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

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.