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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)是世界范围内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的发展中起着至关重要的作用。这项研究揭示了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表达的增加促进了p-SHP-1、SHP2和p-SHP-2的表达。在巨噬细胞中，GM-CSF将SHP-2募集到GM-CSF受体GM-CSFR诱导p-SHP-2去磷酸化。GM-CSF通过上调HoxA10HOXA10来募集p-SHP-2去磷酸化，从而通过与启动子中的串联顺式元件相互作用来激活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p-SHP-1、SHP2和p-SHP-2的SHP-1调节。详细的研究表明，SHP-1调节SHP2的表达，和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的表达，MMP2/9，与肝癌细胞的迁徙相干。SHP-1的过表达通过p-STAT3/6信号传导途径抑制巨噬细胞M2极化经典标记精氨酸酶-1，CD206，CD163，并调节M2极化细胞因子IL-4和IL-10的表达。此外,低氧诱导的ROS通过抑制p-SHP-1的表达来抑制SHP-1的调节。GM-CSF和ROS的联合作用显着增加p-HOXA10/TGFβ2和巨噬细胞M2极化，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的表达可以通过调节TAM中的SHP2/GM-CSF途径来抑制肝细胞癌的进展，从而抑制肝细胞癌的进展。
