Mutant p53 Associates with Human Equilibrative Nucleoside 1 Upregulation and Better Response to Adjuvant Gemcitabine in Intrahepatic Cholangiocarcinoma Patients

The prognostic and predictive role of the human equilibrative nucleoside transporter 1 (hENT-1) has emerged in different cancer types, including intrahepatic cholangiocarcinoma (iCCA), but the mechanisms regulating its expression are poorly understood. Here, we investigated the link between p53 status and hENT-1 regulation in 38 iCCA patients and cell line models; the predictive role of p53 status in response to adjuvant gemcitabine was also investigated. A positive association between mutant p53 cells and hENT-1 expression was observed in iCCA tissue samples; furthermore, patients receiving adjuvant gemcitabine and expressing mutant p53 cells > 4% in tumor tissue had a longer disease-free survival (DFS) than patients expressing mutant p53 cells ≤ 4% (median 18.5 vs. 6 months, <i>p</i> = 0.0229). In iCCA cell line models, transient knockdown of mutant p53 resulted in a decrease in hENT-1 mRNA and protein expression; similarly, restoration of wild-type p53 function induced a significant reduction in hENT-1 mRNA and protein expression. Overall, these findings support a role of p53 status in the regulation of hENT-1 expression, suggesting an opposite effect (activating versus repressive) of mutant and wild-type p53 protein. Furthermore, although the present study should be considered as preliminary, our findings suggest a predictive role of p53 status in iCCA patients treated with gemcitabine, thus deserving future investigations in additional cohorts of cancer patients.