Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.
|Number of pages||15|
|State||Published - Jun 6 2019|
Bibliographical noteFunding Information:
Acknowledgements We thank the NYU Langone Health Genome Technology Center (GTC) for expert library preparation and sequencing; the GTC is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. We thank the NYU Langone Health Experimental Pathology Research Laboratory, which is partially funded by NYU Cancer Institute Center Support Grant NIH/NCI 5 P30CA16087, for expert tissue processing and equipment support. This work was supported by NCI CA168611 (GM), CA155649 (GM), CA193111 (ATH, BD), Society of University Surgeons—Ethicon Resident Research Award (ATH), American Liver Foundation—Thomas F. Nealon, III Postdoctoral Research Fellowship Honoring Zachery Rue (ATH), American Liver Foundation Postdoctoral Research Fellowship (WW), NYU Physician-Scientist Training Program (ATH).
© 2019, Springer Nature Limited.
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research