The Pro-Tumor Biological Function of IL-36α Plays an Important Role in the Tumor Microenvironment of HCC

Purpose: To investigate the role of IL-36 in the tumorigenesis of hepatocellular carcinoma (HCC). IL-36 composed of a natural antagonist (IL-36Ra) and three agonists (IL-36 alpha, -beta, -gamma) that stimulate inflammation by binding to a common receptor consisting of IL-36R and IL-1RAcP. HCC is a common malignancy associated with high morbidity and mortality, often diagnosed at later stages. Although the exact role of IL-36 alpha in HCC remains controversial, it is hypothesized that it may play a significant role in the development and progression of this cancer. Materials and Methods: In the current study, we measured both circulating and intrahepatic levels of IL-36 alpha from HCC patients and healthy controls, using ELISA. The association between IL-36 and the differentiation of HCC was determined. Furthermore, the role IL-36 in both HCC and non-HCC cell lines was evaluated in vitro. Results: Circulating and intra-hepatic IL-36 alpha was inversely correlated with differentiation of HCC, suggesting that IL-36 alpha contribute to protection during the development of HCC. Based on bioinformatics, miR-27b-3p is closely related to downstream IL-36 alpha. Thus, we determined miR-27b-3p expression in HCC tissues, showing upregulated miR-27b-3p was inversely correlated with IL-36 alpha in HCC, perhaps via CXCL1 in HCC cells. It was confirmed that IL-36 alpha inhibited HCC proliferation, viability and migration in vitro, consistent with reduced the expression of cytokines IL-1 beta, IL-18, implying that IL-36 alpha inhibited the possible involvement of pyroptosis. Conclusion: Our data suggests that IL-36 alpha may be a potential therapeutic target and a prediction biomarker for the management of HCC.