title: Involvement of PTEN/Akt signaling and oxidative stress on indole-3-carbinol (I3C)-induced hepatocarcinogenesis in rats.
abstract: We previously reported that indole-3-carbinol (I3C) had hepatocellular tumor-promoting activity in a short-term (8 weeks) two-stage liver carcinogenesis model in rats. It was suggested that this effect was related to the production of reactive oxygen species (ROS) caused by cytochrome P450 1A (CYP1A) induction. In the present study, 0.5% I3C was administered to DEN-initiated rats for 26 weeks to examine the effect of prolonged administration of I3C and to clarify the possible mechanisms of I3C-induced hepatocarcinogenesis. The number and area of GST-P positive foci, ROS production, TBARS level, 8-OHdG content and mRNA levels of Ahr and Nrf2 gene batteries significantly increased in the DEN-I3C group compared with the DEN-alone group. Furthermore, some GST-P positive preneoplastic foci progressed to hepatocellular adenomas with the prolongation of I3C administration. Lack of PTEN and phospho-Smad2/3 expression and translocations of PDPK1 and phospho-Akt substrates to underneath the cell membrane were observed in the majority of hepatocellular adenomas. In addition, the number of Ki-67 positive cells increased in adenomas compared with the preneoplastic foci. These results suggest that the administration of I3C for 26 weeks in DEN-initiated rats induces tumor progression from hepatocellular altered foci to hepatocellular adenomas by ROS-mediated Akt activation that inhibits the TGF-β/Smad signaling and results in the increased cell proliferation.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fujii
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003043:Cocarcinogenesis; D004249:DNA Damage; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000633:toxicity; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D007211:Indoles; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; C016517:indole-3-carbinol; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: Akt; Hepatocarcinogenesis; Indole-3-carbinol; Reactive oxygen species; TGF-β