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-1b) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro-IL-1b 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-1b 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-1b secretion in an inflammasome-dependent manner. IL-1b 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-a following IL-1b stimulation. The conditioned medium of IL-1b-treated OSCC cells exerted significant proangiogenic effects. Crucially, IL-1b 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-1b 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.

Expression and influence of Notch signaling in oral squamous cell carcinoma

“…Expression datasets of human cell line were excluded in the study. The included GEO datasets (GSE) are shown in Table 1 (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

“…Secretion of IL-1b stimulates cells to produce the chemokine CXCL1 in HNSCC. 40 CXCL1 is one of the ligands of the chemokine receptor CXCR2, which is a crucial chemokine for the recruitment of MDSCs to sites of inflammation. 41 Our previous study demonstrated the high level of CXCL1 in tongue SCC as compared with normal tongue.…”

Pattern of invasion in squamous cell carcinomas of the lower lip and oral cavity

“…The higher intensity of inflammation in lower lip SCCs compared to oral cavity neoplasms reported previously 24 and the downregulating effect of inflammation on ECad, 25 may help explain this finding.…”