6533b859fe1ef96bd12b83ef

RESEARCH PRODUCT

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis

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// Johanna Vollmar 1 , Anja Lautem 2 , Ellen Closs 3 , Detlef Schuppan 4 , Yong Ook Kim 4 , Daniel Grimm 1 , Jens U. Marquardt 1 , Peter Fuchs 1 , Beate K. Straub 5 , Arno Schad 5 , Dirk Grundemann 6 , Jorn M. Schattenberg 1 , Nadine Gehrke 1 , Marcus A. Worns 1 , Jan Baumgart 7 , Peter R. Galle 1 and Tim Zimmermann 1 1 Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 2 Department of Hepatobiliary and Transplantation Surgery, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 3 Department of Pharmacology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 4 Institute of Translational Immunology, Fibrosis and Metabolism Center, Johannes Gutenberg-University Mainz, Mainz, Germany 5 Institute of Pathology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 6 Department of Pharmacology, University of Cologne, Mainz, Germany 7 Translational Animal Research Center (TARC), Johannes Gutenberg-University Mainz, Mainz, Germany Correspondence to: Tim Zimmermann, email: tim.zimmermann@unimedizin-mainz.de Keywords: organic cation transporter; OCT3 knockout; hepatocarcinogenesis; SLC22A1; SLC22A3 Received: July 07, 2017     Accepted: December 04, 2017     Published: December 18, 2017 ABSTRACT Background: Organic cation transporters (OCT) are responsible for the uptake of a broad spectrum of endogenous and exogenous substrates. Downregulation of OCT is frequently observed in human hepatocellular carcinoma (HCC) and is associated with a poor outcome. The aim of our current study was to elucidate the impact of OCT3 on hepatocarcinogenesis. Methods: Transcriptional and functional loss of OCT was investigated in primary murine hepatocytes, derived from Oct3-knockout (Oct3 -/- ; FVB.Slc22a3 tm1Dpb ) and wildtype (WT) mice. Liver tumors were induced in Oct3 -/- and WT mice with Diethylnitrosamine and Phenobarbital over 10 months and characterized macroscopically and microscopically. Key survival pathways were investigated by Western Blot analysis. Results: Loss of Oct3 -/- in primary hepatocytes resulted in significantly reduced OCT activity determined by [ 3 H]MPP + uptake in vivo . Furthermore, tumor size and quantity were markedly enhanced in Oct3 -/- mice (p<0.0001). Oct3 -/- tumors showed significant higher proliferation (p<0.0001). Ki-67 and Cyclin D expression were significantly increased in primary Oct3 -/- hepatocytes after treatment with the OCT inhibitors quinine or verapamil (p<0.05). Functional inhibition of OCT by quinine resulted in an activation of c-Jun N-terminal kinase (Jnk), especially in Oct3 -/- hepatocytes. Conclusion: Loss of Oct3 leads to enhanced proliferation and hepatocarcinogenesis in vivo .