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

ABSTRACT: 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.

SUBMITTER: Wang S

PROVIDER: S-EPMC10053426 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Wang Shunyi S Kuai Yihe Y Lin Simin S Li Li L Gu Quliang Q Zhang Xiaohan X Li Xiaoming X He Yajun Y Chen Sishuo S Xia Xiaoru X Ruan Zhang Z Lin Caixia C Ding Yi Y Zhang Qianqian Q Qi Cuiling C Li Jiangchao J He Xiaodong X Pathak Janak L JL Zhou Weijie W Liu Side S Wang Lijing L Zheng Lingyun L

BMC medicine 20230329 1

<h4>Background</h4>Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8<sup>+</sup> T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition.<h4>Methods</h4>This study used spontaneous adenoma-developing Apc<sup>Min/+</sup>, macrophage-specific Act1-knockdown (anti-Act1), and Apc<sup>Min/+</sup>; anti-A ...[more]

PMID: 36978108

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Project description:BackgroundOdd-skipped related 1 (OSR1) has been reported as a tumor suppressor gene in various malignant tumors. The mechanism through which OSR1 regulates ovarian cancer (OC) progression remains unclear.Materials and methodsImmunohistochemistry was utilized to evaluate OSR1 expression in patients with ovarian cancer. We investigated the association between clinicopathological parameters and OSR1 expression in OC patients and the influence of OSR1 expression on patient survival and prognosis. OC cells with OSR1 overexpression or knockdown were established and validated using Western blot and Quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The influence of OSR1 on the NF-κB pathway was examined by analyzing the p-IκBα, IκBα, p65, and p-p65 protein expression. In vitro assays, such as cell cycle assay, Cell Counting Kit-8 (CCK-8), transwell invasion assay, wound healing migration assay, enzyme-linked immunoassay (ELISA), and Annexin V/PI flow cytometry apoptosis assay, were conducted to explore the effect of OSR1 knockdown or dual inhibition of OSR1 and the NF-κB pathway on OC malignant biological behavior.ResultsOSR1 expression was downregulated in OC tissues, with significant associations observed between its expression and The International Federation of Gynecology and Obstetrics (FIGO) stage and tissue differentiation. Low OSR1 expression in OC patients correlated with reduced overall survival (OS) rates and poor prognosis. In vitro, experiments confirmed a negative correlation between OSR1 expression and NF-κB pathway activity. OSR1 knockdown facilitated OC cell malignant biological behavior, while the NF-κB pathway inhibitor (Bay 11-0782) reversed the impacts of OSR1 knockdown on cell proliferation, migration, invasion, and apoptosis.ConclusionOur findings indicate that OSR1 is downregulated and associated with OC prognosis. OSR1 suppresses NF-κB pathway activity and inhibits OC progression by targeting the NF-κB pathway.

Dataset Information

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

Publications

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

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