Inhibition of RON (MST1R) induces apoptosis and decreases the cellular migration and proliferation capacity of mesothelioma cells
LUNG CANCER
Authors: Baird, A. M.; O'Byrne, K. J.; Easty, D.; Soltermann, A.; Nonaka, D.; Fennell, D. A.; Mutti, L.; Pass, H. I.; Opitz, I.; Gray, S. G.
Abstract
Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure
HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL
Authors: Kulkarni, Rishikesh M.; Kutcher, Louis W.; Stuart, William D.; Carson, Daniel J.; Leonis, Mike A.; Waltz, Susan E.
Abstract
BACKGROUND: Prior experimentation has shown that loss of the tyrosine kinase (TK) signaling domain of the Ron receptor leads to marked hepatocyte protection in a model of lipopolysaccharide-induced acute liver failure (ALP) in D-galactosamine (GalN)-sensitized mice. The aim of this study was to identify the role of Ron in the regulation of hepatic gene expression. METHODS: Microarray analyses were performed on liver RNA isolated sequentially from wild-type (WT) and TK-/- mice during the progression of ALF. Gene array data were validated using Western and immunohistochemistry analyses as well as with ex vivo culture systems. RESULTS: At baseline, 101 genes were differentially expressed between WT and TK-/- livers, which regulate processes involved in hypoxia, proliferation, apoptosis and metabolism. One hour after ALF induction, WT livers exhibited increased cytokine expression compared to TK-/- livers, and after 4 hours, an induction of suppressor of cytokine signaling (SOCS) genes as well as JAK-STAT pathway activation were prominent in TK-/- livers compared to controls. CONCLUSION: Our studies suggest a novel hepato-protective mechanism in Ron TK-/- mice wherein increased and sustained SOCS production and JAK-STAT activation in the hepatocyte may inhibit the destructive proinflammatory milieu and promote survival factors which blunt hepatic death and the ensuing development of ALF.
COA
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