Fenofibrate exhibits a high potential to suppress the formation of squamous cell carcinoma in an oral-specific 4-nitroquinoline 1-oxide/arecoline mouse model |
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Authors: | Nai Wen Chang Ming-Hsui TsaiChingju Lin Hui Ting HsuPei-Yi Chu Chung-Min YehChang-Fang Chiu Kun-Tu Yeh |
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Institution: | a Department of Biochemistry, College of Medicine, China Medical University, Taichung, Taiwan, ROCb Department of Otolaryngology, China Medical University Hospital, Taiwan, ROCc Department of Physiology, College of Medicine, China Medical University, Taichung, Taiwan, ROCd Department of Surgical Pathology, Changhua Christian Hospital, 135 Nan-Hsiao Street, Changhua 500, Taiwan, ROCe Department of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan, ROCf School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC |
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Abstract: | The excessive use of areca nut and/or tobacco may induce the production of free radicals and reactive oxygen species, which affect the lipid contents of the cell membrane and are possibly involved in tumorigenic processes in the oral cavity. The aim of this study was to investigate the therapeutic efficacy of fenofibrate (0.1% or 0.3%, w/w), a ligand of the peroxisome proliferator-activated receptor alpha (PPARα), in a 4-nitroquinoline 1-oxide (4-NQO)/arecoline-induced oral cancer mouse model. The carcinogen, 4-NQO/arecoline, was administrated to C57BL/6JNarl mice for 8 weeks followed by fenofibrate treatment for 12 or 20 weeks. After 28 weeks, changes in serum lipids, the multiplicity of tumor lesions, and tumor sizes were determined together with changes in the immunohistochemical expressions of PPARα, acetyl-coenzyme A carboxylase (ACC), the epidermal growth factor receptor (EGFR), and cyclooxygenase-2 (COX2). The results showed that when compared to the 4-NQO/arecoline only group, 0.3% fenofibrate treatment increased serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. 0.3% fenofibrate treatment suppressed the incidence rate of tongue lesions, reduced the multiplicity of squamous cell carcinoma (SCC), decreased the tumor size, and increased the immunoreactivity of EGFR and COX2 in oral dysplasia but decreased EGFR and COX2 expressions in SCC. These findings indicated that fenofibrate reduced the tumor incidence rate and suppressed the tumor progression into SCC and that these molecular events might be linked to the EGFR and COX2 regulatory pathways. We suggest that fenofibrate provides a new strategy for preventing oral tumor progression. |
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Keywords: | ACC acetyl-coenzyme A carboxylase BQ betel quid COX2 cyclooxygenase-2 EGFR epidermal growth factor receptor FAS fatty acid synthase HDL-C high-density lipoprotein cholesterol LDL-C low-density lipoprotein cholesterol 4-NQO 4-nitroquinoline 1-oxide PPARα peroxisome proliferator-activated receptor alpha SCC squamous cell carcinoma TC total cholesterol VLDL very low-density lipoprotein |
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