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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

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
Betel quid chewing associated diseases
  • OSCC
  • NPC
  • Esophagus cancer
  • Liver cancer
  • Central obesity
  • Prematurity
  • Blood pressure regulation
research scheme
Research Scheme

Center of Excellence for Environmental Medicine

ENT for pharynx and larynx

Patients from KMUH,OS

Gastroenterology for Endoscope





Paraffin block

Serum (Protein)


Buffy coat (DNA)

Molecular Epidemiology


Lip N2 / -80℃





Table. Plasma KLK6, KLK7, and KLK10 in OSCC, oral premalignant patients ,

and health control.

(P value analysis by Wilcoxon Rank Sum Test.)


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


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




Table . Expression of KLK6, 7, and 10 mRNA in cancer lesion and surrounding normal

tissues in OSCC patients. (N=12)





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。


global center of excellence for oral health research and development
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




Real time PCR










current and previous studies for genetic susceptibility to oral squamous cell squamous carcinoma
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

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


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


epidemiological studies
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


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

mechanism of osf
Mechanism of OSF

Oral submucosal




of collagen

(1) Lysyl oxidase

activity ↑

collagens ↑

(I, III, V)

(2) Collagenase activity ↓

(3) TIMP-1 ↑

Betel quid


(4)(5) Phagocytosis activity ↓

(individual or same person)

Influences cytokines


(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.

response of immune system
Response of immune system

Oral submucosal


(6) (7) IL-1β: SCC > VH > normal > OSF

(8) TGF-β: OSF > normal




(9) TNF-α:SCC>normal>SCC+betel

IFN-γ:normal > normal+betel

IL-2, TGF-β, IFN-γ:OSF < normal & SCC

Betel quid


(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


(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.

dna polymorphism study
DNA Polymorphism study

Oral submucosal



ACE gene


Systolic BP

“I/I genotype”

“I/D genotype”


Systolic BP

“D/D genotype”

Betel quid


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.


TNF-α 308A



“Wild genotype”

“Mutant genotype”

Unpublished data:

Mutant type: normal(28%), SCC(90.6%)

Wild type: normal(72%), SCC(9.4%)


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.

strategies to help chewers quit
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.