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NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer

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Pubmed体系：

收录情况： ◇ SCIE

作者：
Wang Shunyi[1] * ; Kuai Yihe[1] * ; Lin Simin[2] * ; Li Li[1] * ; Gu Quliang[1] ; Zhang Xiaohan[3] ; Li Xiaoming[4] ; He Yajun[4] ; Chen Sishuo[1] ; Xia Xiaoru[1] ; Ruan Zhang[1] ; Lin Caixia[1] ; Ding Yi[1] ; Zhang Qianqian[1] ; Qi Cuiling[1] ; Li Jiangchao[1] ; He Xiaodong[1] ; Pathak Janak L[5] ; Zhou Weijie[6] ; Liu Side[2] ; Wang Lijing[1] ; Zheng Lingyun[1] ;
机构： [1]School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, P. R. China [2]Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China [3]Hospital of Guangdong Provincial Hospital of Traditional Chinese Medicine, Zhuhai 519015, China [4]Department of Pathology, People’s Hospital of Shenzhen Bao an District, Shenzhen 518101, China [5]Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong 510182 Guangzhou, China [6]Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, P. R. China.
出处：
DOI： 10.1186/s12916-023-02791-0
ISSN：

关键词： Act1 Macrophages Colorectal cancer Adenoma-adenocarcinoma transition CD8+ T cells

摘要：
Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8+ T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition.This study used spontaneous adenoma-developing ApcMin/+, macrophage-specific Act1-knockdown (anti-Act1), and ApcMin/+; anti-Act1 (AA) mice. Histological analysis was performed on CRC tissues of patients and mice. CRC patients' data retrieved from the TCGA dataset were analyzed. Primary cell isolation, co-culture system, RNA-seq, and fluorescence-activated cell sorting (FACS) were used.By TCGA and TISIDB analysis, the downregulation of Act1 expression in tumor tissues of CRC patients negatively correlated with accumulated CD68+ macrophages in the tumor. Relative expression of EMT markers in the tumor enriched ACT1lowCD68+ macrophages of CRC patients. AA mice showed adenoma-adenocarcinoma transition, TAMs recruitment, and CD8+ T cell infiltration in the tumor. Macrophages depletion in AA mice reversed adenocarcinoma, reduced tumor amounts, and suppressed CD8+ T cell infiltration. Besides, macrophage depletion or anti-CD8a effectively inhibited metastatic nodules in the lung metastasis mouse model of anti-Act1 mice. CRC cells induced activation of IL-6/STAT3 and IFN-γ/NF-κB signaling and the expressions of CXCL9/10, IL-6, and PD-L1 in anti-Act1 macrophages. Anti-Act1 macrophages facilitated epithelial-mesenchymal-transition and CRC cells' migration via CXCL9/10-CXCR3-axis. Furthermore, anti-Act1 macrophages promoted exhaustive PD1+ Tim3+ CD8+ T cell formation. Anti-PD-L1 treatment repressed adenoma-adenocarcinoma transition in AA mice. Silencing STAT3 in anti-Act1 macrophages reduced CXCL9/10 and PD-L1 expression and correspondingly inhibited epithelial-mesenchymal-transition and CRC cells' migration.Act1 downregulation in macrophages activates STAT3 that promotes adenoma-adenocarcinoma transition via CXCL9/10-CXCR3-axis in CRC cells and PD-1/PD-L1-axis in CD8+ T cells.© 2023. The Author(s).

基金：
This work was supported by the National Natural Science Foundation of China (no. 31571178 to L.Y.Z., no. 31771578 to L.J.W., no. 92068206 to W.J.Z.). The work was also supported by the Guangdong Key Research and Development Plan (2019B020234003) to W.J.Z. and the Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer (2020B121201004) to W.J.Z.
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外文
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出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
JCR分区：
出版当年[2021]版：
Q1 MEDICINE, GENERAL & INTERNAL
最新[2023]版：
Q1 MEDICINE, GENERAL & INTERNAL

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者机构： [1]School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, P. R. China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Wang Shunyi,Kuai Yihe,Lin Simin,et al.NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer[J].BMC MEDICINE.2023,21(1):doi:10.1186/s12916-023-02791-0.
APA：
Wang Shunyi,Kuai Yihe,Lin Simin,Li Li,Gu Quliang...&Zheng Lingyun.(2023).NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer.BMC MEDICINE,21,(1)
MLA：
Wang Shunyi,et al."NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer".BMC MEDICINE 21..1(2023)

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