title: Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model.
abstract: Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation-mediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis.
authors.affiliation: Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Saitama, Japan.
authors.forename: Xian-Yang
authors.initials: XY
authors.lastname: Qin
authors.affiliation: Department of Basic Medicinal Sciences, Nagoya University Graduate School of Pharmaceutical Sciences, Aichi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tatsukawa
authors.affiliation: Department of Basic Medicinal Sciences, Nagoya University Graduate School of Pharmaceutical Sciences, Aichi, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hitomi
authors.affiliation: Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, KOWA Co. Ltd., Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishibashi
authors.affiliation: Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.affiliation: Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Saitama, Japan. skojima@postman.riken.go.jp.
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002853:Chromatography, Liquid; D004052:Diethylnitrosamine / Q000633:toxicity*; D050155:Lipogenesis / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D004052:Diethylnitrosamine; D014212:Tretinoin; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid