Hypoxia inducible factor-1α expression in areca quid chewing-associated oral squamous cell carcinomas.
OBJECTIVE
Hypoxia inducible factor (HIF)-1α gene expression is mainly induced by tissue hypoxia. Overexpression of HIF-1α has been demonstrated in a variety of cancers. The aim of this study was to compare HIF-1α expression in normal human oral epithelium and areca quid chewing-associated oral squamous cell carcinoma (OSCC) and further to explore the potential mechanisms that may lead to induce HIF-1α expression.


METHODS
Twenty-five OSCC from areca quid chewing-associated OSCC and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms.


RESULTS
Hypoxia inducible factor-1α expression was significantly higher in OSCC specimens than normal specimen (P<0.05). Arecoline was found to elevate HIF-1α expression in a dose- and time-dependent manner (P<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HIF-1α expression (P<0.05).


CONCLUSIONS
Hypoxia inducible factor-1α expression is significantly upregulated in areca quid chewing-associated OSCC and HIF-1α expression induced by arecoline is downregulated by NAC, curcumin, PD98059, and staurosporine.
Lee
S-S
SS
School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
Tsai
C-H
CH
Yang
S-F
SF
Ho
Y-C
YC
Chang
Y-C
YC
D000111:Acetylcysteine / Q000494:pharmacology; D001114:Areca / Q000009:adverse effects; D001115:Arecoline / Q000494:pharmacology; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology*; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000187:drug effects; D007150:Immunohistochemistry; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology*; D009062:Mouth Neoplasms / Q000209:etiology / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018808:Transcription Factor AP-1; D001115:Arecoline; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019311:Staurosporine; D003474:Curcumin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine