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

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• 作者：Anna Aakula^a ; ^b ; ^c ; ^{anna.aakula@fimm.fi" class="auth_mail" title="E-mail the corresponding author} ; Pekka Kohonen^b ; ^d ; Suvi-Katri Leivonen^b ; ^e ; Rami Mä ; kelä ; ^b ; ^f ; Petteri Hintsanen^a ; John Patrick Mpindi^a ; ^b ; Elena Martens-Uzunova^g ; Tero Aittokallio^a ; Guido Jenster^g ; Merja Perä ; lä ; ^b ; ^h ; Olli Kallioniemi^a ; ^b ; Pä ; ivi Ö ; stling^a ; ^b
• 关键词：Functional high-throughput screening ; MicroRNA ; Prostate cancer ; Reverse-phase protein array
• 刊名：European Urology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：69
• 期：6
• 页码：1120-1128
• 全文大小：3271 K

文摘

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.