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TGF-b1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis through Transcriptionally Upregulating PD-L1 and CXCL12

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收录情况： ◇ 自然指数

作者：
Chen Jie[1,2] * ; Feng Weibo[2] * ; Sun Mengyu[1] * ; Huang Wenjie[3] * ; Wang Guodong[2] * ; Chen Xilang[2] ; Yin Yue[2] ; Chen Xiaoping[3] ; Zhang Bixiang[3] ; Nie Yongzhan[2] ; Fan Daiming[2] ; Wu Kaichun[2] ; Xia Limin[1,2,*1] ;
单位： [1]Department of Gastroenterology,Institute of Liver and Gastrointestinal Diseases,Hubei Key Laboratory of Hepato-PancreatoBiliary Diseases,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,HubeiProvince,China [2]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National ClinicalResearch Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, ShaanxiProvince, China [3]Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases,Hepatic Surgery Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Clinical Medicine Research Center for HepaticSurgery of Hubei Province,Key Laboratory of Organ Transplantation,Ministry of Education and Ministry of Public Health,Wuhan,Hubei,China
出处：
DOI： 10.1053/j.gastro.2024.02.025
ISSN：

摘要：
Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis and immunotherapy resistance. Identification of HCC-intrinsic factors regulating immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis.The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride (DEN/CCl4) induced spontaneous models by using murine cell lines, adeno-associated virus 8 and hepatocyte-specific knockin and knockout mice. The immune cellular composition in HCC microenvironment was evaluated by flow cytometry and immunofluorescence.SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically-induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-β1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of CXCR4, the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFβR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis.SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.

基金：
This research was supported by grants from the National Natural Science Foundation of China No. U23A20451 (Limin Xia), No. 82273310 (Limin Xia), No. 82372917 (Wenjie Huang), No. 82173313 (Wenjie Huang), and No. 82273374 (Kaichun Wu); the Natural Science Foundation of Hubei Province 2022CFA016 (Limin Xia); the Basic Research Support Program of Huazhong Q10 University of Science and Technology 2023BR038 (Limin Xia); and the Special Support Program for Young Physicians of Xijing Hospital No. XJZT24QN43 (Jie Chen).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
第一作者：
第一作者单位： [1]Department of Gastroenterology,Institute of Liver and Gastrointestinal Diseases,Hubei Key Laboratory of Hepato-PancreatoBiliary Diseases,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,HubeiProvince,China [2]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National ClinicalResearch Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, ShaanxiProvince, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Gastroenterology,Institute of Liver and Gastrointestinal Diseases,Hubei Key Laboratory of Hepato-PancreatoBiliary Diseases,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,HubeiProvince,China [2]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National ClinicalResearch Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, ShaanxiProvince, China [*1]Department of Gastroenterology,Institute of Liver and Gastrointestinal Diseases,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei Province,China
推荐引用方式(GB/T 7714)：
Chen Jie,Feng Weibo,Sun Mengyu,et al.TGF-b1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis through Transcriptionally Upregulating PD-L1 and CXCL12[J].Gastroenterology.2024,doi:10.1053/j.gastro.2024.02.025.
APA：
Chen Jie,Feng Weibo,Sun Mengyu,Huang Wenjie,Wang Guodong...&Xia Limin.(2024).TGF-b1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis through Transcriptionally Upregulating PD-L1 and CXCL12.Gastroenterology,,
MLA：
Chen Jie,et al."TGF-b1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis through Transcriptionally Upregulating PD-L1 and CXCL12".Gastroenterology .(2024)

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