Interleukin (IL)-33/ST2 pathway plays a pivotal role in tumorigenesis through influencing
cancer stemness, tumor growth, metastasis, angiogenesis, and accumulation of regulatory
T cells in tumor microenvironments. The aim of this study was to investigate the association
of IL-33 rs7025417 and ST2 rs3821204 with the risk of hepatocellular carcinoma (HCC).
Genotyping of IL-33 rs7025417 and ST2 rs3821204 was carried out using a Taqman assay.
IL-33 and ST2 mRNA was examined using real-time PCR and plasma IL-33 and sST2 levels
were measured using enzyme-linked immunosorbent assay. The ST2 rs3821204 CC genotype
was associated with a significantly increased risk of HCC (CC vs. GG: adjusted OR = 2.29,
95% CI, 1.39-3.78; dominant model: adjusted OR = 1.58, 95% CI, 1.12-2.23; recessive
model: adjusted OR = 1.88, 95% CI, 1.21-2.93; C vs. G: adjusted OR = 1.53, 95% CI,
1.20-1.95). Gene-environment interaction analysis showed that the risk effect of rs3821204
CG/CC genotypes was more evident in smokers (adjusted OR = 1.70, 95% CI, 1.13-2.55)
and drinkers (adjusted OR = 1.57, 95% CI, 1.04-2.37). The increased risk was also
observed in combined analysis. Moreover, HCC patients with ST2 rs3821204 CC genotype
had higher levels of mRNA and protein expression (P < 0.05). These findings suggest
that ST2 rs3821204 CC genotype may contribute to hepatocarcinogenesis by enhancing
ST2 production at the transcriptional and translational level.