The Role of Interleukin-1 Receptor Antagonist (icIL1RN) in Oral Cancer

Interleukin 1 Receptor antagonist (IL1RA) acts to inhibit the actions of IL1 and is important in the modulation of immune responses. A number of splice variants exist, only one of which is secreted.  The intracellular forms of IL1RN (icIL1RA) are expressed in keratinocytes and endothelial cells. Their function is poorly understood, but they appear to be involved in control of proliferation and cellular lifespan by pathways both involving and distinct from IL1 receptor inhibition.  Interestingly, polymorphisms in the IL1RN gene have been associated with the development of a number of cancers including gastric carcinoma.

Objectives: to investigate down-regulation of icIL1RA protein in oral cancer and precancer in vivo and in vitro and its functional consequences.

Methods: IL1, IL1RA and IL1R expression was investigated by qPCR and western blot in oral keratinocytes.  IL1RA expression was assessed in tissues by IHC.  IL1RNv3 was inserted into oral cancer cells by transient transfection.  The resulting phenotype was assessed by the MTS assay, modified transwell migration assay and adhesion to fibronectin.

Results: icIL1RA expression was reduced in oral SCC and oral precancer cells when compared to normal oral keratinocytes.  Conversely there was no difference in the expression of IL1α/β, IL1R1/R2 or the secreted form of IL1RA. The expression in tissues showed loss of expression in the majority of dysplastic precancerous lesions (p<0.05) and almost all oral SCCs (p<0.01) when compared to normal oral mucosa.   Re-expression of IL1RN in oral SCC cells resulted in a reduction in proliferation (p<0.005) and migration (p<0.001), with no effect on adhesion to fibronectin. 

Conclusions: We have demonstrated that loss of icIL1RA expression can occur early in the development of oral SCC and given the pronounced effect on cell behaviour this may be a novel biomarker and target for therapy in early oral SCC.