Universität zu Köln

Vollmar, Johanna, Lautem, Anja, Closs, Ellen ORCID: 0000-0002-9505-2289, Schuppan, Detlef, Kim, Yong Ook, Grimm, Daniel, Marquardt, Jens U., Fuchs, Peter, Straub, Beate K., Schad, Arno, Grundemann, Dirk, Schattenberg, Jorn M. ORCID: 0000-0002-4224-4703, Gehrke, Nadine, Worns, Marcus A., Baumgart, Jan, Galle, Peter R. and Zimmermann, Tim (2017). Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis. Oncotarget, 8 (70). S. 115667 - 115681. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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 [H-3] 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vollmar, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Lautem, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Closs, Ellen UNSPECIFIED orcid.org/0000-0002-9505-2289 UNSPECIFIED Schuppan, Detlef UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Yong Ook UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimm, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Marquardt, Jens U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuchs, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Straub, Beate K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schad, Arno UNSPECIFIED UNSPECIFIED UNSPECIFIED Grundemann, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Schattenberg, Jorn M. UNSPECIFIED orcid.org/0000-0002-4224-4703 UNSPECIFIED Gehrke, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Worns, Marcus A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumgart, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Galle, Peter R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-207590
DOI:	10.18632/oncotarget.23372
Journal or Publication Title:	Oncotarget
Volume:	8
Number:	70
Page Range:	S. 115667 - 115681
Date:	2017
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; DOWN-REGULATION; C-MYC; CELLS; IMATINIB; SORAFENIB; LIVER; MICE; HEPATOCYTES Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20759