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USP8通过抑制TRAF6介导的TLR4激活NF-κB和诱导自噬的信号来调节肝癌进展。

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

作者信息

Kim Mi-Jeong, Choi Bongkum, Kim Ji Young, Min Yoon, Kwon Do Hee, Son Juhee, Lee Ji Su, Lee Joo Sang, Chun Eunyoung, Lee Ki-Young

机构信息

Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.

Department of Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.

出版信息

Transl Oncol. 2022 Jan;15(1):101250. doi: 10.1016/j.tranon.2021.101250. Epub 2021 Oct 20.

DOI:10.1016/j.tranon.2021.101250
PMID:34688043
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8546492/
Abstract

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.

摘要

在此，我们旨在阐明泛素特异性蛋白酶8（USP8）通过TRAF6介导的信号参与肝癌进展的分子和细胞机制。USP8诱导TRAF6、TAB2、TAK1、p62和BECN1的去泛素化，这些对于NF-κB激活和自噬诱导起着关键作用。值得注意的是，USP8 mRNA表达低的肝癌患者生存时间明显缩短，而在其他18种人类癌症中没有显著差异。重要的是，对肝癌的TCGA数据分析以及对USP8基因敲除（USP8KO）的SK-HEP-1细胞的转录组分析显示，USP8与TRAF6、TAB2、TAK1、p62和BECN1之间存在显著相关性，并且在LPS刺激下，NF-κB依赖性和自噬相关的癌症进展/转移相关基因增强。此外，USP8KO SK-HEP-1细胞在TLR4刺激下癌症迁移和侵袭增加，并且在异种移植的NSG小鼠中致瘤性和转移显著增加。结果表明，USP通过调节TRAF6介导的信号以激活NF-κB激活和自噬诱导，从而对肝癌进展产生负向影响。我们的发现为肝癌进展的发病机制提供了有用的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/5930cbc0d7cf/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/c66f061d44bf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/9322d84f3ef2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/d1ba2ca9ce8e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/6baa88b67d77/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/a3878e9fce11/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/96fd9eaabede/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/d8e3da470541/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/5930cbc0d7cf/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/c66f061d44bf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/9322d84f3ef2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/d1ba2ca9ce8e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/6baa88b67d77/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/a3878e9fce11/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/96fd9eaabede/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/d8e3da470541/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eac0/8546492/5930cbc0d7cf/gr8.jpg

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