M2‐polarized tumor‐associated macrophage‐secreted exosomal lncRNA NEAT1 upregulates galectin‐3 by recruiting KLF5 and promotes HCC immune escape

Abstract

HCC cell immune escape is a critical element in the evolution of HCC malignancy. Herein, the regulatory mechanism of lncRNA NEAT1 in regulating HCC immune escape was investigated. Exosomes were isolated from M2 TAMs using ExoQuick‐TC. Then, HCC cells were incubated with M2 TAMs‐derived exosomes (M2‐exos). The activation of perforin+CD8+ T cells was measured using flow cytometry. The secretion of IFN‐γ was assessed using ELISA. Cell viability and migration were detected using CCK8 and Transwell assays, respectively. RIP and RNA pull‐down assays were used to investigate the link between NEAT1 and KLF5. ChIP and dual‐luciferase reporter assays were used to investigate the interaction between KLF5 and the LGALS3 promoter. Our results showed that NEAT1, KLF5 and galectin‐3 were overexpressed in HCC tissues. M2‐exos treatment promoted HCC proliferation, migration, and immune escape. It was found that NEAT1 was enriched in M2‐TAMs and M2‐exos. M2‐exos facilitated HCC immune escape, whereas NEAT1 silencing reversed this effect. NEAT1 upregulated galectin‐3 in HCC cells by recruiting KLF5. Mechanically, M2‐TAM‐derived exosomal NEAT1 induced HCC immune escape by upregulating KLF5/galectin‐3 axis. M2‐TAM‐derived exosomal NEAT1 upregulated galectin‐3 in HCC cells by recruiting KLF5 to promote perforin+CD8+ T cell depletion and further accelerate HCC immune escape.