Aijuan Qu1, Changtao Jiang1, Yan Cai1, Jung-Hwan Kim1, Naoki Tanaka1, Jerrold M Ward2, Yatrik M Shah3, Frank J Gonzalez4. 1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. 2. Global VetPathology, Montgomery Village, MD 20866, United States. 3. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Department of Molecular and Integrative Physiology and Internal Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, MI 48109, United States. 4. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: gonzalef@mail.nih.gov.
Abstract
BACKGROUND & AIMS: Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice. METHODS: Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ER(T2) recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. RESULTS: Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/fl) mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice. CONCLUSIONS: Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis. Published by Elsevier B.V.
BACKGROUND & AIMS:Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice. METHODS: Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ER(T2) recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. RESULTS:Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/fl) mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamineliver cancer bioassay, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice. CONCLUSIONS:Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis. Published by Elsevier B.V.
Authors: I M de Alboran; R C O'Hagan; F Gärtner; B Malynn; L Davidson; R Rickert; K Rajewsky; R A DePinho; F W Alt Journal: Immunity Date: 2001-01 Impact factor: 31.745
Authors: Q Liu; S Guntuku; X S Cui; S Matsuoka; D Cortez; K Tamai; G Luo; S Carattini-Rivera; F DeMayo; A Bradley; L A Donehower; S J Elledge Journal: Genes Dev Date: 2000-06-15 Impact factor: 11.361
Authors: Catherine M Shachaf; Andrew M Kopelman; Constadina Arvanitis; Asa Karlsson; Shelly Beer; Stefanie Mandl; Michael H Bachmann; Alexander D Borowsky; Boris Ruebner; Robert D Cardiff; Qiwei Yang; J Michael Bishop; Christopher H Contag; Dean W Felsher Journal: Nature Date: 2004-10-10 Impact factor: 49.962
Authors: Huabo Wang; James M Dolezal; Sucheta Kulkarni; Jie Lu; Jordan Mandel; Laura E Jackson; Frances Alencastro; Andrew W Duncan; Edward V Prochownik Journal: J Biol Chem Date: 2018-08-07 Impact factor: 5.157
Authors: Atsushi Umemura; Feng He; Koji Taniguchi; Hayato Nakagawa; Shinichiro Yamachika; Joan Font-Burgada; Zhenyu Zhong; Shankar Subramaniam; Sindhu Raghunandan; Angeles Duran; Juan F Linares; Miguel Reina-Campos; Shiori Umemura; Mark A Valasek; Ekihiro Seki; Kanji Yamaguchi; Kazuhiko Koike; Yoshito Itoh; Maria T Diaz-Meco; Jorge Moscat; Michael Karin Journal: Cancer Cell Date: 2016-05-19 Impact factor: 31.743