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Networks and miRNAs implicated in aggressive prostate cancer

ABSTRACT: Background: Prostate cancer (PC), a complex disease, can be relatively harmless or extremely aggressive. To identify candidate genes involved in causal pathways of aggressive PC, we implemented a systems biology approach by combining differential expression analysis and co-expression network analysis to evaluate transcriptional profiles using lymphoblastoid cell lines from 62 PC patients with aggressive phenotype (Gleason grade > 8) and 63 PC patients with nonaggressive phenotype (Gleason grade < 5). From 13935 mRNA genes and 273 microRNAs tested, we identified significant differences in 1100 mRNAs and 7 microRNAs with false discovery rate < 0.01. We also identified a co-expression module demonstrating significant association with the aggressive phenotype of PC (p=3.67x10-11). The module of interest was characterized by over-representation of cell cycle-related genes (false discovery rate = 3.50x10-50). From this module, we further defined 20 hub genes that were highly connected to other genes. Interestingly, five of the 7 differentially expressed microRNAs have been implicated in cell cycle regulation and two (miR-145 and miR-331-3p) are predicted to target three of the 20 hub genes. Ectopic expression of these two microRNAs reduced expression of target hub genes and subsequently resulted in cell growth inhibition and apoptosis. These results suggest that cell cycle is likely to be a molecular pathway causing aggressive phenotype of PC. Further characterization of cell cycle-related genes (particularly, the hub genes) and miRNAs that regulate these hub genes could facilitate identification of candidate genes responsible for the aggressive phenotype and lead to a better understanding of PC etiology and progression [Cancer Res 2009;69(24):9490–7]. Keywords: weighted gene coexpression analysis, network analysis, microRNA regulation

ORGANISM(S): Homo sapiens

PROVIDER: GSE20161 | GEO | 2010/02/04

SECONDARY ACCESSION(S): PRJNA125623

REPOSITORIES: GEO

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Project description:We aimed to investigate the transcriptional program associated with pimonidazole staining in prostate cancer. A pimonidazole gene signature was identified that showed positive correlation to Ki67 labeling index, indicating increased proliferation in pimonidazole positive tumors. A positive correlation to clinical tumor stage and presence of lymph node metastasis was also found, consistent with associations between pimonidazole staining and clinico-pathological parameters. Moreover, the gene signature was associated with high Gleason score in a validation cohort of 59 patients and showed prognostic impact independent of Gleason score and other clinical markers in a watchful waiting validation cohort of 281 patients. Our work reveals the molecular basis of an aggressive prostate cancer phenotype reflected by pimonidazole staining, and suggests that genes involved in proliferation, DNA repair and hypoxia response contribute to this phenotype. We combined pimonidazole immunohistochemistry data and expression profiles to identify transcriptional program activated in pimonidazole positive tumors. Whole-genome gene expression profiles were determined in tumor biopsies from an investigation cohort of 46 patients, where 39 patients had received pimonidazole prior to surgery. Gene ontology analysis of 1046 genes upregulated in pimonidazole positive tumors, as defined by a staining fraction above 10%, showed significant enrichment of the biologic processes cell cycle, translation and cellular response to stress. Gene set analysis based on this result identified gene expressions in proliferation, DNA repair and hypoxia response as major parts of the transcriptional program associated with pimonidazole staining. Gene expression data of four prostate cancer cell lines were used to generate hypoxia response gene sets for this analysis. A signature of the 32 most essential genes in the program was constructed and shown to be associated with prostate cancer aggressiveness in two independent validation cohorts.

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Networks and miRNAs implicated in aggressive prostate cancer

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