A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma

Abstract

The immune system is critical in modulating cancer progression. Pseudogenes are a special type of long non-coding RNAs that regulate different tumorigenic processes. However, the potential roles of pseudogenes in tumor-immune interaction remain largely unclear. Here, we reported that pseudogene RP11-424C20.2 and its parental gene UHRF1 were frequently up-regulated and positively correlated in liver hepatocellular carcinoma (LIHC) and thymoma (THYM), but associated with distinct clinical outcomes. We further found that RP11-424C20.2 may act as a competing endogenous RNA (ceRNA) to increase UHRF1 expression through sponging miR-378a-3p. Functional enrichment analysis showed a strong association of UHRF1 with immune-related biological processes. We also observed that UHRF1 expression significantly correlated with immune infiltration, and different types of tumor-infiltrating immune cells displayed different impacts on clinical outcomes. Furthermore, UHRF1 expression in LIHC and THYM showed an opposite correlation with biomarkers from monocyte, dendritic cell, Th1 and T cell exhaustion. Mechanism investigations revealed that RP11-424C20.2/UHRF1 axis regulated immune escape of LIHC and THYM at least partly through IFN-γ-mediated CLTA-4 and PD-L1 pathway. These findings demonstrate a disparate role of RP11-424C20.2/UHRF1 axis in LIHC and THYM via regulating immune infiltrates, and also indicate a therapeutic value for UHRF1 inhibitors in combination with anti-PD-L1/CLTA-4 blockade.