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

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.

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

“…Several lncRNAs and miRNAs can exert immunosuppressive influence to facilitate HCC progression, such as lncMALAT1 ( 72 ), lncHULC ( 73 ), lncHOTAIR ( 74 ), lncLINC01132 ( 75 ), lncPVT1 ( 76 ), lncLINC00662 ( 77 ), lncβ-Catm ( 78 ), miR-23a-3p ( 79 ), and miR-146a-5p ( 80 ). Dysregulated expression of epigenetic regulators, including DNMT3α ( 81 ), KDM1A ( 82 , 83 ), YTHDF2 ( 84 ), and RALYL ( 85 ), as well as kinases and phosphatases such as IRAK1 ( 86 ) and SHP2 ( 87 ), may also contribute to the formation of an immunosuppressive TME in HCC. As an intricate malignancy, HCC is characterized by metabolic reprogramming, in which glycolytic and lipid metabolism aberrations can contribute to an immunosuppressive TME.…”