Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that function in transcriptional and post-transcriptional regulation of gene expression. Several miRNAs have been implicated in regulating prostate cancer (PCa) progression. Deregulations of miRNA regulatory networks have been reported in ERG positive PCa, which accounts for ~50 % of PCa and have been suggested to affect tumor aggressiveness. The function of miR338-3p, its prognostic significance, and its association with ERG positive PCa has not been fully investigated. Using microarray expression profiling, we identified miRNA338-3p as among the top deregulated miRNAs associated with ERG status in PCa. We investigated miR338-3p function using in vitro and in vivo experimental models and its expression was assessed and validated in clinical samples and a public cohort of localized and metastatic prostate cancer. miR338-3p was significantly down-regulated with disease progression from benign prostate tissue to primary and metastatic lesions. In localized disease, patients with lower miR338-3p expression levels showed increased association to biochemical recurrence and several adverse pathological parameters compared to patients with higher miRNA338-3p tissue expression levels. Using in vitro PCa cell models, overexpression of miR338-3p resulted in a decrease in cell invasion and expression of chemokine signalling genes CXCL12, CXCR4, and CXCR7. In vivo, orthotropic implantation of PC3 cells stably expressing miR338-3p was associated with a significant decrease in tumor weights compared to control cells. miR338-3p has anti-proliferative and anti-invasive properties. It affects CXCR4 axis, and its down-regulation is associated with adverse clinical outcomes in PCa patients.
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Abbreviations
- AR:
-
Androgen receptor
- CRPC:
-
Castration resistant prostate cancer
- GS:
-
Gleason score
- miRNA:
-
microRNA
- PCa:
-
Prostate cancer
- PSA:
-
Prostate specific antigen
- MSKCC:
-
Memorial Sloan-Kettering Cancer Center
- SCID:
-
Severe combined immunodeficiency
- TFs:
-
Transcription factors
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Acknowledgments
The authors would like to thank Shuhong Liu, Sabrina Daniela Silva, Samir Al Bashir, Tingting Wang and Liang Hong Teng for technical assistance in this study.
Author contribution
AB; executed and planned in vitro experiments and drafted the manuscript. MA and RA; carried out all bioinformatics work in this study and assisted in drafting manuscript. LP; carried out ERG cloning experiments and participated in the preparation of figures; HA helped in performing qPCR experiments, writing the manuscript and preparing of figures; and AA and TW performed western blots, SH performed Q-PCR and contributed to manuscript writing, KB carried out in vitro experiments. MAJ designed and supervised in vitro and in vivo experiments of the study and revised manuscript. TAB; carried out pathological analysis, and contributed to manuscript drafting.
Funding
This work was supported by the Prostate Cancer Foundation Young Investigator Award (T.A.B) and in part by the Canadian Institutes for Health Research, the Canadian Cancer Society, and Quebec Breast Cancer Foundation (MAAJ). This work was also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation-Grant #B2013-01.
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Bakkar, A., Alshalalfa, M., Petersen, L.F. et al. microRNA 338-3p exhibits tumor suppressor role and its down-regulation is associated with adverse clinical outcome in prostate cancer patients. Mol Biol Rep 43, 229–240 (2016). https://doi.org/10.1007/s11033-016-3948-4
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DOI: https://doi.org/10.1007/s11033-016-3948-4