Association between functional polymorphisms in IL-33/ST2 pathway and risk of osteosarcoma

Interleukin (IL)-33/ST2 pathway plays crucial roles in tumour growth and metastasis. The aim of this study was to investigate the association of two functional polymorphisms (IL-33 rs7025417 and ST2 rs3821204) with osteosarcoma (OS) risk. The rs7025417 and rs3821204 were genotyped by Taqman assay. IL-33mRNA and protein levels were measured by real-time PCR or enzyme-linked immunosorbent assay. The luciferase activity was measured by a dual luciferase reporter gene assay. The allele-specific transcription factor binding for rs7025417 was examined by ChIP-seq. The IL-33 rs7025417 CC genotype was significantly associated with a decreased risk of OS (CC vs TT: OR = 0.59, 95% CI, 0.41-0.85; recessive model: OR = 0.68, 95% CI, 0.49-0.94; C vs T: OR = 0.76, 95% CI, 0.63-0.91). Combined analysis showed that the IL-33 rs7025417CT/CC-ST2 rs3821204CG/CC and the IL-33 rs7025417CT/CC-ST2 rs3821204GG genotypes also had a decreased risk of OS. IL-33mRNA and protein levels in OS patients were significantly higher than controls. Patients with the rs7025417 CC genotype exhibited lower levels of IL-33 (P = .03). The rs7025417 C allele presented a lower transcriptional activity by disrupting the binding site to c-Myb (P < .01). Moreover, the rs3821204 G/C influences the transcriptional activity and ST2mRNA expression by altering the binding site of miR-202-3p. These findings suggest that the rs7025417 and rs3821204 may have a combined effect to protect against the development of OS by decreasing the expression levels of IL-33 or ST2.