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
SN - 0302-2838
VL - 69
SP - 1120
EP - 1128
JO - European Urology
JF - European Urology
IS - 6
ER -
