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SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy

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收录情况： ◇ SCIE

作者：
Luo Xiangyuan[1] * ; Zhang Zerui[1] ; Li Siwen[1] ; Wang Yijun[1] ; Sun Mengyu[1] ; Hu Dian[1] ; Jiang Junqing[1] ; Wang Yufei[1] ; Ji Xiaoyu[1] ; Chen Xiaoping[2] ; Zhang Bixiang[2] ; Liang Huifang[2] ; Li Yiwei[3] ; Liu Bifeng[3] ; Xu Xiao[4] ; Wang Shuai[4] ; Xu Shengjun[4] ; Nie Yongzhan[5] ; Wu Kaichun[5] ; Fan Daiming[5] ; Liu Danfei[1,*1] ; Huang Wenjie[2,*1] ; Xia Limin[1,5,*1] ;
单位： [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 [2]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 Hepatic Surgery of Hubei Province,Key Laboratory of Organ Transplantation,Ministry of Education and Ministry of Public Health,Wuhan,Hubei 430030,China [3]The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China [4]Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China [5]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’ an 710032, China
出处：
DOI： 10.1016/j.intimp.2023.111376
ISSN：

关键词： Hepatocellular carcinoma Alternative splicing Mouse double minute 4 Programmed death ligand 1 CD8+T cell Anti-PD-L1 therapy

摘要：
RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood.Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10△hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment.SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity.SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

基金：
Research was supported by grants from the National Natural Science Foundation of China No. 82273310 (L.X.), No. 82372917(W.H.), No. 82173313 (W.H.), No. 82303356 (D.L.), the Natural Science Foundation of Hubei Province 2022CFA016 (L.X.), and the Basic Research Support Program of Huazhong University of Science and Technology 2023BR038 (L.X.).
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 2 区 免疫学 2 区 药学
最新[2025]版：
大类 | 2 区 医学
小类 | 2 区 药学 3 区 免疫学
JCR分区：
出版当年[2022]版：
Q1 PHARMACOLOGY & PHARMACY Q2 IMMUNOLOGY
最新[2023]版：
Q1 PHARMACOLOGY & PHARMACY Q2 IMMUNOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

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-Pancreato-Biliary Diseases,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei Province,China
通讯作者：
通讯机构： [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 [2]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 Hepatic Surgery of Hubei Province,Key Laboratory of Organ Transplantation,Ministry of Education and Ministry of Public Health,Wuhan,Hubei 430030,China [5]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’ an 710032, 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)：
Luo Xiangyuan,Zhang Zerui,Li Siwen,et al.SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy[J].INTERNATIONAL IMMUNOPHARMACOLOGY.2024,127:111376.doi:10.1016/j.intimp.2023.111376.
APA：
Luo Xiangyuan,Zhang Zerui,Li Siwen,Wang Yijun,Sun Mengyu...&Xia Limin.(2024).SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy.INTERNATIONAL IMMUNOPHARMACOLOGY,127,
MLA：
Luo Xiangyuan,et al."SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy".INTERNATIONAL IMMUNOPHARMACOLOGY 127.(2024):111376

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