Mechanism study of tyrosine phosphatase shp-1 in inhibiting hepatocellular carcinoma progression by regulating the SHP2/GM-CSF pathway in TAMs.
Sci Rep
; 14(1): 9128, 2024 04 21.
Article
in En
| MEDLINE
| ID: mdl-38644382
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 TGFß2 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 TGFß2 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/TGFß2 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Granulocyte-Macrophage Colony-Stimulating Factor
/
Carcinoma, Hepatocellular
/
Protein Tyrosine Phosphatase, Non-Receptor Type 6
/
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/
Liver Neoplasms
/
Macrophages
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Rep
Year:
2024
Document type:
Article
Affiliation country:
China