Exosomal ZFPM2‐AS1 contributes to tumorigenesis, metastasis, stemness, macrophage polarization, and infiltration in hepatocellular carcinoma through PKM mediated glycolysis

Abstract

AbstractBackgroundWith high morbidity and mortality, hepatocellular carcinoma (HCC) deserves further exploration in its pathogenesis mechanisms for promising prognostic and therapeutic markers. This research was conducted to dig out roles of exosomal ZFPM2‐AS1 in HCC.MethodsThe level of exosomal ZFPM2‐AS1 in HCC tissue and cells was determined by Real‐time fluorescence quantitative PCR. Pull‐down assay and dual‐luciferase reporter assay were performed to identify interactions between ZFPM2‐AS1 and miRNA‐18b‐5p, as well as miRNA‐18b‐5p and PKM. Western blotting was employed to explore the potential regulatory mechanism. Several in vitro assays were conducted in mice xenograft and orthotopic transplantation models to investigate impacts of exosomal ZFPM2‐AS1 on HCC development, metastasis, and macrophage infiltration.ResultsZFPM2‐AS1 was activated in HCC tissue and cells, with high enrichment in HCC‐derived exosomes. Exosomal ZFPM2‐AS1 enhances the cell abilities and stemness of HCC. MiRNA‐18b‐5p was directly targeted by ZFPM2‐AS1 which triggered PKM expression via sponging miR‐18b‐5p. Exosomal ZFPM2‐AS1 modulated glycolysis via PKM in an HIF‐1α dependent way in HCC, promoting M2 polarization, and macrophage recruitment. Furthermore, exosomal ZFPM2‐AS1 enhanced HCC cell growth, metastasis, and M2 infiltration in vivo.ConclusionsExosomal ZFPM2‐AS1 exerted regulatory function on the progression of HCC via miR‐18b‐5p/PKM axis. ZFPM2‐AS1 could be promising biomarker for the diagnosis and therapies of HCC.