title: IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer.
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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chia-Huei
authors.initials: CH
authors.lastname: Lee
authors.forename: Jeffrey Shu-Ming
authors.initials: JS
authors.lastname: Chang
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Syu
authors.forename: Thian-Sze
authors.initials: TS
authors.lastname: Wong
authors.forename: Jimmy Yu-Wai
authors.initials: JY
authors.lastname: Chan
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Tang
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Yang
authors.forename: Wen-Chan
authors.initials: WC
authors.lastname: Yang
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Lu
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Tang
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Yang
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Jenn-Ren
authors.initials: JR
authors.lastname: Hsiao
authors.forename: Ko-Jiunn
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001115:Arecoline / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D009062:Mouth Neoplasms / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D001115:Arecoline