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Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.

ABSTRACT: Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27.3. Moreover, as miR-888 maps within HPCX1, a locus associated with susceptibility and/or hereditary prostate cancer, it was hypothesized that additional miRNA cluster members also play functional roles in the prostate. Expression analysis determined that cluster members were similarly elevated in metastatic PC3-ML prostate cells and their secreted exosomes, as well as enriched in expressed prostatic secretions urine-derived exosomes obtained from clinical patients with high-grade prostate cancer. In vitro assays revealed that miR-888 cluster members selectively modulated PC3-derived and LNCaP cell proliferation, migration, invasion, and colony formation. Mouse xenograft studies verified miR-888 and miR-891a as pro-oncogenic factors that increased prostate tumor growth in vivo Further analysis validated RBL1, KLF5, SMAD4, and TIMP2 as direct miR-888 targets and that TIMP2 is also coregulated by miR-891a. This study provides the first comprehensive analysis of the entire miR-888 cluster and reveals biological insight.Implications: This work reveals a complex noncoding RNA network in the prostate that could be developed as effective diagnostic and therapeutic tools for advanced prostate cancer. Mol Cancer Res; 16(4); 669-81. ©2018 AACR.

SUBMITTER: Hasegawa T

PROVIDER: S-EPMC5882523 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.

Hasegawa Tsuyoshi T Glavich Garrison J GJ Pahuski Mary M Short Aleena A Semmes O John OJ Yang Lifang L Galkin Vitold V Drake Richard R Esquela-Kerscher Aurora A

Molecular cancer research : MCR 20180112 4

Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. ...[more]

PMID: 29330297

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Project description:Prostate cancer (PCa) is the second most frequently diagnosed solid tumor and the fifth leading cause of cancer mortality among men worldwide. The prostate specific antigen (PSA) test for PCa remains controversial. Therefore, the development of more effective non-invasive biomarkers for PCa is necessary. The present study evaluated the diagnostic value of microRNA (miR)-20b-5p in PCa. Tissue miR-20b-5p expression levels and their correlation with clinical parameters were assessed using The Cancer Genome Atlas (TCGA) datasets, and the diagnostic value of the miR-20b-5p expression levels in PCa tissues was assessed using receiver operating characteristic curve analysis. Reverse transcription-quantitative PCR (RT-qPCR) was used to assess the relative expression levels of miR-20b-5p in PCa tissues compared with benign prostate hyperplasia (BPH) tissues. In addition, miR-20b-5p expression levels in PCa cell lines and non-tumorigenic prostate epithelial cells were compared. In this study, exosomes were extracted from the prostatic fluid as a source of liquid biopsy for the detection of PCa. The prostatic fluid exosomal miR-20b-5p expression levels between patients with PCa and the biopsy-negative patients were compared, and the diagnostic efficiency of prostatic fluid exosomal miR-20b-5p expression levels in PCa was compared with PSA and with the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator. The mechanism by which miR-20b-5p may function in PCa was assessed using bioinformatic analysis and validation experiments. miR-20b-5p was expressed at a markedly higher level in PCa tissues compared with normal prostate tissues with high diagnostic efficiency (area under the curve: 0.826). The expression levels of miR-20b-5p were also significantly higher in PCa tissues compared with BPH tissues; similarly, miR-20b-5p was more highly expressed in PCa cells compared with non-tumorigenic prostate epithelial cells. Prostatic fluid exosomal miR-20b-5p expression levels in patients with PCa were significantly higher compared with confirmed to be biopsy-negative, and the diagnostic performance of miR-20b-5p was superior to PSA and ERSPC risk calculator. The results of RT-qPCR and western blotting following transfection of DU145 cells with miR-20b-5p mimics and inhibitor showed that miR-20b-5p reduced the expression of retinoblastoma-associated protein 1 (RB1). Therefore, RB1 may be a significant target gene for miR-20b-5p. In conclusion, the present study demonstrated that miR-20b-5p was upregulated in PCa at the tissue and cellular levels, as well as in prostatic fluid exosomes. Therefore, miR-20b-5p may be a promising early diagnostic biomarker for PCa and an important tool to guide the decision-making of prostate biopsy.

Dataset Information

Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.

Publications

Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.

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