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酪氨酸磷酸酶shp-1通过调节肿瘤相关巨噬细胞中的SHP2/GM-CSF途径抑制肝癌进展的机制研究

Mechanism study of tyrosine phosphatase shp-1 in inhibiting hepatocellular carcinoma progression by regulating the SHP2/GM-CSF pathway in TAMs.

作者信息

Wei Qiang, Luo ShuBin, He Gang

机构信息

Bethune International Peace Hospital of PLA Hepatobiliary Surgery, Shijiazhuang, 050082, China.

Department of General Surgery (Section 1), The First People's Hospital of Jinghong, Jinghong, 666100, China.

出版信息

Sci Rep. 2024 Apr 21;14(1):9128. doi: 10.1038/s41598-024-59725-w.

DOI:10.1038/s41598-024-59725-w
PMID:38644382
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11033275/
Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Macrophage-mediated innate immune responses play a crucial role in tumor development. This study revealed the mechanism of SHP-1 in regulating HCC progression. SHP-1 inhibits tumour development in vivo. Increasing SHP-1 expression in macrophages promotes the expression of p-SHP-1, SHP2, and p-SHP-2. In macrophages GM-CSF recruits SHP-2 to the GM-CSF receptor GM-CSFR induces p-SHP-2 dephosphorylation. GM-CSF recruits p-SHP-2 for dephosphorylation by up-regulating HoxA10HOXA10 activates the transcription of TGFβ2 by interacting with tandem cis-elements in the promoter thereby regulating the proliferation and migration of liver cancer cells. GM-CSF inhibits SHP-1 regulation of p-SHP-1, SHP2, and p-SHP-2 in macrophages. Detailed studies have shown that SHP-1 regulates SHP2 expression, and SHP-1 and SHP2 are involved in macrophage M2 polarisation. SHP-1 inhibits HOXA10 and TGFβ2 which in turn regulates the expression of the migration-associated proteins, MMP2/9, and the migration of hepatocellular carcinoma cells. Overexpression of SHP-1 inhibits macrophage M2 polarisation via the p-STAT3/6 signalling pathway Classical markers arginase-1, CD206, CD163 and regulate the expression of M2 polarisation cytokines IL-4 and IL-10. In addition, hypoxia-induced ROS inhibited SHP-1 regulation by suppressing the expression of p-SHP-1. The combined effect of GM-CSF and ROS significantly increased p-HOXA10/TGFβ2 and macrophage M2 polarisation, and the regulatory effect of ROS was significantly suppressed by GM-CSF knockdown. These findings suggest that increasing the expression of tyrosine phosphatase SHP-1 can inhibit hepatocellular carcinoma progression by modulating the SHP2/GM-CSF pathway in TAM and thus inhibit the progression of hepatocellular carcinoma.

摘要

肝细胞癌（HCC）是全球最常见的恶性肿瘤之一。巨噬细胞介导的先天性免疫反应在肿瘤发展中起关键作用。本研究揭示了SHP-1调节HCC进展的机制。SHP-1在体内抑制肿瘤发展。巨噬细胞中SHP-1表达增加会促进p-SHP-1、SHP2和p-SHP-2的表达。在巨噬细胞中，粒细胞-巨噬细胞集落刺激因子（GM-CSF）将SHP-2招募至GM-CSF受体（GM-CSFR），诱导p-SHP-2去磷酸化。GM-CSF通过上调HoxA10招募p-SHP-2进行去磷酸化，HoxA10通过与启动子中的串联顺式元件相互作用激活转化生长因子β2（TGFβ2）的转录，从而调节肝癌细胞的增殖和迁移。GM-CSF抑制巨噬细胞中SHP-1对p-SHP-1、SHP2和p-SHP-2的调节。详细研究表明，SHP-1调节SHP2表达，且SHP-1和SHP2参与巨噬细胞M2极化。SHP-1抑制HoxA10和TGFβ2，进而调节迁移相关蛋白MMP2/9的表达以及肝癌细胞的迁移。SHP-1的过表达通过p-STAT3/6信号通路抑制巨噬细胞M2极化，经典标志物精氨酸酶-1、CD206、CD163并调节M2极化细胞因子IL-4和IL-10的表达。此外，缺氧诱导的活性氧（ROS）通过抑制p-SHP-1的表达抑制SHP-1调节。GM-CSF和ROS的联合作用显著增加p-HoxA10/TGFβ2和巨噬细胞M2极化，且GM-CSF敲低可显著抑制ROS的调节作用。这些发现表明，增加酪氨酸磷酸酶SHP-1的表达可通过调节肿瘤相关巨噬细胞（TAM）中的SHP2/GM-CSF途径抑制肝细胞癌进展，从而抑制肝细胞癌进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/684437230ff7/41598_2024_59725_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/adbba5cca7b5/41598_2024_59725_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/482ae673eb01/41598_2024_59725_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/8adebd504da3/41598_2024_59725_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/ac96db5373bc/41598_2024_59725_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/684437230ff7/41598_2024_59725_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/adbba5cca7b5/41598_2024_59725_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/482ae673eb01/41598_2024_59725_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/8adebd504da3/41598_2024_59725_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/ac96db5373bc/41598_2024_59725_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6960/11033275/684437230ff7/41598_2024_59725_Fig5_HTML.jpg

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引用本文的文献

[1]
Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma.

J Exp Clin Cancer Res. 2025-8-5

[2]
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[3]
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[4]
Ferrocenyl-Substituted Curcumin Derivatives as Potential SHP-2 Inhibitors for Anticolorectal Cancer: Design, Synthesis and Evaluation.

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[5]
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本文引用的文献

[1]
Targeting pathogenic macrophages by the application of SHP-1 agonists reduces inflammation and alleviates pulmonary fibrosis.

Cell Death Dis. 2023-6-8

[2]
Macrophage STING signaling promotes NK cell to suppress colorectal cancer liver metastasis via 4-1BBL/4-1BB co-stimulation.

J Immunother Cancer. 2023-3

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Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function.

Cells. 2023-2-3

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