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Background/Aims Inhibition of hepatoma cells by cyclooxygenase (COX)-2-dependent and -independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/β-catenin pathway and human hepatoma cells. Methods Hep3B and HepG2 cell lines were treated with Celecoxib or R-Etodolac, and examined for viability, DNA synthesis, Wnt/β-catenin pathway components, and downstream target gene expression. Results Celecoxib at high doses affected β-catenin protein by inducing its degradation via GSK3β and APC along with diminished tumor cell proliferation and survival. R-Etodolac at physiological doses caused decrease in total and activated β-catenin protein secondary to decrease in its gene expression and post-translationally through GSK3β activation. In addition, increased β-catenin-E–cadherin was also observed at the membrane. An associated inhibition of β-catenin-dependent Tcf reporter activity, decreased levels of downstream target gene products glutamine synthetase and cyclin-D1, and decreased proliferation and survival of hepatoma cells was evident. Conclusions The antitumor effects of Celecoxib (at high concentrations) and R-Etodolac (at physiological doses) on HCC cells were accompanied by the down-regulation of β-catenin demonstrating a useful therapeutic strategy in hepatocellular cancer.

Background/Aims Wnt/β-catenin activation is seen during early liver regeneration (LR) observed as stabilization and translocation to the nucleus followed by an overall decrease. However, β-catenin continues to be in hepatocyte nucleus and membrane, secondary to its increased gene expression at 6–72h. Methods In the present study, we examined the effect of ablating β-catenin transcription on LR. Twelve male fisher rats were subjected to two-third partial hepatectomy followed by administration of β-catenin antisense phospho-morpholino oligonucleotide (AS) in six or mismatch control (CON) injection in the remaining 6 via superior mesenteric vein. Three animals from each group were sacrificed at 24h and 7 days for liver assessment. Results AS group exhibited a significant decrease in total β-catenin at 24h. A significant decrease in liver/body weight ratio was also observed in the AS group at 24h and 7 days that was due to decreased proliferation. Among the targets of this pathway c-myc and uPAR levels showed significant decrease while cyclin-D1 remained unaffected. Conclusions We demonstrate the importance of β-catenin in early liver regeneration especially in hepatocyte proliferation. Also, c-myc and uPAR might be crucial downstream effectors of β-catenin during liver regeneration.