Hypoxia-responsive lncRNA MIR155HG promotes PD-L1 expression in hepatocellular carcinoma cells by enhancing HIF-1α mRNA stability.

ABSTRACT

The microenvironment of hepatocellular carcinoma (HCC) is characterized by hypoxia, which leads to immune evasion of HCC. Therefore, gaining a comprehensive understanding of the mechanism underlying the impact of hypoxia on HCC cells may provide valuable insights into immune checkpoint therapy. Based on analysis of databases and clinical samples, we observed that expression level of programmed cell death ligand 1 (PD-L1) and long non-coding RNA (lncRNA) MIR155HG in patients in the hypoxia group were higher than those in the non-hypoxia group. Furthermore, there was a positive correlation between the expression of PD-L1 and MIR155HG with that of HIF-1α. In vitro experiments using hypoxic treatment demonstrated an increase in PD-L1 and MIR155HG expression levels in HCC cells. While the hypoxia-induced upregulation of PD-L1 could be reversed by knocking down MIR155HG. Mechanistically, as a transcription factor, HIF-1α binds to the promoter region of MIR155HG to enhance its transcriptional activity under hypoxic conditions. Hypoxia acts as a stressor promoting nuclear output of ILF3 leading to increased binding of ILF3 to MIR155HG, thereby enhancing stability for HIF-1α mRNA. In vivo, knocking down MIR155HG inhibit subcutaneous tumor growth, reduce the expression of HIF-1α and PD-L1 within tumors; additionally, it enhances anti-tumor immunity response. These findings suggested that through inducing MIR155HG to interact with ILF3, hypoxia increases HIF-1α mRNA stability resulting in elevated PD-L1 expression in HCC and thus promoting immune escape. In summary, this study provides new insights into the effects of hypoxia on HCC immunosuppression.