The aim of this study is to evaluate chemopreventive and therapeutic efficacy of
tea polyphenols epigallocatechin gallete (EGCG) and
theaflavin (TF) on self-renewal Wnt and Hedgehog (Hh) pathways during CCl4/N-nitosodiethylamine-induced mouse liver
carcinogenesis. For this purpose, the effect of EGCG/TF was investigated in liver lesions of different groups at pre-, continuous and post initiation stages of
carcinogenesis. Comparatively increased
body weights were evident due to EGCG/TF treatment than
carcinogen control mice. Both EGCG and TF could restrict the development of
hepatocellular carcinoma at 30th week of
carcinogen application showing potential
chemoprevention in continuous treated group (mild dysplasia) followed by pretreated (moderate dysplasia) and therapeutic efficacy in posttreated group (mild dysplasia). This restriction was associated with significantly reduced proliferation, increased apoptosis, decreased prevalence of hepatocyte progenitor cell (AFP) and stem cell population (CD44) irrespective of EGCG/TF treatments. The EGCG/TF could modulate the Wnt pathway by reducing β-
catenin and phospho-β-catenin-Y-654 expressions along with up-regulation of sFRP1 (
secreted frizzled-related protein 1) and adenomatosis
polyposis coli during the restriction. In case of the Hh pathway, EGCG/TF could also reduce expressions of
glioma-associated oncogene homolog 1 (Gli1) and SMO (smoothened homolog) along with up-regulation of PTCH1 (
patched homolog 1). As a result, in Wnt/Hh regulatory pathways decreased expressions of β-
catenin/Gli1 target genes like CyclinD1, cMyc and EGFR/phospho-EGFR-Y-1173 and up-regulation of
E-cadherin were seen during the restriction. Thus, the restriction of liver
carcinogenesis by EGCG/TF was due to reduction in hepatocyte progenitor cell/stem cell population along with modulation of Wnt/Hh and other regulatory pathways.