Abstract
Dysregulation of miRNAs has been demonstrated in several human malignancies including prostate cancer. Due to tissue limitation and variable disease progression, stage-specific miRNAs changes in prostate cancer is unknown. Using chip-based microarray, we investigated global miRNA expression in human prostate cancer LNCaP, PC3, DU145 and 22Rv1 cells representing early-stage, advanced-stage and castration resistant prostate cancer in comparison with normal prostate epithelial cells. A total of 292 miRNAs were differentially expressed with 125 upregulated and 167 downregulated. These miRNAs were involved in pathways including drug resistance drug-efflux, adipogenesis, epithelial-to-mesenchymal transition, bone metamorphosis, and Th1/Th2 signaling. Regulation of miRNAs were interlinked with upstream regulators such as Argonaut 2 (AGO2), Double-Stranded RNA-Specific Endoribonuclease (DICER1), Sjogren syndrome antigen B (SSB), neurofibromatosis 2 (NF2), and peroxisome proliferator activated receptor alpha (PPARA), activated during stage-specific disease progression. Candidate target genes and pathways dysregulated in stage-specific prostate cancer were identified using CS-miRTar database and confirmed in clinical specimens. Integrative network analysis suggested some genes targeted by miRNAs include miR-17, let7g, miR-146, miR-204, miR-205, miR-221, miR-301 and miR-520 having a major effect on their dysregulation in prostate cancer. MiRNA-microarray analysis further identified miR-130a, miR-181, miR-328, miR146 and miR-200 as a panel of novel miRNAs associated with drug resistance drug-efflux and epithelial-to-mesenchymal transition in prostate cancer. Our findings provide evidence on miRNA dysregulation and its association with key functional components in stage-specific prostate cancer.
Highlights
Prostate cancer, by far, remains the leading cause of cancer morbidity and mortality in males in the United States, and approximately 20% of these men will develop invasive disease during their lifetime [1]
Dysregulation of miRNAs has been reported in prostate malignancy from early- to advancedstage and castration resistant disease progression
Using glass chip-based miRNA-microarray we comprehensively evaluated and profiled miRNA expression using four prostate cancer cell lines as representative of early-stage, advanced-stage and castration-resistant prostate cancer (CRPC) progression, compared with normal prostate epithelial cells as control (Fig 1; S1 Fig)
Summary
By far, remains the leading cause of cancer morbidity and mortality in males in the United States, and approximately 20% of these men will develop invasive disease during their lifetime [1]. Prostate cancer in humans exhibits a distinctive continuum of features including heterogeneity, multi-focality, inconsistent clinical progression including metastasis to bone, and emergence of androgen-independent disease [4]. The growth of early prostate lesions are androgen dependent, progressing to an androgen-refractory stage, resulting in patients’ death [5]. Most patients diagnosed with advance-stage disease are treated with androgen deprivation therapy [6], which results in tumor shrinkage [7]. About 70–80% of patients initially respond to this therapy, but the tumor eventually becomes resistant with the emergence of castration-resistant prostate cancer (CRPC) [8]. Understanding the molecular abnormalities during various stages of prostate cancer, in particular CRPC, will lead to the development of approaches for early detection, prevention and therapeutic intervention benefiting patients
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