INTERLEUKIN 1 RECEPTOR ANTAGONIST (IL-1RA) BIOLOGY IN ORAL EPITHELIUM, ORAL DYSPLASIA AND ORAL SQUAMOUS CELL CARCINOMA

Abstract

Objectives Knowledge of molecular biology of oral dysplasia (OD) and oral squamous cell carcinoma (OSCC) is essential in order to find novel biological markers that could serve as predictor markers for malignant transformation. IL-1 receptor antagonist (IL-1RA), IL-1 natural inhibitor, is encoded by the IL1RN gene and has been reported to be downregulated in head and neck squamous cell carcinoma, but the effects of its downregulation in OSCC and OD are largely unknown. Thus, the aim of this research was to study the role of IL-1RA in oral carcinogenesis and oral keratinocyte senescence. Findings IL1RN, specifically intracellular IL-1RA type 1 (icIL-1RA1), is constitutively expressed in normal oral epithelium, but is downregulated, both in vitro and in vivo, in OD and OSCC cell lines. We also found an upregulation of IL-1R1 (IL-1 agonist receptor) in OSCC and OD cell lines. Using confocal microscopy, we have found that both proteins, IL-1RA and IL-1R1, are able to localize inside the nucleus, which suggests a new possible ways of interactions of intra-nuclear IL-1α in oral keratinocytes. Transient transfection in OSCC and OD cell lines with a plasmid encoding for icIL-1RA1, showed no or limited effects on cell migration (by cell exclusion and transwell assay), cell proliferation (by EDU incorporation) and IL-6 and IL-8 secretion (by ELISA). Preliminary data suggests an increase of IL-1 alpha and a decrease of icIL1-RA mRNA expression as primary oral keratinocytes and mortal OD cells senesce. Conclusions IL1RN is downregulated in oral dysplasia and oral cancer. How this downregulation favours oral carcinogenesis it is not yet known, but might be related with the oral senescence program.