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Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis

Oncogene volume 38, pages 4512–4526 (2019)Cite this article

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Abstract

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.

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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).

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  1. These authors contributed equally: Alejandro Torres-Hernandez, Wei Wang

Authors and Affiliations

  1. S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA

    Alejandro Torres-Hernandez, Wei Wang, Yuri Nikiforov, Karla Tejada, Luisana Torres, Aleksandr Kalabin, Yue Wu, Muhammad Israr Ul Haq, Mohammed Y. Khan, Zhen Zhao, Wenyu Su, Jimmy Camargo, Mautin Hundeyin, Brian Diskin, Salma Adam, Juan A. Kochen Rossi, Emma Kurz, Berk Aykut, Sorin A. A. Shadaloey, Joshua Leinwand & George Miller

  2. Departments of Cell Biology, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA

    George Miller

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Torres-Hernandez, A., Wang, W., Nikiforov, Y. et al. Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. Oncogene 38, 4512–4526 (2019). https://doi.org/10.1038/s41388-019-0734-5

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