Membrane human equilibrative nucleoside transporter 1 is associated with a high proliferation rate and worse survival in resected intrahepatic cholangiocarcinoma patients not receiving adjuvant treatments.

ABSTRACT

Human equilibrative nucleoside transporter 1 (hENT-1) is a membrane nucleoside transporter mediating the intracellular uptake of nucleosides and their analogues. hENT-1 was recently reported to have a predictive role in intrahepatic cholangiocarcinoma (iCC) patients receiving adjuvant gemcitabine-based chemotherapy, but its biological and clinical significance in iCC remains unsettled. This study investigated the role of hENT-1 in regulating tumour growth and predicting the survival of 40 resected iCC patients not receiving adjuvant treatments. hENT-1 expression was found to be significantly higher in iCC than in the matched non-tumoural liver. Patients harbouring hENT-1 localised on the tumour cell membrane had a worse overall survival than membrane hENT-1-negative patients (median 21.2 months vs 30.3 months, p = 0.031), with an adjusted hazard ratio of 2.8 (95% confidence interval 1.01-7.76). Moreover, membrane hENT-1-positive patients had a higher percentage of Ki67-positive cells in tumour tissue than membrane hENT-1-negative patients (median 23% vs 5%, p < 0.0001). Functional analyses in iCC cell lines revealed that hENT-1 silencing inhibited cell proliferation and induced apoptosis in HUH-28 cells expressing hENT-1 on the cell membrane, but not in SNU-1079 cells expressing the transporter only in the cytoplasm. Overall, these findings suggest that membrane hENT-1 is involved in iCC proliferation and associated with worse survival in resected iCC patients. Further prospective studies on larger cohorts are required to confirm these results and better define the potential prognostic role of membrane hENT-1 in this setting of patients.