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

Johanna Vollmar; Anja Lautem; Ellen Closs; Detlef Schuppan; Yong Ook Kim; Daniel Grimm; Jens U Marquardt; Peter Fuchs; Beate K Straub; Arno Schad; Dirk Gründemann; Jörn M Schattenberg; Nadine Gehrke; Marcus A Wörns; Jan Baumgart; Peter R Galle; Tim Zimmermann

doi:10.18632/oncotarget.23372

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

Oncotarget. 2017 Dec 18;8(70):115667-115680. doi: 10.18632/oncotarget.23372. eCollection 2017 Dec 29.

Authors

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, Tim Zimmermann¹

Affiliations

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.

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 [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.

Keywords: OCT3 knockout; SLC22A1; SLC22A3; hepatocarcinogenesis; organic cation transporter.