Abstract | BACKGROUND AND AIMS: APPROACHES AND RESULTS: We took both genetic and pharmaceutical approaches to examine the effects of Shp2 inhibition on primary liver cancers driven by various oncogenes and on metastasized liver tumors. We show here that the catalytic activity of Shp2 was essential for relay of oncogenic signals from RTKs in HCC and that chemical inhibition of Shp2 robustly suppressed HCC driven by RTKs. However, in contrast to a tumor-promoting hepatic niche generated by genetically deleting Shp2 in hepatocytes, treatment with a specific Shp2 inhibitor had a tumor-suppressing effect on metastasized liver tumor progression. Mechanistically, the Shp2 inhibitor enhanced antitumor innate immunity by down-regulating inflammatory cytokines, suppressing the chemokine (C-C motif) receptor 5 signaling axis, but up-regulating interferon-β secretion. CONCLUSIONS: These results unveil complex mechanisms for the tumor-suppressing effect of pharmaceutical Shp2 inhibition in the liver immune environment. We provide a proof of principle for clinical trials with specific Shp2 inhibitors in patients with primary and metastasized liver cancer.
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Authors | Jacey J Liu, Bing Xin, Li Du, Lydia Chen, Yanyan Long, Gen-Sheng Feng |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 77
Issue 5
Pg. 1512-1526
(05 01 2023)
ISSN: 1527-3350 [Electronic] United States |
PMID | 35503714
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2023 American Association for the Study of Liver Diseases. |
Chemical References |
- Receptor Protein-Tyrosine Kinases
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Tyrosine
- Pharmaceutical Preparations
|
Topics |
- Humans
- Liver Neoplasms
(drug therapy)
- Carcinoma, Hepatocellular
- Receptor Protein-Tyrosine Kinases
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
(metabolism)
- Tyrosine
- Immunity, Innate
- Pharmaceutical Preparations
|