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USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4

ABSTRACT: Highlights • The cellular activity of USPs is functionally implicated in cancer progression.• USP8 negatively regulates the TRAF6-mediated signals for NF-κB and autophagy.• USP8KO SK-HEP-1 cells reveal increases of cancer progression in vivo and in vitro.• TCGA and transcriptome data support the functional role of USP8 in liver cancers. Herein, we aimed to elucidate the molecular and cellular mechanism in which ubiquitin-specific protease 8 (USP8) is implicated in liver cancer progression via TRAF6-mediated signal. USP8 induces the deubiquitination of TRAF6, TAB2, TAK1, p62, and BECN1, which are pivotal roles for NF-κB activation and autophagy induction. Notably, the LIHC patient with low USP8 mRNA expression showed markedly shorter survival time, whereas there was no significant difference in the other 18-human cancers. Importantly, the TCGA data analysis on LIHC and transcriptome analysis on the USP8 knockout (USP8KO) SK-HEP-1 cells revealed a significant correlation between USP8 and TRAF6, TAB2, TAK1, p62, and BECN1, and enhanced NF-κB-dependent and autophagy-related cancer progression/metastasis-related genes in response to LPS stimulation. Furthermore, USP8KO SK-HEP-1 cells showed an increase in cancer migration and invasion by TLR4 stimulation, and a marked increase of tumorigenicity and metastasis in xenografted NSG mice. The results demonstrate that USP8 is negatively implicated in the LIHC progression through the regulation of TRAF6-mediated signal for the activation of NF-κB activation and autophagy induction. Our findings provide useful insight into the LIHC pathogenesis of cancer progression.

SUBMITTER: Kim M

PROVIDER: S-EPMC8546492 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Hirsutella sinensis mycelium (HSM) has potent anti-pulmonary fibrotic activities and has been proposed as an effective treatment for idiopathic pulmonary fibrosis. Macrophages are the main innate immune cells in the lung tissue, playing key roles in pulmonary fibrosis repair and homeostasis. Excessive macrophage autophagy plays a vital role in pulmonary fibrosis. The protective effect of HSM on macrophages of bleomycin (BLM)-induced pulmonary fibrotic mice remain unclear. Methods: In this study, we collected lung tissue and bronchoalveolar lavage fluid (BALF) samples from pulmonary fibrotic mice. Meanwhile, alveolar macrophages were isolated and murine macrophage RAW264.7 cell line was cultured for further study of HSM autophagy. Results: First, we found that HSM decreased the number of autophagosomes, as well as the levels of LC3B and ATG5, and increased the protein level of P62 during the development of pulmonary fibrosis. Meanwhile, HSM reduced alveolar macrophages infiltration into the BALF and inhibited their accumulation in the fibrotic lung tissue. Flow cytometry analysis showed that HSM administration inhibited the autophagy marker LC3B expression in CD11bloCD11chi alveolar macrophages in BLM-induced lung fibrosis without affecting CD11bhiCD11clo interstitial macrophages. Transmission electron microscopy and JC-1 staining for mitochondrial membrane potential of alveolar macrophages also verified that the HSM significantly decreased autophagy in the alveolar macrophages of BLM-treated mice. In vitro, autophagosomes-lysosome fusion inhibitor chloroquine (CQ) was pre-incubated with RAW264.7 cells, and HSM reduced CQ-induced autophagosomes accumulation. TLR4 signaling inhibitor CLI095 reversed the above effects, suggesting HSM could reduce the cumulation of autophagosomes dependent on TLR4. Furthermore, lipopolysaccharide (LPS)-stimulated TLR4-related autophagy was significantly inhibited by HSM treatment. In addition, the protein expressions of TLR4 and phospho-NF-κB p65 were markedly inhibited in cells treated with HSM. Conclusions: These results indicated that HSM could inhibit the autophagy of alveolar macrophages through TLR4/NF-κB signaling pathway to achieve anti-fibrotic effect.

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USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4

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