IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer

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

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)875-884
Number of pages10
JournalJournal of Cellular Physiology
Volume230
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    Lee, C. H., Chang, J. S. M., Syu, S. H., Wong, T. S., Chan, J. Y. W., Tang, Y. C., Yang, Z. P., Yang, W. C., Chen, C. T., Lu, S. C., Tang, P. H., Yang, T. C., Chu, P. Y., Hsiao, J. R., & Liu, K. J. (2015). IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer. Journal of Cellular Physiology, 230(4), 875-884. https://doi.org/10.1002/jcp.24816