Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2025; 31(13): 100566
Published online Apr 7, 2025. doi: 10.3748/wjg.v31.i13.100566
Suppressor of cytokine signaling 2 modulates regulatory T cell activity to suppress liver hepatocellular carcinoma growth and metastasis
Xi Lan, Heng Zhang, Ze-Yan Chen, Jing Wang, Shi-Chang Zhang, Qing Li, Juan-Yu Ke, Wei Wei, Rong Huang, Xi Tang, Si-Ping Chen, Ting-Ting Huang, Yi-Wen Zhou
Xi Lan, Heng Zhang, Ze-Yan Chen, Jing Wang, Shi-Chang Zhang, Qing Li, Juan-Yu Ke, Wei Wei, Rong Huang, Xi Tang, Si-Ping Chen, Ting-Ting Huang, Yi-Wen Zhou, Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
Co-first authors: Xi Lan and Heng Zhang.
Author contributions: Lan X and Zhang H contributed equally to this work; Lan X and Zhang H designed and performed the majority of the experiments, analyzed the data, and wrote the manuscript; Chen ZY and Wang J assisted with the in vitro experiments and data analysis; Zhang SC and Li Q provided support in bioinformatics analysis and interpretation of TCGA data; Ke JY, Wei W, Huang R, and Tang X contributed to the animal model experiments and histological analyses; Chen SP, Huang TT, and Zhou YW provided overall guidance, supervision, and contributed to the final manuscript revision; Zhou YW was responsible for project conceptualization, funding acquisition, and manuscript correspondence.
Supported by Wu Jieping Medical Foundation, No. 320.6750.2021-06-30; Guangdong Basic and Applied Basic Research Foundation, No. 2019A1515110120; and National Natural Science Foundation of China, No. 82002974.
Institutional animal care and use committee statement: The animal experiments in this study were approved by Ethics Committee of Shenzhen Hospital of Southern Medical University on Laboratory Animal Care (No. 2024-0332), adhering to ethical standards and regulations to ensure animal welfare.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data analyzed in this paper have been provided in the main manuscript and in supplementary documents, and it is permissible to contact the corresponding author at 1810010207@stu.hrbust.edu.cn to try to obtain it if necessary.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yi-Wen Zhou, PhD, Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, No. 1333 Xinhu Road, Bao'an District, Shenzhen 518101, Guangdong Province, China. yiwenzhou21@aliyun.com
Received: August 22, 2024
Revised: December 27, 2024
Accepted: March 11, 2025
Published online: April 7, 2025
Processing time: 224 Days and 0.9 Hours
Abstract
BACKGROUND

Liver hepatocellular carcinoma (LIHC) is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment (TME) and immune evasion. Regulatory T cells (Tregs) play a critical role in tumor progression. Suppressor of cytokine signaling 2 (SOCS2), a key immune regulator, may modulate Treg activity and impact LIHC growth and metastasis.

AIM

To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis.

METHODS

LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis, Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data, and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration. Key prognostic genes were identified using Weighted Gene Co-expression Network Analysis and machine learning. In vitro, co-culture experiments, migration assays, apoptosis detection, and enzyme-linked immunosorbent assay were conducted. In vivo, tumor growth, metastasis, and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining, Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling, and immunohistochemistry analyses.

RESULTS

SOCS2 overexpression inhibited Treg cell activity, reducing LIHC cell migration and invasion while increasing apoptosis. In vivo, SOCS2 suppressed tumor growth and metastasis, confirming its therapeutic potential.

CONCLUSION

SOCS2 modulates CD4+ T function in the TME, contributing to LIHC progression. Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.

Keywords: Liver hepatocellular carcinoma; Regulatory T cells; Suppressor of cytokine signaling 2; Immune microenvironment; Tumor metastasis

Core Tip: This study provides novel insights into the role of the suppressor of cytokine signaling 2 (SOCS2) in inhibiting liver hepatocellular carcinoma (LIHC) growth and metastasis by modulating regulatory T-cell (Treg) activity. Through comprehensive bioinformatics analysis and both in vitro and in vivo experiments, we demonstrated that SOCS2 overexpression suppresses Treg cell activity, enhances cancer cell apoptosis, and reduces tumor migration and invasion. These findings highlight SOCS2 as a potential therapeutic target for improving LIHC prognosis by modulating immune responses in the tumor microenvironment.