title: microRNA 338-3p exhibits tumor suppressor role and its down-regulation is associated with adverse clinical outcome in prostate cancer patients.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.|Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza, Egypt.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Bakkar
authors.affiliation: Department of Computer Science, University of Calgary, Calgary, AB, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.
authors.forename: Lars F
authors.initials: LF
authors.lastname: Petersen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.
authors.forename: Hatem
authors.initials: H
authors.lastname: Abou-Ouf
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Mami
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.
authors.forename: Samar A
authors.initials: SA
authors.lastname: Hegazy
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Computer Science, University of Calgary, Calgary, AB, Canada.
authors.forename: Reda
authors.initials: R
authors.lastname: Alhajj
authors.affiliation: Departments of Medicine and Oncology, McGill University and Segal Cancer Centre of the Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Krikor
authors.initials: K
authors.lastname: Bijian
authors.affiliation: Departments of Medicine and Oncology, McGill University and Segal Cancer Centre of the Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Moulay A
authors.initials: MA
authors.lastname: Alaoui-Jamali
authors.affiliation: Departments of Oncology, Biochemistry and Molecular Biology, Calgary, AB, Canada. tarek.bismar@cls.ab.ca.|Southern Alberta Cancer Institute and Tom Baker Cancer Center, Calgary, AB, Canada. tarek.bismar@cls.ab.ca.|Rockyview General Hospital, Department of Pathology, 7007 14th st sw, Calgary, AB, T2V 1P9, Canada. tarek.bismar@cls.ab.ca.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D054387:Receptors, CXCR / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C532050:MIRN338 microRNA, human; D035683:MicroRNAs; D054387:Receptors, CXCR; D019718:Receptors, CXCR4
keywords: CXCR axis; ERG gene rearrangements; Invasion; MiR338-3p; Prognosis; Prostate cancer