Anna Aakula1, Pekka Kohonen2, Suvi-Katri Leivonen3, Rami Mäkelä4, Petteri Hintsanen5, John Patrick Mpindi6, Elena Martens-Uzunova7, Tero Aittokallio5, Guido Jenster7, Merja Perälä8, Olli Kallioniemi6, Päivi Östling6. 1. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1); Turku Centre for Biotechnology, University of Turku, Turku, Finland(1). Electronic address: anna.aakula@fimm.fi. 2. VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1); Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. 3. VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1); Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland. 4. VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1); Misvik Biology Corporation, Turku, Finland. 5. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 6. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1). 7. Department of Urology, Erasmus MC, Rotterdam, The Netherlands. 8. VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland(1); Natural Resources Institute Finland (Luke), Helsinki, Finland.
Abstract
BACKGROUND: Systematic approaches to functionally identify key players in microRNA (miRNA)-target networks regulating prostate cancer (PCa) proliferation are still missing. OBJECTIVE: To comprehensively map miRNA regulation of genes relevant for PCa proliferation through phenotypic screening and tumor expression data. DESIGN, SETTING, AND PARTICIPANTS: Gain-of-function screening with 1129 miRNA molecules was performed in five PCa cell lines, measuring proliferation, viability, and apoptosis. These results were integrated with changes in miRNA expression from two cohorts of human PCa (188 tumors in total). For resulting miRNAs, the predicted targets were collected and analyzed for patterns with gene set enrichment analysis, and for their association with biochemical recurrence free survival. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rank product statistical analysis was used to evaluate miRNA effects in phenotypic screening and for expression differences in the prostate tumor cohorts. Expression data were analyzed using the significance analysis of microarrays (SAM) method and the patient material was subjected to Kaplan-Meier statistics. RESULTS AND LIMITATIONS: Functional screening identified 25 miRNAs increasing and 48 miRNAs decreasing cell viability. Data integration resulted in 14 miRNAs, with aberrant expression and effect on proliferation. These miRNAs are predicted to regulate >3700 genes, of which 28 were found up-regulated and 127 down-regulated in PCa compared with benign tissue. Seven genes, FLNC, MSRB3, PARVA, PCDH7, PRNP, RAB34, and SORBS1, showed an inverse association to their predicted miRNA, and were identified to significantly correlate with biochemical recurrence free survival in PCa patients. CONCLUSIONS: A systematic in vitro screening approach combined with in vivo expression and gene set enrichment analysis provide unbiased means for revealing novel miRNA-target links, possibly driving the oncogenic processes in PCa. PATIENT SUMMARY: This study identified novel regulatory molecules, which impact on PCa proliferation and are aberrantly expressed in clinical tumors. Thus, our study reveals regulatory nodes with potential for therapy.
BACKGROUND: Systematic approaches to functionally identify key players in microRNA (miRNA)-target networks regulating prostate cancer (PCa) proliferation are still missing. OBJECTIVE: To comprehensively map miRNA regulation of genes relevant for PCa proliferation through phenotypic screening and tumor expression data. DESIGN, SETTING, AND PARTICIPANTS: Gain-of-function screening with 1129 miRNA molecules was performed in five PCa cell lines, measuring proliferation, viability, and apoptosis. These results were integrated with changes in miRNA expression from two cohorts of human PCa (188 tumors in total). For resulting miRNAs, the predicted targets were collected and analyzed for patterns with gene set enrichment analysis, and for their association with biochemical recurrence free survival. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rank product statistical analysis was used to evaluate miRNA effects in phenotypic screening and for expression differences in the prostate tumor cohorts. Expression data were analyzed using the significance analysis of microarrays (SAM) method and the patient material was subjected to Kaplan-Meier statistics. RESULTS AND LIMITATIONS: Functional screening identified 25 miRNAs increasing and 48 miRNAs decreasing cell viability. Data integration resulted in 14 miRNAs, with aberrant expression and effect on proliferation. These miRNAs are predicted to regulate >3700 genes, of which 28 were found up-regulated and 127 down-regulated in PCa compared with benign tissue. Seven genes, FLNC, MSRB3, PARVA, PCDH7, PRNP, RAB34, and SORBS1, showed an inverse association to their predicted miRNA, and were identified to significantly correlate with biochemical recurrence free survival in PCa patients. CONCLUSIONS: A systematic in vitro screening approach combined with in vivo expression and gene set enrichment analysis provide unbiased means for revealing novel miRNA-target links, possibly driving the oncogenic processes in PCa. PATIENT SUMMARY: This study identified novel regulatory molecules, which impact on PCa proliferation and are aberrantly expressed in clinical tumors. Thus, our study reveals regulatory nodes with potential for therapy.
Authors: Ding Ren; Xiaoping Zhu; Ren Kong; Zhen Zhao; Jianting Sheng; Jiang Wang; Xiaoyun Xu; Jiyong Liu; Kemi Cui; Xiang H-F Zhang; Hong Zhao; Stephen T C Wong Journal: Cancer Res Date: 2018-03-22 Impact factor: 12.701
Authors: Binod Kumar; Salar Khaleghzadegan; Brian Mears; Koji Hatano; Tarana A Kudrolli; Wasim H Chowdhury; David B Yeater; Charles M Ewing; Jun Luo; William B Isaacs; Luigi Marchionni; Shawn E Lupold Journal: Oncotarget Date: 2016-11-08