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Androgen Receptor Regulates CD44 Expression in Bladder Cancer.
Sottnik, Joseph L; Vanderlinden, Lauren; Joshi, Molishree; Chauca-Diaz, Ana; Owens, Charles; Hansel, Donna E; Sempeck, Colin; Ghosh, Debashis; Theodorescu, Dan.
Afiliação
  • Sottnik JL; Department of Pathology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Vanderlinden L; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Joshi M; Department of Pharmacology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Chauca-Diaz A; Functional Genomics Facility, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Owens C; Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Hansel DE; Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
  • Sempeck C; Department of Pathology & Laboratory Medicine, Oregon Health & Science University, Portland, Oregon.
  • Ghosh D; Department of Molecular Cellular & Developmental Biology, University of Colorado - Boulder, Boulder, Colorado.
  • Theodorescu D; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado - Anschutz Medical Campus, Aurora, Colorado.
Cancer Res ; 81(11): 2833-2846, 2021 06 01.
Article em En | MEDLINE | ID: mdl-33687952
The androgen receptor (AR) is important in the development of both experimental and human bladder cancer. However, the role of AR in bladder cancer growth and progression is less clear, with literature indicating that more advanced stage and grade disease are associated with reduced AR expression. To determine the mechanisms underlying these relationships, we profiled AR-expressing human bladder cancer cells by AR chromatin immunoprecipitation sequencing and complementary transcriptomic approaches in response to in vitro stimulation by the synthetic androgen R1881. In vivo functional genomics consisting of pooled shRNA or pooled open reading frame libraries was employed to evaluate 97 genes that recapitulate the direction of expression associated with androgen stimulation. Interestingly, we identified CD44, the receptor for hyaluronic acid, a potent biomarker and driver of progressive disease in multiple tumor types, as significantly associated with androgen stimulation. CRISPR-based mutagenesis of androgen response elements associated with CD44 identified a novel silencer element leading to the direct transcriptional repression of CD44 expression. In human patients with bladder cancer, tumor AR and CD44 mRNA and protein expression were inversely correlated, suggesting a clinically relevant AR-CD44 axis. Collectively, our work describes a novel mechanism partly explaining the inverse relationship between AR and bladder cancer tumor progression and suggests that AR and CD44 expression may be useful for prognostication and therapeutic selection in primary bladder cancer. SIGNIFICANCE: This study describes novel AREs that suppress CD44 and an expected inverse correlation of AR-CD44 expression observed in human bladder tumors.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Bexiga Urinária / Receptores Androgênicos / Biomarcadores Tumorais / Regulação Neoplásica da Expressão Gênica / Receptores de Hialuronatos Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Bexiga Urinária / Receptores Androgênicos / Biomarcadores Tumorais / Regulação Neoplásica da Expressão Gênica / Receptores de Hialuronatos Idioma: En Ano de publicação: 2021 Tipo de documento: Article