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. 2025 Oct 4:uxaf067.
doi: 10.1093/cei/uxaf067. Online ahead of print.

Post-transarterial chemoembolization hypoxia-induced HIF-1α/WNT/β-catenin signaling promotes hepatocellular carcinoma progression via programmed death ligand 1 upregulation

Jiayan Ni  1 , Shanshan Liu  2 , Xue Han  3 , Gefan Guo  1 , Xiong Zhou  4 , Hongliang Sun  1 , Jinhua Huang  3 , Linfeng Xu  1
Affiliations

Post-transarterial chemoembolization hypoxia-induced HIF-1α/WNT/β-catenin signaling promotes hepatocellular carcinoma progression via programmed death ligand 1 upregulation

Jiayan Ni et al. Clin Exp Immunol. .

Abstract

Introduction: Post-transarterial chemoembolization (TACE) hypoxia plays a crucial role in hepatocellular carcinoma (HCC) progression. However, the effects of post-TACE hypoxia on HCC progression are not fully understood yet. This study aims to elucidate the effects of post-TACE hypoxia-induced hypoxia-inducible factor-1α (HIF-1α)/WNT/β-catenin signaling on HCC progression.

Methods: In this study, serum concentrations of soluble programmed death ligand 1 (sPD-L1) and HIF-1α in HCC patients who underwent TACE were measured using enzyme-linked immunosorbent assay (ELISA). In vitro, WNT/β-catenin pathway activation was assessed by TOP/FOP luciferase activity, while HIF-1α-siRNA transfection was used to observe the interaction between HIF-1α and WNT/β-catenin. In vivo, mouse xenograft tumor models were used to examine the effects of programmed death ligand 1 (PD-L1) on HCC progression and to verify the correlations among HIF-1α, WNT/β-catenin, and PD-L1. The mechanisms underlying hypoxia-induced PD-L1 overexpression were studied using chromatin immunoprecipitation (ChIP).

Results: Median post-TACE serum sPD-L1 and HIF-1α concentrations in HCC patients were significantly higher compared to pre-TACE levels, with a significant correlation observed between sPD-L1 and HIF-1α. In vitro studies demonstrated that hypoxia promoted WNT/β-catenin activation and PD-L1 expression. HIF-1α silencing significantly inhibited WNT/β-catenin activation. In vivo, hypoxia-induced PD-L1 overexpression significantly promoted HCC progression. WNT/β-catenin activation increased PD-L1 promoter luciferase activity, and ChIP confirmed that LEF1 bound to the PD-L1 promoter in hypoxic hepatoma cells.

Conclusion: Post-TACE hypoxia-induced activation of HIF-1α/WNT/β-catenin signaling promotes HCC progression by upregulating PD-L1 expression.

Keywords: Hepatocellular carcinoma; Hypoxia; Programmed death ligand 1; Transarterial chemoembolization; Tumor microenvironment.

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