Vitamin A Rich Diet Diminishes Early Urothelial Carcinogenesis by Altering Retinoic Acid Signaling.

Daša Zupančič,Janoš Terzić,Jera Jeruc,Katarina Vilović,Lucija Franković,Mateja Erdani Kreft,Jelena Korać-Prlić,Rok Romih

doi:10.3390/cancers12071712

Daša Zupančič, Janoš Terzić + Show 6 more

Open Access

https://doi.org/10.3390/cancers12071712

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Journal: Cancers	Publication Date: Jun 28, 2020
Citations: 11	License type: CC BY 4.0

Affiliation: University of Ljubljana, University of Split

Abstract

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.

Highlights

Urinary bladder carcinoma is the tenth most common malignancy affecting both genders worldwide with high recurrence rate [1,2,3]
There was no difference in the localization of lecithin retinol acyltransferase (LRAT) between the butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and BBN + VitA groups. These results suggest that in normal urothelium, LRAT is localized in the cytoplasm of the urothelial cells, and during early carcinogenesis of the bladder, LRAT is predominantly transported into the nuclei of urothelial cells
The emerging picture is that a vitamin A rich diet diminishes early bladder carcinogenesis by decreasing urothelial atypia and apoptosis of urothelial cells

Summary

Introduction

Urinary bladder carcinoma is the tenth most common malignancy affecting both genders worldwide with high recurrence rate [1,2,3]. The main structural basis for this barrier is urothelial plaques composed of four major integral membrane protein uroplakins, which cover almost the entire apical plasma membrane of terminally differentiated superficial umbrella cells [6,7,8,9]. Earlier studies showed that uroplakin expression and plaque formation are disturbed in urothelial cancers, causing decreased urothelial differentiation [10,11,12,13,14,15,16]. Cancers are usually accompanied by increased proliferation and decreased apoptosis. In early carcinogenesis, apoptotic cell death is increased in the urinary bladder, liver, and thyroid [17,18]

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