PMID- 23290887 OWN - NLM STAT- MEDLINE DCOM- 20140213 LR - 20161125 IS - 1618-1433 (Electronic) IS - 0940-2993 (Linking) VI - 65 IP - 6 DP - 2013 Sep TI - Involvement of PTEN/Akt signaling and oxidative stress on indole-3-carbinol (I3C)-induced hepatocarcinogenesis in rats. PG - 845-52 LID - S0940-2993(12)00147-9 [pii] LID - 10.1016/j.etp.2012.12.003 [doi] AB - 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-beta/Smad signaling and results in the increased cell proliferation. CI - Copyright (c) 2012 Elsevier GmbH. All rights reserved. FAU - Yamamoto, Ryuichi AU - Yamamoto R AD - Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan. FAU - Shimamoto, Keisuke AU - Shimamoto K FAU - Ishii, Yuji AU - Ishii Y FAU - Kimura, Masayuki AU - Kimura M FAU - Fujii, Yuta AU - Fujii Y FAU - Morita, Reiko AU - Morita R FAU - Suzuki, Kazuhiko AU - Suzuki K FAU - Shibutani, Makoto AU - Shibutani M FAU - Mitsumori, Kunitoshi AU - Mitsumori K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130104 PL - Germany TA - Exp Toxicol Pathol JT - Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie JID - 9208920 RN - 0 (Indoles) RN - 0 (Reactive Oxygen Species) RN - 3IQ78TTX1A (Diethylnitrosamine) RN - C11E72455F (indole-3-carbinol) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, rat) SB - IM MH - Animals MH - Body Weight/drug effects MH - Cocarcinogenesis MH - *DNA Damage MH - Diethylnitrosamine/administration & dosage/toxicity MH - Immunohistochemistry MH - Indoles/administration & dosage/*toxicity MH - Liver Neoplasms, Experimental/*chemically induced/enzymology/metabolism/pathology MH - Male MH - Microsomes, Liver/drug effects/enzymology/metabolism MH - Organ Size/drug effects MH - Oxidative Stress/*drug effects MH - PTEN Phosphohydrolase/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Inbred F344 MH - Reactive Oxygen Species/metabolism MH - Real-Time Polymerase Chain Reaction MH - Signal Transduction OTO - NOTNLM OT - Akt OT - Hepatocarcinogenesis OT - Indole-3-carbinol OT - Reactive oxygen species OT - TGF-beta EDAT- 2013/01/08 06:00 MHDA- 2014/02/14 06:00 CRDT- 2013/01/08 06:00 PHST- 2012/11/14 00:00 [received] PHST- 2012/12/06 00:00 [accepted] PHST- 2013/01/08 06:00 [entrez] PHST- 2013/01/08 06:00 [pubmed] PHST- 2014/02/14 06:00 [medline] AID - S0940-2993(12)00147-9 [pii] AID - 10.1016/j.etp.2012.12.003 [doi] PST - ppublish SO - Exp Toxicol Pathol. 2013 Sep;65(6):845-52. doi: 10.1016/j.etp.2012.12.003. Epub 2013 Jan 4.