HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway

Journal of Experimental & Clinical Cancer Research

Research

Qifan Zhang¹  Zhuojun Zheng²  Ping Wang²  Qishan Xu²  Fan Deng²  Daming Zuo³  Jialiang Luo⁴  Yunzhi Liu⁵  Liyun Zhang⁶  Zhengliang Chen⁶  Xiao Lu⁶  Jia Zhou⁶  Qingyun Chen⁷ 

[1]Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China

[2]Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515, Guangzhou, Guangdong, China

[3]Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515, Guangzhou, Guangdong, China

[4]Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515, Guangzhou, Guangdong, China

[5]Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, 510282, Guangzhou, Guangdong, China

[6]Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515, Guangzhou, Guangdong, China

[7]Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, Guangdong, China

[8]Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, 510515, Guangzhou, Guangdong, China

[9]Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, Guangdong, China

[10]Clinical Oncology Center, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China

[11]Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China

[12]Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, Guangdong, China

[13]Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 510080, Guangzhou, Guangdong, China

关键词: HERC2;    Hepatocellular carcinoma;    JAK2/STAT3 signaling;    Cancer stemness;    PD-L1;   

DOI  :  10.1186/s13046-023-02609-0

 received in 2022-09-06, accepted in 2023-01-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis.MethodsRNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan–Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development.ResultsWe found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model.ConclusionOur data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 5

Fig. 9

Fig. 3

Fig. 7

Fig. 6

40249_2023_1060_Article_IEq2.gif

Fig. 3

Fig. 2

Fig. 2