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.

Plasma microRNA signature is associated with risk stratification in prostate cancer patients

“…The significant upregulation of miR‐148a in PCa patients detected in our analyses is in line with other studies . Previously, its correlation with biochemical recurrence of PCa was demonstrated, and importantly was independent of PSA values . The reported association of miR‐148a with biochemical recurrence substantiates our finding showing its involvement in high‐risk PCa patients who are commonly at higher risk for developing biochemical recurrence.…”

MiR‐145 detection in urinary extracellular vesicles increase diagnostic efficiency of prostate cancer based on hydrostatic filtration dialysis method

“…A number of previous studies addressing the expression levels of circulating miRNAs in clinical patients with PCa were performed on serum, plasma, and urine samples . It is important to note that several miRNA signatures have been identified and linked to PCa progression, such as miR‐572, miR‐1290, miR‐141, and miR‐145 . In the present study, we sought to determine the expression of such PCa‐related miRNAs in UEVs and compared with the levels in serum EVs.…”

The Role of c‐SKI in Regulation of TGFβ‐Induced Human Cardiac Fibroblast Proliferation and ECM Protein Expression

“…A, Venn diagram generated by http://bioinformatics.psb.ugent.be/webtools/Venn/). Combined with previous studies, 15 candidate upstream miRNAs which are related to ECM were chosen for further assays: miR‐17 [Yu et al, ], miR‐449a [Han et al, ], miR‐33a [Li et al, ], miR‐15b [Kang et al, ], miR‐29c [Chuang et al, ], miR‐25 [Divakaran et al, ], miR‐155 [Sipert et al, ], miR‐24 [Wang et al, ], miR‐29b [Wang et al, ], miR‐29a [James et al, ], miR‐23b [Zhao et al, ], miR‐34a [Lichner et al, ], miR‐17 [Liu et al, ], miR‐204 [Chen et al, ], and miR‐21 [Rubis et al, ] (Fig. A).…”