Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis
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Johanna Vollmar1, Anja Lautem2, Ellen Closs3, Detlef Schuppan4, Yong Ook Kim4, Daniel Grimm1, Jens U. Marquardt1, Peter Fuchs1, Beate K. Straub5, Arno Schad5, Dirk Gründemann6, Jörn M. Schattenberg1, Nadine Gehrke1, Marcus A. Wörns1, Jan Baumgart7, Peter R. Galle1 and Tim Zimmermann1
1Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
2Department of Hepatobiliary and Transplantation Surgery, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
3Department of Pharmacology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
4Institute of Translational Immunology, Fibrosis and Metabolism Center, Johannes Gutenberg-University Mainz, Mainz, Germany
5Institute of Pathology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
6Department of Pharmacology, University of Cologne, Mainz, Germany
7Translational Animal Research Center (TARC), Johannes Gutenberg-University Mainz, Mainz, Germany
Tim Zimmermann, email: email@example.com
Keywords: organic cation transporter; OCT3 knockout; hepatocarcinogenesis; SLC22A1; SLC22A3
Received: July 07, 2017 Accepted: December 04, 2017 Published: December 18, 2017
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.Slc22a3tm1Dpb) 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 [3H]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.
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