lee, Y-H Yang, T-Y Shieh: Effects of arecoline, safrole, and nicotine on collagen phagocytosis by human buccal mucosal fibroblasts as a possible mechanism for oral submucous fibrosis in Taiwan. J Oral Pathol Med 33;581-7,2004. (5) C-C Tsai, R-H Ma, T-Y Shieh: Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro as a possible mechanism for oral submucous fibrosis. J Oral Pathol Med 28: 59-63, 1999.

  16. Response of immune system Oral submucosal Fibroblasts (6) (7) IL-1β: SCC > VH > normal > OSF (8) TGF-β: OSF > normal Abnormal immune response (9) TNF-α:SCC>normal>SCC+betel IFN-γ:normal > normal+betel IL-2, TGF-β, IFN-γ:OSF < normal & SCC Betel quid chewing (10) mRNA→ TNF-α, TGF-β: SCC > normal IFN-γ: SCC < normal (11) sTNF-RI & sTNF-RII: SCC > normal (TNF-α/ sTNF-RII)*100 ratio: SCC < normal Influences cytokines production (12) Longitudinal study: TNF-α/sTNF-RII: recurred SCC > non-recurred SCC (pre-OP) sTNF-RII/sTNF-RI: recurred SCC > non-recurred SCC (post-OP 6 months) (6) C-C Tsai, C-C Chen, C-C Lin, C-H Chen, T-S Lin, T-Y Shieh. Kaohsiung J. Med. sci. 15(9): 513-9, 1999 (7) T-S Lin, T-Y Shieh. Chin J Oral Maxillofac Surg. 6:34-42, 1995. (8) C-H Huang, T-Y Shieh. J Academy Formosan Stomatology 15: 227-239,1999. (9) H-J Hsu, K-L Chang, Y-H Yang, T-Y Shieh. Kaohsiung J Med Sci 17：175-182,2001. (10) M-C Chang, T-Y Shieh. Thesis of Master of Dental Science, KMU 2000. (11) T-R Su, K-L Chang, C-H Lee, C-H Chen, Y-H Yang, T-Y Shieh. Oral Oncology 40;804-810,2004. (12) C-Y Huang, T-Y Shieh. Thesis of Master of Dental Science, KMU 2006.

  17. DNA Polymorphism study Oral submucosal Fibroblasts Pre-cancer ACE gene Hypertension Systolic BP “I/I genotype” “I/D genotype” Hypertension Systolic BP “D/D genotype” Betel quid chewing Environmental factors Genetic factors F-M Chung, D-M Chang, M-P Chen, C-R.Tsai, Y-H Yang, T-Y Shieh, S-J Shin, T H-H Chen, T-Y Tai, Y-J Lee : Areca Nut Chewing is Associated with Metabolic Syndrome. Diabetes Care 29(7):1714, 2006. SCC TNF-α 308A DNA mutation “Wild genotype” “Mutant genotype” Unpublished data: Mutant type: normal(28%), SCC(90.6%) Wild type: normal(72%), SCC(9.4%)

  18. Establish a self-rating screening test for betel quid abusers or addicts In order to divide betel quid chewers into abusers, addicts or non-abusers three groups to develop different abstinence strategies. We have already established a self-report screening test for areca quid abusers（SSTAA）. An areca quid chewer’s answers with a score of 4 or more in these 11 qestions would be considered a betel quid abuser. Public Health（2002）116, 195-200.

  19. Strategies to help chewers quit 1) In conjunct with Association of Oral and Maxillofacial Surgery in Taiwan, a guide book on how to diagnose oral precancerous and oral cancer and what should be assessed for further evaluation will be published. 2) According to the guide book, the Taiwan Dentist Association should provide adequate training to dentists, family physicians and public health nurses for oral cancer screening. 3) Establish a national oral cancer surveillance system. 4) Establish an oral health self-examining activity (include oral cancer examination) such as a new ’333’ activity: the first ‘3’－oral health self examining ’3’ minutes after teeth brushing in every morning. the second ‘3’－everyday practice ’3’ minutes of oral health exercise including gnashing teeth, tongue movement, gum massage the third ’3’－every ’3’ months visiting dental clinic for oral examination 5) Taxation The Bureau of Health Promotion of the Department of Health would consider planning the possible procedures to levy tax from betel-quid chewers. With taxation, the chewers might think to quit the chewing habit. Consequently, chewers’ extra medical expenditure can be avoided.

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