title: miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways.
abstract: The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Lichner
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Samaan
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Saleh
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5G 1L5, Canada.
authors.forename: Aurfan
authors.initials: A
authors.lastname: Nasser
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5G 1L5, Canada.
authors.forename: Sahar
authors.initials: S
authors.lastname: Al-Haddad
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Samuel
authors.affiliation: Department of Surgery, University Health Network, Toronto, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Department of Urology, University Hospital Charité, D-10117, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stephan
authors.affiliation: Department of Urology, University Hospital Charité, D-10117, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, M5G 1L5, Canada.
authors.forename: George M
authors.initials: GM
authors.lastname: Yousef
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019295:Computational Biology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D017211:Treatment Failure
chemical_list: C410798:AR protein, human; D035683:MicroRNAs; D011944:Receptors, Androgen
keywords: Gleason grade; biochemical failure; miRNA; prognosis; prostate cancer; tumour markers