| First Author | Vollmar J | Year | 2017 |
| Journal | Oncotarget | Volume | 8 |
| Issue | 70 | Pages | 115667-115680 |
| PubMed ID | 29383190 | Mgi Jnum | J:309221 |
| Mgi Id | MGI:6756874 | Doi | 10.18632/oncotarget.23372 |
| Citation | Vollmar J, et al. (2017) Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis. Oncotarget 8(70):115667-115680 |
| abstractText | 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. |
