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ABSTRACT: Today, the majority of prostate tumours are detected at early stages with uncertain prognosis. Therefore, we set out to identify early predictive markers of prostate cancer with aggressive progression characteristics. We measured the expression of microRNAs (miRNA) using qRT-PCR in FFPE prostatic tissue samples from a Swedish cohort of 49 patients with prostate cancer and 25 without cancer and found eight of 14 preselected miRNAs to discriminate between the two groups. Subsequently four discriminatory miRNAs were combined to a quota, denoted the miRNA index quote (miQ); ((miR-96-5p x miR-183-5p)/(miR-145-5p x miR221-5p)). The advantage using a quote is increased discrimination, no need for house-keepings, and most important it may be an advantage considering the heterogeneity of the disease. miQ was found to successfully predict diagnosis (p<0.0001) with high accuracy (AUC=0.931) that was verified in an independent Dutch cohort and three external cohorts, and significantly outperforming PSA. Importantly, miQ also has prognostic power to predict aggressiveness of tumours (AUC=0.895), metastatic statues (AUC=0.827), and overall survival (p=0.0013, Wilcoxon test HR=6.5, median survival 2 versus 5 years), verified in the Dutch cohort. In this preliminary study we propose that miQ has potential to be used as a clinical tool for prostate cancer diagnosis and as a prognostic marker of disease progression. © 2012 Wiley Periodicals, Inc.
International Journal of Cancer 11/2012; · 5.44 Impact Factor
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Päivi Östling,
Suvi-Katri Leivonen,
Anna Aakula,
Pekka Kohonen,
Rami Mäkelä, Zandra Hagman,
Anders Edsjö,
Sara Kangaspeska,
Henrik Edgren,
Daniel Nicorici,
Anders Bjartell,
Yvonne Ceder,
Merja Perälä,
Olli Kallioniemi
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ABSTRACT: Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3'UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3'UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371-3p, miR-421, miR-449a, miR-449b, miR-634, miR-654-5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.
Cancer Research 02/2011; 71(5):1956-67. · 7.86 Impact Factor
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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 = 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 = 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.
International Journal of Cancer 12/2010; 127(12):2768-76. · 5.44 Impact Factor
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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 = 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 = 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.
International Journal of Cancer 02/2010; 127(12):2768 - 2776. · 5.44 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. There have been several reports of miRNA deregulation in prostate cancer 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 prostate cancer (p = 0.0005) by performing qRT-PCR on 49 TURPs from prostate cancer patients compared to 25 from patients with benign prostatic hyperplasia. The miR-34c expression was found to inversely correlate to aggressiveness of the tumour, 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 (<50(th) percentile) and high (> 50(th) percentile) expression, significantly divides the patients into high risk and low risk patients (p = 0.0003, long-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 prostate cancer 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. (c) 2010 UICC.
International Journal of Cancer 02/2010; · 5.44 Impact Factor
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ABSTRACT: EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics. Berlin, Germany, 16-19 Nov. 2010
