In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing
J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor GSK3235025 clinical trial size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (Hepatology 2012) Thyroid hormone, 3,3′-5-triiodo-l-thyronine (T3), is a potent mediator of many physiological processes including embryonic development, cell differentiation, metabolism, and the regulation of cell proliferation.1, 2 The actions Mitomycin C clinical trial of T3 are mediated by nuclear thyroid hormone receptors (TRs). TRs are ligand-dependent transcription factors that comprise modular functional domains that mediate hormone binding (ligands), DNA binding, receptor homo- and heterodimerization, and
interaction with other transcription factors and cofactors.3 TRs are derived from two genes, TRα and TRβ, Sclareol located on human chromosomes 17 and 3, respectively. Transcripts of each of these genes undergo alternative promoter choice to generate TRα1 and TRα2 as well as TRβ1 and TRβ2 receptor isoforms.2–4 Using a complementary DNA (cDNA) microarray technique, we previously identified 148 genes that are positively regulated by T3 in a TRα1-overexpressing hepatoma cell line (HepG2-TRα1).5
Increasing evidence suggests that aberrant TR regulation or mutant TR genes may be associated with human neoplasia.6 Lin et al.7 reported truncated TRα1 and TRβ1 cDNA in 53% of human hepatocellular carcinomas (HCCs). Other groups8 have reported mutated TRs in HCC and cultured cells. However, an increasing number of studies have indicated that TR is a potent suppressor of tumorigenesis, invasiveness, and metastasis formation.9 This study focused on a set of genes (i.e., tumor suppressor genes) that are normally activated by the TR but are aberrantly repressed because of reduced TR expression or mutation during carcinogenesis. The Dickkopf (DKK) family comprises secreted antagonists of Wnt signaling. Wnt/β-catenin signaling plays an important role in embryogenesis, tissue homeostasis, and tumor development.10 Wnt proteins participate in various types of cancer development and progression by binding to frizzled receptor and low density lipoprotein-receptor-related protein 5 and 6 (LRP5/6) and by signaling through the canonical and noncanonical Wnt pathways.