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Neoplasia. 2018 Sep;20(9):894-904. doi: 10.1016/j.neo.2018.07.006. Epub 2018 Aug 15.

A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.

Author information

1
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
2
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
3
University of Virginia, Charlottesville, VA, USA.
4
Department of Pathology, Urology and Oncology, Johns Hopkins University, Baltimore, MD, USA; The Johns Hopkins University Greenberg Bladder Cancer Institute and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Johns Hopkins University Greenberg Bladder Cancer Institute and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
George Washington University, Washington, DC, USA.
7
Department of Scientific Research, Norte University, Asunción, Paraguay.
8
Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.
9
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: svarambally@uabmc.edu.

Abstract

Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3'-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.

PMID:
30121007
PMCID:
PMC6098199
DOI:
10.1016/j.neo.2018.07.006
[Indexed for MEDLINE]
Free PMC Article

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