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

Lee, Shiuan-Shinn; Yang, Shun-Fa; Tsai, Chung-Hung; Chou, Ming-Chih; Chou, Ming-Yung; Chang, Yu-Chao

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

« Previous Next »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
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
Chung-Hung Tsai
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Oral Pathology, Taichung, Taiwan
Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
Ming-Yung Chou
- Oral Medicine Center, Chung Shan Medical University Hospital, Taichung, Taiwan
Yu-Chao Chang
- Oral Medicine Center, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Stomatology, Chung Shan Medical University, Taichung, Taiwan
- Correspondence 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.

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