Urinary bladder cancer is one of the leading malignancies worldwide, with the highest recurrence rates. A diet rich in vitamin A has proven to lower the risk of cancer, yet the molecular mechanisms underlying this effect are unknown. We found that vitamin A decreased urothelial atypia and apoptosis during early bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Vitamin A did not alter urothelial cell desquamation, differentiation, or proliferation rate. Genes like Wnt5a, involved in retinoic acid signaling, and transcription factors Pparg, Ppara, Rxra, and Hoxa5 were downregulated, while Sox9 and Stra6 were upregulated in early urothelial carcinogenesis. When a vitamin A rich diet was provided during BBN treatment, none of these genes was up- or downregulated; only Lrat and Neurod1 were upregulated. The lecithin retinol acyltransferase (LRAT) enzyme that produces all-trans retinyl esters was translocated from the cytoplasm to the nuclei in urothelial cells as a consequence of BBN treatment regardless of vitamin A rich diet. A vitamin A-rich diet altered retinoic acid signaling, decreased atypia and apoptosis of urothelial cells, and consequently diminished early urothelial carcinogenesis.
Cancers. 2020 Jun 28*** epublish ***
Daša Zupančič, Jelena Korać-Prlić, Mateja Erdani Kreft, Lucija Franković, Katarina Vilović, Jera Jeruc, Rok Romih, Janoš Terzić
Institute of Cell Biology, Faculty of Medicine, University of Ljubljana,1000 Ljubljana, Slovenia., Laboratory for Cancer Research, School of Medicine, University of Split, 21000 Split, Croatia., Department of Pathology, University Hospital of Split, 21000 Split, Croatia., Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.