Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue

Anna Aakula, Pekka Kohonen, Suvi-Katri Leivonen, Rami Mäkelä, Petteri Hintsanen, John Patrick Mpindi, Elena Martens-Uzunova, Tero Aittokallio, Guido Jester, Merja Perälä, Olli Kallioniemi, Päivi Östling

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16 Citations (Scopus)

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. A comprehensive approach of functional microRNA screening and expression analyses, identifies miR-19a, miR-32, miR-124a, miR-130b, miR-148a, and miR-583 as potential regulators of. FLNC,. MSRB3,. PARVA,. PCDH7,. PRNP,. RAB34, and. SORBS1, which correlate with prostate specific antigen-relapse in prostate cancer patients.
Original languageEnglish
Pages (from-to)1120-1128
JournalEuropean Urology
Volume69
Issue number6
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

Fingerprint

MicroRNAs
Prostatic Neoplasms
Neoplasms
Recurrence
Genes
Survival
Microarray Analysis
Prostate-Specific Antigen
Prostate
Cell Survival
Apoptosis
Gene Expression

Keywords

  • functional high-throughput screening
  • MicroRNA
  • prostate cancer
  • reverse-phase protein array

Cite this

Aakula, Anna ; Kohonen, Pekka ; Leivonen, Suvi-Katri ; Mäkelä, Rami ; Hintsanen, Petteri ; Mpindi, John Patrick ; Martens-Uzunova, Elena ; Aittokallio, Tero ; Jester, Guido ; Perälä, Merja ; Kallioniemi, Olli ; Östling, Päivi. / Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue. In: European Urology. 2016 ; Vol. 69, No. 6. pp. 1120-1128.
@article{7995773e085e4ebf91a9d98db1483cd6,
title = "Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue",
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. A comprehensive approach of functional microRNA screening and expression analyses, identifies miR-19a, miR-32, miR-124a, miR-130b, miR-148a, and miR-583 as potential regulators of. FLNC,. MSRB3,. PARVA,. PCDH7,. PRNP,. RAB34, and. SORBS1, which correlate with prostate specific antigen-relapse in prostate cancer patients.",
keywords = "functional high-throughput screening, MicroRNA, prostate cancer, reverse-phase protein array",
author = "Anna Aakula and Pekka Kohonen and Suvi-Katri Leivonen and Rami M{\"a}kel{\"a} and Petteri Hintsanen and Mpindi, {John Patrick} and Elena Martens-Uzunova and Tero Aittokallio and Guido Jester and Merja Per{\"a}l{\"a} and Olli Kallioniemi and P{\"a}ivi {\"O}stling",
year = "2016",
doi = "10.1016/j.eururo.2015.09.019",
language = "English",
volume = "69",
pages = "1120--1128",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "6",

}

Aakula, A, Kohonen, P, Leivonen, S-K, Mäkelä, R, Hintsanen, P, Mpindi, JP, Martens-Uzunova, E, Aittokallio, T, Jester, G, Perälä, M, Kallioniemi, O & Östling, P 2016, 'Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue', European Urology, vol. 69, no. 6, pp. 1120-1128. https://doi.org/10.1016/j.eururo.2015.09.019

Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue. / Aakula, Anna; Kohonen, Pekka; Leivonen, Suvi-Katri; Mäkelä, Rami; Hintsanen, Petteri; Mpindi, John Patrick; Martens-Uzunova, Elena; Aittokallio, Tero; Jester, Guido; Perälä, Merja; Kallioniemi, Olli; Östling, Päivi.

In: European Urology, Vol. 69, No. 6, 2016, p. 1120-1128.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue

AU - Aakula, Anna

AU - Kohonen, Pekka

AU - Leivonen, Suvi-Katri

AU - Mäkelä, Rami

AU - Hintsanen, Petteri

AU - Mpindi, John Patrick

AU - Martens-Uzunova, Elena

AU - Aittokallio, Tero

AU - Jester, Guido

AU - Perälä, Merja

AU - Kallioniemi, Olli

AU - Östling, Päivi

PY - 2016

Y1 - 2016

N2 - 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. A comprehensive approach of functional microRNA screening and expression analyses, identifies miR-19a, miR-32, miR-124a, miR-130b, miR-148a, and miR-583 as potential regulators of. FLNC,. MSRB3,. PARVA,. PCDH7,. PRNP,. RAB34, and. SORBS1, which correlate with prostate specific antigen-relapse in prostate cancer patients.

AB - 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. A comprehensive approach of functional microRNA screening and expression analyses, identifies miR-19a, miR-32, miR-124a, miR-130b, miR-148a, and miR-583 as potential regulators of. FLNC,. MSRB3,. PARVA,. PCDH7,. PRNP,. RAB34, and. SORBS1, which correlate with prostate specific antigen-relapse in prostate cancer patients.

KW - functional high-throughput screening

KW - MicroRNA

KW - prostate cancer

KW - reverse-phase protein array

U2 - 10.1016/j.eururo.2015.09.019

DO - 10.1016/j.eururo.2015.09.019

M3 - Article

VL - 69

SP - 1120

EP - 1128

JO - European Urology

JF - European Urology

SN - 0302-2838

IS - 6

ER -