title: Upregulation of heme oxygenase-1 expression in areca-quid-chewing-associated oral squamous cell carcinoma.
abstract: OBJECTIVE
  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 arecolineinduced HO-1 expression (p < 0.05). Moreover, addition of NAC markedly inhibited arecoline-induced HO-1 expression (p < 0.05).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Tsai
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Chou
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Chou
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D001114:Areca / Q000009:adverse effects*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000209:etiology*; D005260:Female; D051547:Heme Oxygenase-1 / Q000032:analysis*; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000209:etiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D051547:Heme Oxygenase-1