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Thyroid receptor beta agonist reduces tumor burden in an established murine model of human hepatocellular cancer
Author(s) -
Min Qian,
Puliga Elisabetta,
Columbano Amedeo,
Monga SatdarshanPaul Singh
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.805.4
Subject(s) - cyclin d1 , wnt signaling pathway , hepatocellular carcinoma , medicine , endocrinology , agonist , cancer , cancer research , triiodothyronine , carcinogenesis , thyroid , chemistry , biology , receptor , signal transduction , microbiology and biotechnology , cell cycle
Triiodothyronine (T3) or selective TRβ agonist GC‐1 induces hepatocyte proliferation at least in part through the activation of Wnt/β‐catenin signaling. This mitogenic effect has formed the basis to support their preclinical use to induce liver regeneration in mice. However, to enable its use in clinical setting, it is highly relevant to directly investigate the effect of compounds like GC‐1 in carcinogenesis especially since Wnt pathway activation due to CTNNB1 mutations is common in hepatocellular cancer (HCC) cases. Our current study was aimed to explore the effect of GC‐1 in preclinical model of HCC driven by CTNNB1 mutations. We co‐expressed hMet and S45Y‐mutant‐β‐catenin in hepatocytes by sleeping beauty transposon/transposase and hydrodynamic tail vein injection, which induces HCC by 4 weeks. At this time mice were randomly stratified into two groups, one that recieved regular diet ad libitum versus second which received GC‐1 diet (5mg/kg) ad libitum. At least 4 mice from each group were euthanized at 10 days and at 21 days after starting the diets. Mice on GC‐1 diet showed a significantly reduced tumor burden as reflected by lower liver weight to body weight ratios at both timepoints. Immunohistochemistry (IHC) for Glutamine synthetase showed fewer and smaller tumor nodules in GC‐1 group. A modest decrease in cyclin‐D1 was visible in GC‐1 group and was shown to occur in tumor nodules where as increased cyclin‐D1 was evident in non tumor areas of the liver. A dramatic decrease in phospho‐Met and phospho‐ERK was clearly evident in GC‐1 treated livers, which coincided with a pronounced decrease in tumor proliferation as detected by both Ki‐67 and Brdu IHC. In conclusion GC‐1 reduces HCC tumor proliferation through blocking hMet signaling while not having any impact on Wnt signaling within tumors. Thus, GC‐1 actually leads to less tumor burden and hence may be safe to use in promoting liver regeneration in chronic liver diseases and transplantation settings.