IL‐1β Promotes Malignant Transformation and Tumor Aggressiveness in Oral Cancer |
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| Authors: | Chia‐Huei Lee Jeffrey Shu‐Ming Chang Shih‐Han Syu Thian‐Sze Wong Jimmy Yu‐Wai Chan Ya‐Chu Tang Zhi‐Ping Yang Wen‐Chan Yang Chiung‐Tong Chen Shao‐Chun Lu Pei‐Hua Tang Tzu‐Ching Yang Pei‐Yi Chu Jenn‐Ren Hsiao Ko‐Jiunn Liu |
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| Institution: | 1. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan;2. Department of Surgery, University of Hong Kong, Hong Kong, Special Administrative Region, China;3. Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan;4. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taiwan;5. Department of Pathology, St. Martin De Porres Hospital, Chiayi, Taiwan;6. Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan;7. School of Medical, Department of Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan;8. Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan |
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| Abstract: | Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin‐1 beta (IL‐1β) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro‐IL‐1β expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4‐Nitroquinolin‐1‐oxide (4‐NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro‐IL‐1β was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine‐derived nitrosamine ketone (NNK) and arecoline stimulated IL‐1β secretion in an inflammasome‐dependent manner. IL‐1β treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL‐6, IL‐8, and growth‐regulated oncogene‐α following IL‐1β stimulation. The conditioned medium of IL‐1β‐treated OSCC cells exerted significant proangiogenic effects. Crucially, IL‐1β increased the invasiveness of OSCC cells through the epithelial‐mesenchymal transition (EMT), characterized by downregulation of E‐cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL‐1β can be induced by tobacco and betel quid‐related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC. J. Cell. Physiol. 230: 875–884, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. |
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