title: The expression of O(6) -methylguanine-DNA methyltransferase in human oral keratinocytes stimulated with arecoline.
abstract: BACKGROUND
  O(6) -methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that can protect cells from carcinogenic effects of alkylating agents by removing adducts from the O(6) position of guanine. Evidences indicated that areca quid chewing may increase the risk of oral squamous cell carcinoma (OSCC). This study was to investigate the role of MGMT expression in OSCCs and the normal oral tissues.
  
  
  METHODS
  Thirty-two OSCCs from areca quid chewers and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by the immunohistochemistry for MGMT. Primary human oral keratinocytes (HOKs) were challenged with arecoline, the major alkaloid of areca nut, by Western blot. Nicotine, an important component of cigarette smoke, was added to find the possible regulatory mechanisms.
  
  
  RESULTS
  Significant association was observed between low MGMT expression and advanced clinical stage of OSCCs and lymph node metastasis (P = 0.03). MGMT expression was significantly higher in patients only chewing areca quid than patients both chewing areca quid and smoking (P = 0.028). Arecoline was found to elevate MGMT expression in a dose- and time-dependent manner. The addition of nicotine was found to enhance arecoline-induced MGMT expression.
  
  
  CONCLUSIONS
  Our results indicate that MGMT could be used clinically as a predictive marker for tumor processing, the potential for lymph node metastasis as well as advanced clinical stage. MGMT expression was significantly upregulated by arecoline in HOKs. Nicotine has a synergistic effect of arecoline-induced MGMT expression. The cigarette smoking may act synergistically in the pathogenesis of OSCC in areca quid chewers via the upregulation of MGMT.
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Tsai
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Yung-Chuan
authors.initials: YC
authors.lastname: Ho
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Hsu
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D001114:Areca; D001115:Arecoline / Q000008:administration & dosage / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000556:secondary; D002460:Cell Line; D018679:Cholinergic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects*; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects*; D009062:Mouth Neoplasms / Q000473:pathology; D009367:Neoplasm Staging; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000187:drug effects*; D012907:Smoking
chemical_list: D014408:Biomarkers, Tumor; D018679:Cholinergic Agonists; D018722:Nicotinic Agonists; D001115:Arecoline; D009538:Nicotine; D019853:O(6)-Methylguanine-DNA Methyltransferase
keywords: MGMT; arecoline; nicotine; oral squamous cell carcinoma; synergistic effect