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Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

ABSTRACT: BACKGROUND:Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. METHODS:Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). RESULTS:Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. CONCLUSIONS:Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

SUBMITTER: Goto Y

PROVIDER: S-EPMC5537499 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

Goto Yusuke Y Kurozumi Akira A Arai Takayuki T Nohata Nijiro N Kojima Satoko S Okato Atsushi A Kato Mayuko M Yamazaki Kazuto K Ishida Yasuo Y Naya Yukio Y Ichikawa Tomohiko T Seki Naohiko N

British journal of cancer 20170622 3

<h4>Background</h4>Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed.<h4>Methods</h4>Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene e ...[more]

PMID: 28641312

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Project description:BackgroundExtracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer.ObjectiveTo identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC).Design, setting, and participantsRNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients.Outcome measurements and statistical analysisCox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors.Results and limitationsRNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥ 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10(-6)).ConclusionsPlasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs.Patient summaryIn this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.

Dataset Information

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

Publications

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

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