IL35 modulates HBV-related HCC progression via IL6-STAT3 signaling

Hepatocellular carcinoma (HCC) is a common malignant tumor with incidences reported worldwide along with high mortality rates. It is a significant public health concern as hepatitis B virus (HBV) infection is the leading cause of HCC. IL35, a novel heterodimeric cytokine belonging to the IL-12 family, comprises two subunits, namely IL-12p35 and Epstein-Barr virus-induced gene 3 (EBI3). They are crucial in regulating immune responses to tumors and infectious diseases. However, their function in HBV-related HCC is unclear. The objective of this study was to identify the regulatory role of IL35 in the occurrence of HBV-related HCC and its underlying molecular mechanisms. The expression of IL35 was enhanced in human HBV-related HCC tissues. HBV induction, particularly HBx, enhanced the expression of IL-35 in hepatoma cell lines. Silencing IL-35 promoted apoptosis and suppressed proliferation, cell cycle progression, migration, and invasion of HBx-induced hepatoma cells. Mechanistically, silencing IL-35 effectively inhibited the activation of the IL-6-STAT3 signaling pathway by suppressing the expression of IL-6 and nuclear import and phosphorylation of STAT3 in HBx-induced hepatoma cells. Therefore, inhibiting the IL6-STAT3 signaling pathway by silencing IL35 effectively alleviated the progression of HBV-related HCC. IL35 is a potential target for treating HBV-related HCC.