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Thyroid Hormone Receptor-? Agonist GC-1 Inhibits Met-?-Catenin-Driven Hepatocellular Cancer.

ABSTRACT: The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/?-catenin signaling and may promote regeneration in both acute and chronic liver insufficiencies. However, ?-catenin activation due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it is critical to address any effect of GC-1 on HCC growth and development before its use can be advocated to stimulate regeneration in chronic liver diseases. In this study, we first examined the effect of GC-1 on ?-catenin-T cell factor 4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assessed the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-?-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed 5 mg/kg GC-1 or basal diet for 10 or 21 days. GC-1 treatment showed no effect on ?-catenin-T cell factor 4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation and dramatic decreases in phospho-(p-)Met (Y1234/1235), p-extracellular signal-related kinase, and p-STAT3 without affecting ?-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y-?-catenin HCC by inactivating Met signaling. GC-1 does not promote ?-catenin activation in HCC. Thus, GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.

PROVIDER: S-EPMC5809589 | BioStudies | 2017-01-01T00:00:00Z

REPOSITORIES: biostudies

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