Dataset Information

Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

ABSTRACT: Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.

SUBMITTER: Laufer-Amorim R

PROVIDER: S-EPMC6480132 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Laufer-Amorim Renée R Fonseca-Alves Carlos Eduardo CE Villacis Rolando Andre Rios RAR Linde Sandra Aparecida Drigo SAD Carvalho Marcio M Larsen Simon Jonas SJ Marchi Fabio Albuquerque FA Rogatto Silvia Regina SR

International journal of molecular sciences 20190328 7

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by re ...[more]

PMID: 30925701

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Project description:MicroRNAs are important epigenetic regulators of protein expression by triggering degradation of target mRNAs and/or inhibiting their translation. Dysregulation of microRNA expression has been reported in several cancers, including prostate cancer (PC). We comprehensively characterized the proteomic footprint of a panel of 12 microRNAs that are potently suppressed in metastatic PC (SiM-miRNAs: miR-1, miR-133a, miR-133b, miR-135a, miR-143-3p, miR-145-3p, miR-205, miR-221-3p, miR-221-5p, miR-222-3p, miR-24-1-5p, and miR-31) using reverse-phase proteomic arrays. Re-expression of these SiM-miRNAs in PC cells suppressed cell proliferation and targeted key oncogenic pathways, including cell cycle, apoptosis, Akt/mammalian target of rapamycin signaling, metastasis and the androgen receptor (AR) axis. However, only 12%, at most, of these observed protein expression changes could be explained by predicted direct binding of miRNAs to corresponding mRNAs, suggesting that the majority of these proteomic effects result indirectly. AR and its steroid receptor coactivators (SRCs; SRC-1, -2 and -3) were recurrently affected by these SiM-miRNAs. In agreement, we identified inverse correlations between expression of these SiM-miRNAs and early clinical recurrence, as well as with AR transcriptional activity in human PC tissues. We also identified robust induction of miR-135a by androgen and strong direct binding of AR to the miR-135a locus. As miR-135a potently suppresses AR expression, this results in a negative feedback loop that suppresses AR protein expression in an androgen-dependent manner, while de-repressing AR expression upon androgen deprivation. Our results demonstrate that epigenetic silencing of these SiM-miRNAs can result in increased AR axis activity and cell proliferation, thus contributing to disease progression. We further demonstrate that a negative feedback loop involving miR-135a can restore AR expression under androgen-deprivation conditions, thus contributing to the upregulation of AR protein expression in castration-resistant PC. Finally, our unbiased proteomic profiling demonstrates that the majority of actual protein expression changes induced by SiM-miRNAs cannot be explained based on predicted direct interactions.

Dataset Information

Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Publications

Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Similar Datasets

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