title: Tea polyphenols epigallocatechin gallete and theaflavin restrict mouse liver carcinogenesis through modulation of self-renewal Wnt and hedgehog pathways.
abstract: 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.
authors.affiliation: Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal, India. Electronic address: subhayansur18@gmail.com.
authors.forename: Subhayan
authors.initials: S
authors.lastname: Sur
authors.affiliation: Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal, India. Electronic address: dbln.pl@gmail.com.
authors.forename: Debolina
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Epidemiology and Biostatistics, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, India.
authors.forename: Syamsundar
authors.initials: S
authors.lastname: Mandal
authors.affiliation: North Bengal Medical College and Hospital, West Bengal, India.
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.affiliation: Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal, India. Electronic address: ckpanda.cnci@gmail.com.
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D013662:Tea / Q000737:chemistry*; D051153:Wnt Proteins / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D044946:Biflavonoids; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D013662:Tea; D051153:Wnt Proteins; D000509:alpha-Fetoproteins; C056068:theaflavin; D002392:Catechin; C045651:epigallocatechin gallate
keywords: CD44; EGCG; Gli1; Hepatocellular carcinoma; TF; β-Catenin