microRNAs In Prostate Cancer Research Articles

MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer

Ubiquitin-specific protease 2a (USP2a) is overexpressed in almost half of human prostate cancers and c-Myc is amplified in one third of these tumor types. Transgenic MYC expression drives invasive adenocarcinomas in the murine prostate. We show that overexpression of USP2a downregulates a set of microRNAs that collectively increase MYC levels by MDM2 deubiquitination and subsequent p53 inactivation. By establishing MYC as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature that is enriched for MYC-regulated transcripts and transcription factor binding sites in USP2a overexpressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer and that the proliferative and invasive properties of USP2a overexpressing cells are MYC-dependent. These results highlight an unrecognized mechanism of MYC regulation in prostate cancer and suggest alternative therapeutic strategies in targeting MYC. The deubiquitinating enzyme USP2a has previously been shown to be oncogenic, overexpressed in almost half of human prostate adenocarcinomas, and prolongs the half-life of targets such as fatty acid synthase, MDM2, and cyclin D1. Here, we highlight a new mechanism by which USP2a enhances MYC levels through the modulation of specific subsets of microRNAs in prostate cancer, suggesting alternative therapeutic strategies for targeting MYC.

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

MicroRNAs (miRNAs) are effective regulators of gene expression that have a significant role in the pathogenesis of prostate and various other cancers. The high prevalence of aberrant miRNA expression in prostate cancer, and miRNAs' distinctive properties, give much hope that they can be used as biomarkers and next generation of molecular anticancer therapeutics. Herein, we review the literature on miRNA involvement in prostate cancer pathogenesis and the current understanding of their role as oncogenes, tumor suppressors and metastasis-regulators. We also review the latest research on miRNAs in prostate cancer preclinical studies and clinical trials, and highlight the advantages and challenges of possible miRNA-based therapies. The emerging information regarding the biology of miRNAs in prostate cancer is promising, and may lead to a role(s) for these molecules as diagnostic/prognostic markers and effective therapeutic tools for better molecularly targeted treatment of prostate cancer.

MicroRNA in Prostate Cancer: An Opportunity to Individualize Patient Care

MicroRNA in Prostate Cancer: An Opportunity to Individualize Patient Care

MicroRNA expression profiles in the progression of prostate cancer—from high-grade prostate intraepithelial neoplasia to metastasis

IntroductionModels of the multistep process related to cancer progression have been designed for many cancers including prostate. The aim of this study is to propose a new model including a possible role for recently described micro RNAs in prostate cancer (CaP) progression. MethodsSixty-three patients underwent radical prostatectomy to treat localized prostate carcinoma. The specimens of 15 patients were representative of high grade prostate intraepithelial neoplasia (HGPIN). Fourteen specimens represented localized favorable CaP, and 34 unfavorable, mostly non-organ-confined disease. Representing the advanced disease we studied 4 metastatic androgen-independent CaP and 2 cell lines. Micro RNAs were isolated using the mirVana miRNA Isolation kit and cDNA was obtained using the TaqMan miRNA Reverse Transcription kit to the miRNAs: hsa-miR-let7c, hsa-miR-15a, hsa-miR-16, hsa-miR-21, hsa-miR-25, hsa-miR-32, hsa-miR-100, hsa-miR-143, hsa-miR-145, hsa-miR-146a, hsa-miR-191, hsa-miR-199a, hsa-miR-206, and hsa-miR-218. Quantitative RT-PCR was carried out using the ABI 7500 Fast Real-Time PCR System and the TaqMan Universal PCR Master Mix. miRNA expression levels were measured by relative quantification, and fold expression changes were determined by the 2–ΔΔCT method. The small nucleolar RNA RNU43 was used as an endogenous control. ResultsExcept for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. Interestingly, there was a significant global loss of miRNA expression between HGPIN and metastasis at 2 important steps. The first was related to the transition from HGPIN to invasive adenocarcinoma, and the second was related to the transition from localized to metastatic adenocarcinomas. ConclusionThrough the analysis of 14 miRNAs in 4 groups of prostate lesions, which reproduced the progression of CaP, we showed that there is a global loss of miRNA expression at 2 distinct steps. The first related to the transition between HGPIN and localized invasive carcinoma, and the second associated with the transition from localized to metastatic CaP. The importance of our study is in the identification of possible miRNAs and miRNA-targeted genes involved in the progression of prostate carcinogenesis that may help the development of potential diagnostic or prognostic markers as well as the design of new target therapies.

1285 REGULATORY ROLE OF MIR-203 IN PROSTATE CANCER PROGRESSION AND METASTASIS

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 20111285 REGULATORY ROLE OF MIR-203 IN PROSTATE CANCER PROGRESSION AND METASTASIS Sharanjot Saini, Shahana Majid, Soichiro Yamamura, Z. Laura Tabatabai, Varahram Shahryari, Guoren Deng, Yuichiro Tanaka, Peter R. Carroll, and Rajvir Dahiya Sharanjot SainiSharanjot Saini San Francisco, CA More articles by this author , Shahana MajidShahana Majid San Francisco, CA More articles by this author , Soichiro YamamuraSoichiro Yamamura San Francisco, CA More articles by this author , Z. Laura TabatabaiZ. Laura Tabatabai San Francisco, CA More articles by this author , Varahram ShahryariVarahram Shahryari San Francisco, CA More articles by this author , Guoren DengGuoren Deng San Francisco, CA More articles by this author , Yuichiro TanakaYuichiro Tanaka San Francisco, CA More articles by this author , Peter R. CarrollPeter R. Carroll San Francisco, CA More articles by this author , and Rajvir DahiyaRajvir Dahiya San Francisco, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.971AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES MicroRNAs (miRNAs) constitute an evolutionarily conserved class of small RNAs that suppress gene expression posttranscriptionally via sequence-specific interactions with the 3'- untranslated regions of cognate mRNA targets. Dysregulation of miRNA expression has been identified in various cancers. Accumulating data suggests that miRNAs may function as classical oncogenes, tumor suppressor genes or play a role in metastasis of various cancers. Advanced metastatic prostate cancer is a fatal disease, with only palliative therapeutic options. Advanced prostate cancer is mostly associated with bone metastatic dissemination. Though almost 80% of metastatic prostate cancer cases present bone metastasis, our current understanding of the molecular mechanisms that govern this metastatic dissemination remains fragmentary. Understanding molecular controls that signal prostate cancer progression and metastasis is important in developing better therapeutic and diagnostic interventions for the disease. The main objective of the present study was to identify microRNA genes that regulate metastatic prostate cancer. METHODS MicroRNA expression profiling was done in human prostate cell lines to identify dysregulated microRNA components of advanced prostate cancer. miR-203 expression was assessed in prostate carcinoma cell lines and clinical specimens by quantitative real-time PCR and in situ hybridization. To assess the biological significance of miR-203, miR-203 was reexpressed in bone metastatic prostate cancer cell lines followed by in vitro and in vivo functional assays. RESULTS miR-203 expression is specifically attenuated in bone metastatic prostate cancer suggesting a fundamental anti-metastatic role for this miRNA. Reintroduction of miR-203 in bone metastatic prostate cancer cell lines suppressed metastasis via inhibition of several critical steps of the metastatic cascade including epithelial-mesenchymal transition, invasion and motility. Ectopic miR-203 significantly attenuated the development of metastasis in a bone metastatic model of prostate cancer. Importantly, miR-203 regulated a cohort of pro-metastatic genes including ZEB2, Bmi (polycomb repressor), Survivin and bone specific effectors including Runx2, a master regulator of bone metastasis. CONCLUSIONS miR-203 is an ‘anti-metastatic' microRNA in prostate cancer that acts at multiple steps of the prostate cancer metastatic cascade via repression of a cohort of prometastatic targets. miR-203 may be an attractive target for therapeutic intervention in advanced prostate cancer. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e514 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sharanjot Saini San Francisco, CA More articles by this author Shahana Majid San Francisco, CA More articles by this author Soichiro Yamamura San Francisco, CA More articles by this author Z. Laura Tabatabai San Francisco, CA More articles by this author Varahram Shahryari San Francisco, CA More articles by this author Guoren Deng San Francisco, CA More articles by this author Yuichiro Tanaka San Francisco, CA More articles by this author Peter R. Carroll San Francisco, CA More articles by this author Rajvir Dahiya San Francisco, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Diet, microRNAs and prostate cancer.

MicroRNAs (miRNAs) constitute an evolutionarily conserved class of small non-coding RNAs that are endogenously expressed with crucial functions in fundamental cellular processes such as cell cycle, apoptosis and differentiation. Disturbance of miRNA expression and function leads to deregulation of basic cellular processes leading to tumorigenesis. A growing body of experimental evidence suggests that human tumors have deregulated expression of microRNAs, which have been proposed as novel oncogenes or tumor suppressors. Recent studies have shown that microRNA expression patterns serve as phenotypic signatures of different cancers and could be used as diagnostic, prognostic and therapeutic tools. A few studies have analyzed global microRNA expression profiles or the functional role of microRNAs in prostate cancer. Here we have reviewed the role of microRNAs in prostate carcinogenesis by summarizing the findings from such studies. In addition, recent evidence indicates that dietary factors play an important role in the process of carcinogenesis through modulation of miRNA expression, though such studies are lacking in regards to prostate cancer. It has been proposed that dietary modulation of miRNA expression may contribute to the cancer-protective effects of dietary components. In this review, we have summarized findings from studies on the effect of dietary agents on miRNA expression and function.

Towards the definition of prostate cancer-related microRNAs: where are we now?

Eradication of advanced prostate cancer still represents an unsolved clinical problem, making the development of alternative treatment approaches highly desirable. Understanding the molecular alterations that distinguish non-progressive from progressive disease would provide mechanistic information for the identification of new therapeutic targets. Recent findings indicate that human tumors have deregulated expression of microRNAs, which have thus been proposed as novel oncogenes or tumor suppressors. A few studies have analyzed the expression profiles or the functional role of microRNAs in prostate cancer, generating largely inconsistent data. Here we review the major issues that have hindered the identification of prostate cancer-related microRNAs, outlining an approach for rational validation of candidates that might be clinically relevant in the management of this disease.

MiR-205 Exerts Tumor-Suppressive Functions in Human Prostate through Down-regulation of Protein Kinase Cε

Limited information is available concerning the expression and role of microRNAs in prostate cancer. In this study, we investigated the involvement of miR-205 in prostate carcinogenesis. Significantly lower miR-205 expression levels were found in cancer than in normal prostate cell lines as well as in tumor compared with matched normal prostate tissues, with a particularly pronounced reduction in carcinomas from patients with local-regionally disseminated disease. Restoring the expression of miR-205 in prostate cancer cells resulted in cell rearrangements consistent with a mesenchymal-to-epithelial transition, such as up-regulation of E-cadherin and reduction of cell locomotion and invasion, and in the down-regulation of several oncogenes known to be involved in disease progression (i.e., interleukin 6, caveolin-1, EZH2). Our evidence suggests that these events are driven by the concurrent repression of specific predicted miR-205 targets, namely N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase Cepsilon. Strikingly, the latter seemed to play a direct role in regulating epithelial-to-mesenchymal transition. In fact, its down-regulation led to a cell phenotype largely reminiscent of that of cells ectopically expressing miR-205. Overall, we showed for the first time that miR-205 exerts a tumor-suppressive effect in human prostate by counteracting epithelial-to-mesenchymal transition and reducing cell migration/invasion, at least in part through the down-regulation of protein kinase Cepsilon.

Molecular assays for the detection of microRNAs in prostate cancer

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs (about 21 to 24 nucleotides in length) that effectively reduce the translation of their target mRNAs. Several studies have shown miRNAs to be differentially expressed in prostate cancer, many of which are found in fragile regions of chromosomes. Expression profiles of miRNAs can provide information to separate malignancies based upon stage, progression and prognosis. Here we describe research prototype assays that detect a number of miRNA sequences with high analytical sensitivity and specificity, including miR-21, miR-182, miR-221 and miR-222, which were identified through expression profiling experiments with prostate cancer specimens. The miRNAs were isolated, amplified and quantified using magnetic bead-based target capture and a modified form of Transcription-Mediated Amplification (TMA).ResultsAnalytical sensitivity and specificity were demonstrated in model system experiments using synthetic mature microRNAs or in vitro miRNA hairpin precursor transcripts. Research prototype assays for miR-21, miR-182, miR-221 and miR-222 provided analytical sensitivities ranging from 50 to 500 copies of target per reaction in sample transport medium. Specific capture and detection of mature miR-221 from complex samples was demonstrated in total RNA isolated from human prostate cancer cell lines and xenografts.ConclusionResearch prototype real-time TMA assays for microRNAs provide accurate and reproducible quantitation using 10 nanograms of input total RNA. These assays can also be used directly with tissue specimens, without the need for a preanalytic RNA isolation step, and thus provide a high-throughput method of microRNA profiling in clinical specimens.

Expression of 6 microRNAs in prostate cancer and its significance

OBJECTIVE Numerous microRNAs (miRNAs) are deregulated in human cancers. The experimental evidence supports that miRNAs plays a role in the initiation and progression of human malignancies.The present study was undertaken to evaluate the differential expression of 6 miRNAs as biomarker for early detection of prostate cancer, and then to determine whether the expression profi ling of these miRNAs could predict the prognosis of prostate cancer. METHODS The expression profi lings of these 6 miRNAs were investigated using the method of locked nucleic acid (LNA)modified oligonucleotide in situ hybridization (ISH). And the technology of tissue microarray (TMA) was employed using the formalin-fixed, paraffin-embedd (FFPE) specimens taken from 52 patients with prostate carcinoma (PCa) and 38 patients with benign prostatic hyperplasia (BPH). RESULTS The rates of positive expression for 6 miRNAs (miR15b, miR-16, let-7g, miR- 96,miR-182 and miR-183) were 26.92%, 15.38%, 15.38%, 67.31%, 61.54% and 71.15% in the specimens of prostate cancer, and 57.89%, 76.32%, 68.42%, 44.74%, 31.58%, 47.37% in the tissues of benign prostatic hyperplasia, respectively. The expressions of all 6 miRNAs between the prostate cancer and benign prostatic hyperplasia tissues were significantly different (P 0.05). We also found that the expression of miR-15b, miR-96 and miR-182 correlated with clinical stages of tumor (P 0.05). In addition, the expression of miR-15b was negatively related to that of miR-96, miR-182 and miR-183, respectively (P 0.00). The expression of miR-16 was positively related to that of miR-let-7g (P 0.00). CONCLUSION The results suggest that miRNA expression profiling could have relevance to the biological and clinical behavior of prostate cancer,and they might be important biomarkers for early detection and prognostic assessment of prostate cancer.

Genomic Profiling of MicroRNA and Messenger RNA Reveals Deregulated MicroRNA Expression in Prostate Cancer

MicroRNAs are small noncoding RNAs that regulate the expression of protein-coding genes. To evaluate the involvement of microRNAs in prostate cancer, we determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 nontumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. Consistent with these findings, tumors expressed the miR-106b-25 cluster, which maps to intron 13 of MCM7, and miR-32, which maps to intron 14 of C9orf5, at significantly higher levels than nontumor prostate. The expression levels of other microRNAs, including a number of miR-106b-25 cluster homologues, were also altered in prostate tumors. Additional differences in microRNA abundance were found between organ-confined tumors and those with extraprostatic disease extension. Lastly, we found evidence that some microRNAs are androgen-regulated and that tumor microRNAs influence transcript abundance of protein-coding target genes in the cancerous prostate. In cell culture, E2F1 and p21/WAF1 were identified as targets of miR-106b, Bim of miR-32, and exportin-6 and protein tyrosine kinase 9 of miR-1. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells.