Journal of the Formosan Medical Association
Volume 107, Issue 5 , Pages 355-363, May 2008

Upregulation of Heme Oxygenase-1 Expression in Areca-quid-chewing-associated Oral Squamous Cell Carcinoma

  • Shiuan-Shinn Lee

      Affiliations

    • Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
    • ,
  • Shun-Fa Yang

      Affiliations

    • Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
    • ,
  • Chung-Hung Tsai

      Affiliations

    • Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
    • Department of Oral Pathology, Taichung, Taiwan
    • ,
  • Ming-Chih Chou

      Affiliations

    • Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
    • ,
  • Ming-Yung Chou

      Affiliations

    • Oral Medicine Center, Chung Shan Medical University Hospital, Taichung, Taiwan
    • ,
  • Yu-Chao Chang

      Affiliations

    • Oral Medicine Center, Chung Shan Medical University Hospital, Taichung, Taiwan
    • Institute of Stomatology, Chung Shan Medical University, Taichung, Taiwan
    • Corresponding Author InformationCorrespondence to: Dr Yu-Chao Chang, Institute of Stomatology, Chung Shan Medical University, 110, Section 1, Chien-Kuo North Road, Taichung, Taiwan

Received 30 November 2007; received in revised form 30 January 2008; accepted 12 February 2008.

Article Outline

Background/Purpose

Heme oxygenase-1 (HO-1) is known as an oxidative stress responsive protein that is upregulated by various physiologic and endogenous stimuli. HO-1 has been proposed to provide an important cellular response that protects cells against oxidative damage. Areca quid chewing is a major risk factor in the development and further progression of oral squamous cell carcinoma (OSCC). The aim of the present study was to investigate the difference in HO-1 expression in normal human oral epithelium and OSCC, and further explore the potential mechanism that may lead to HO-1 expression.

Methods

Thirty-five OSCC and 10 normal epithelium specimens were examined by immunohistochemistry and analyzed by clinicopathologic profiles. The oral epithelial GNM cell line was challenged with arecoline, a major areca nut alkaloid, by reverse-transcriptase polymerase chain reaction. Furthermore, tobacco smoke carcinogen benzo[a]pyrene (BaP) and glutathione (GSH) precursor N-acetyl-L-cysteine were added to find the possible regulatory mechanisms.

Results

HO-1 expression was significantly higher in OSCC specimens (p < 0.05). No significant difference in HO-1 expression was observed with respect to age, sex, T category, and stage (p > 0.05). The high HO-1 expression was associated with lymph node metastasis (p = 0.005). In addition, arecoline was found to elevate HO-1 mRNA in a dose-dependent manner (p < 0.05). The addition of BaP enhanced arecoline-induced HO-1 expression (p < 0.05). Moreover, addition of NAC markedly inhibited arecoline-induced HO-1 expression (p < 0.05).

Conclusion

Taken together, these results suggest that HO-1 expression is significantly upregulated in OSCC from areca quid chewers, and arecoline may be responsible for enhanced HO-1 expression in vivo. The compounds of cigarette smoke may act synergistically in the pathogenesis of areca-quid-chewing-associated OSCC. The regulation of HO-1 expression induced by arecoline is critically dependent on intracellular GSH concentration.

Key Words:  areca quid , arecoline , benzo[a]pyrene , heme oxygenase-1 , N-acetyl-L-cysteine , oral squamous cell carcinoma

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References 

  1. Silverman S . In: Oral cancer . 4th ed.. Hamilton, Ontario: American Cancer Society, B.C. Decker; 1998;p. 1–40
  2. IARC  . Betel-quid and areca-nut chewing . Lyon: International Agency for Research on Cancer, Monographs . 1986;37:141–202
  3. Ko YC , Chiang TA , Chang SJ , et al.   Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors . J Oral Pathol Med . 1992;21:261–264
  4. Kwan HW . A statistical study on oral carcinomas in Taiwan with emphasis on the relationships with betel nut chewing: a preliminary report . J Formos Med Assoc . 1976;75:497–505
  5. Ko YC , Huang YL , Lee CH , et al.   Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan . J Oral Pathol Med . 1995;24:450–453
  6. Choi AM , Alam J . Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidantinduced lung injury . Am J Respir Cell Mol Biol . 1996;15:9–19
  7. Ryter SW , Choi AM . Heme oxygenase-1: redox regulation of a stress protein in lung and cell culture models . Antioxid Redox Signal . 2005;7:80–91
  8. Maines MD , Gibbs PE . 30 some years of heme oxygenase: from a “molecular wrecking ball” to a “mesmerizing” trigger of cellular events . Biochem Biophys Res Commun . 2005;338:568–577
  9. Maines MD . Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications . FASEB J . 1988;2:257–268
  10. Maines MD , Abrahamsson PA . Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution . Urology . 1996;47:727–733
  11. Tsuji MH , Yanagawa T , Iwasa S , et al.   Heme oxygenase-1 expression in oral squamous cell carcinoma as involved in lymph node metastasis . Cancer Lett . 1999;138:53–59
  12. Sunamura M , Duda DG , Ghattas MH , et al.   Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer . Angiogenesis . 2003;6:15–24
  13. Yanagawa T , Omura K , Harada H , et al.   Heme oxygenase-1 expression predicts cervical lymph node metastasis of tongue squamous cell carcinomas . Oral Oncol . 2004;40:21–27
  14. Maines MD , Panahian N . The heme oxygenase system and cellular defense mechanisms. Do HO-1 and HO-2 have different functions? . Adv Exp Med Biol . 2001;502:249–272
  15. Doi K , Akaike T , Fujii S , et al.   Induction of heme oxygenase-1 nitric oxide and ischemic in experimental solid tumors and implications for tumor growth . Br J Cancer . 1999;80:1945–1954
  16. Fang J , Sawa T , Akike T , et al.   In vivo antitumor activity of pegylated zinc protorophyrin: targeted inhibition of heme oxygenase in solid tumor . Cancer Res . 2003;63:3567–3574
  17. Chang KW , Lee TC , Yeh WI , et al.   Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers . Br J Cancer . 2004;91:1551–1555
  18. Lin SC , Liu CJ , Yeh Wi , et al.   Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers . Cancer Lett . 2006;243:47–54
  19. Hoffmann D , Lavoie EJ , Hocht SS . Nicotine: a precursor for carcinogens . Cancer Lett . 1985;26:67–75
  20. Halliwell B . Antioxidants: the basics-what they are and how to evaluate them . Adv Pharmacol . 1997;38:3–20
  21. Tsai CH , Hsieh YS , Yang SF , et al.   Matrix metalloproteinase 2 and 9 expression in human oral squamous cell carcinoma and the effect of protein kinase C inhibitors: preliminary observations . Oral Surg Oral Med Oral Pathol . 2003;95:710–716
  22. Lee SS , Yang SF , Ho YC , et al.   The upregulation of metallothionein-1 expression in areca quid chewingassociated oral squamous cell carcinomas . Oral Oncol . 2008;44:180–186
  23. Salinas M , Diaz R , Abraham NG , et al.   Nerve growth factor protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner . J Biol Chem . 2003;278:13898–13904
  24. Hanahan D , Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis . Cell . 1996;86:353–364
  25. Jazwa A , Loboda A , Golda S , et al.   Effect of heme oxygenase-1 on VEGF synthesis and angiogenic potency of human keratinocytes . Free Radic Biol Med . 2006;40:1250–1263
  26. Suzuki M , Iso-o N , Takeshita S , et al.   Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model of hindlimb ischemia . Biochem Biophys Res Commun . 2003;302:138–143
  27. Nishie A , Ono M , Shono T , et al.   Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas . Clin Cancer Res . 1999;5:1107–1113
  28. Nair UJ , Obe G , Friesen M , et al.   Role of lime in the generation of reactive oxygen species from betel-quid ingredients . Environ Health Perspect . 1992;98:203–205
  29. Chen CL , Chi CW , Liu TY . Hydroxyl radical formation and oxidative DNA damage induced by areca quid in vivo . J Toxicol Enviro Health A . 2002;65:327–336
  30. Vayssier-Taussat M , Camilli T , Aron Y , et al.   Effects of tobacco smoke and benzo[α]pyrene on human endothelial cell and monocyte stress responses . Am J Physiol Heat Circ Physiol . 2001;280:1293–1300
  31. Chang YC , Lai CC , Lin LF , et al.   The up-regulation of heme oxygenase-1 expression in human gingival fibroblasts stimulated with nicotine . J Periodont Res . 2005;40:252–257
  32. Shanta V , Krishnamurthy S . Further study in aetiology of carcinomas of the upper alimentary tract . Br J Cancer . 1963;17:8–23
  33. Hirayama T . An epidemiological study of oral and pharyngeal cancer in central and south-east Asia . Bull World Health Organ . 1966;34:41–69
  34. Jafarey NA , Mahmood Z , Zaidi SHM . Habits and dietary pattern of cases of carcinoma of oral cavity and oropharynx . J Pakistan Med Assoc . 1977;27:340–343
  35. Chang YC , Tai KW , Chou MY , et al.   Synergistic effects of peroxynitrite on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts . Toxicol Lett . 2000;118:61–68

PII: S0929-6646(08)60100-X

doi:10.1016/S0929-6646(08)60100-X

Journal of the Formosan Medical Association
Volume 107, Issue 5 , Pages 355-363, May 2008

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