title: Metformin inhibits early stage diethylnitrosamine‑induced hepatocarcinogenesis in rats.
abstract: Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)‑induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma‑specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S‑transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK‑dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high‑risk patients, including chronic hepatitis and cirrhosis.
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Woori
authors.initials: W
authors.lastname: Jo
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Eun-Sil
authors.initials: ES
authors.lastname: Yu
authors.affiliation: Department of Medical and Pharmaceutical Sciences, Sookmyung Woman's University, Seoul 140‑742, Republic of Korea.
authors.forename: Minsun
authors.initials: M
authors.lastname: Chang
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Hyun-Kyu
authors.initials: HK
authors.lastname: Park
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Jae-Eun
authors.initials: JE
authors.lastname: Ryu
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Sungwoong
authors.initials: S
authors.lastname: Jang
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Hyo-Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea.
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Comparative Pathology Core, Asan Institute for Life Sciences, Asan Medical Center, Seoul 138‑736, Republic of Korea.
authors.forename: Woo-Chan
authors.initials: WC
authors.lastname: Son
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D004052:Diethylnitrosamine / Q000008:administration & dosage; D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D004052:Diethylnitrosamine; D008687:Metformin; D005982:Glutathione Transferase; D000263:Adenylate Kinase