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*

*Corresponding author for this work
8 Citations (Scopus)


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.

Original languageEnglish
Issue number70
Pages (from-to)115667-115680
Number of pages14
Publication statusPublished - 2017


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