miR‐34c is downregulated in prostate cancer and exerts tumor suppressive functions

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. There have been several reports of miRNA deregulation in prostate cancer (PCa) and the biological evidence for an involvement of miRNAs in prostate tumorigenesis is increasing. In this study, we show that miR-34c is downregulated in PCa (p 5 0.0005) by performing qRT-PCR on 49 TURPs from PCa patients compared to 25 from patients with benign prostatic hyperplasia. The miR-34c expression was found to inversely correlate to aggressiveness of the tumor, WHO grade, PSA levels and occurrence of metastases. Furthermore, a Kaplan-Meier analysis of patient survival based on miR-34c expression levels divided into low (< 50th percentile) and high (> 50th percentile) expression, significantly divides the patients into high risk and low risk patients (p 5 0.0003, log-rank test). The phenotypic effects of miR-34c deregulation were studied in prostate cell lines, where ectopic expression of miR-34c decreased cell growth, due to both a decrease in cellular proliferation rate and an increase in apoptosis. In concordance to this, miR-34c was found to negatively regulate the oncogenes E2F3 and BCL-2, which stimulates proliferation and suppress apoptosis in PCa cells, respectively. Reversely, we could also show that blocking miR-34c in vitro increases cell growth. Further, ectopic expression of miR-34c was found to suppress migration and invasion. Our findings provide new insight into the role of miR-34c in the prostate, exhibiting tumor suppressing effects on proliferation, apoptosis and invasiveness.

miQ—A novel microRNA based diagnostic and prognostic tool for prostate cancer

“…The tissues are described in the work by Hagman et al 11 and in Table 1. Cohort 2 consists of 71 FFPE samples (52 primary prostate cancers and 19 nonmalignant adjacent prostate) from radical prostatectomy (RP) obtained at Erasmus Medical Centre, Rotterdam, The Netherlands (Table 1).…”

“…In Cohort 1 small RNAs were extracted according to a modified protocol of mirVana TM miRNA Isolation Kit (Ambion, Austin, TX) as described in Hagman et al 11 In Cohort 2 deparaffinization and proteinase K treatment was done using High Pure RNA Paraffin Kit (Roche, Basel, Switzerland) according to the instructions of the supplier. Samples were mixed with 1 ml RNABee reagent (Campro Scientific, GmbH, Berlin, Germany) and total RNA was isolated according to the manufacturer's protocol.…”

“…In addition to the miRNAs found here, we also included the promising marker miR-34c-5p analyzed in the same material. 11 In order to avoid dependence on normalization factors we chose to arrange the miRNAs as a ratio with an equal number of denominators and numerators, aiming at a limited set to be manageable in clinical practice. A miRNA signature consisting of four miRNAs ((miR-96-5p  miR-183-5p)/(miR-145-5p  miR221-5p)), which we denoted the miRNA index quote (miQ) was found to give optimal diagnostic discrimination given these restrictions.…”

MicroRNA-497 Suppresses Proliferation and Induces Apoptosis in Prostate Cancer Cells

“…Up to now, more than 50 miRNAs are abnormally expressed, leading to alteration in the expression and activity of their targets in PCa, such as miR-21, miR-320, miR-29b and miR34c (Ribas et al, 2009;Hagman et al, 2010;Hsieh et al, 2012;Ru et al, 2012 all prostate carcinoma samples compared with the BPH samples (Porkka et al, 2007;Watahiki et al, 2011). Several studies showed that the potential functions of miR-497 in human breast cancer (Li et al, 2011;Shen et al, 2012), neuroblastoma (Yadav et al, 2011), cervical cancer (Zheng et al, 2012), gastric cancer (Zhu et al, 2012) and colorectal cancer (Guo et al, 2012).…”

microRNA-34 family and treatment of cancers with mutant or wild-type p53 (Review)

“…the tumour (82). restoration reduced levels of e2f3, a gene involved in cell cycle regulation at the g1/S checkpoint and was responsible for catalysing proliferation in prostate cell lines.…”