Abstract
Prostate cancer (PCa) is a significant cause of male morbidity in the United States. Despite recent advances in diagnosis and therapeutic interventions, significant fraction of cases still progress to an advanced stage. Various genetic/epigenetic elements that facilitate this progression are not yet completely known and the mechanism that favors advanced disease is an area of investigation. A characteristic feature associated with progressive disease is deletion of chromosome 8p (chr8p) region, that harbors tumor-suppressor NKX3.1. Previous studies from our group has shown that there are cluster of microRNAs (miRNAs) located within this region whose loss favors advanced, metastatic disease. miR-4287 is a novel miRNA located within this region that has not been studied before. In the present study, we analyzed the role of miR-4287 in PCa using clinical tissues and cell lines. We observed that miR-4287 is significantly downregulated in patient-derived tumor tissues. Receiver operating curve (ROC) analysis showed that miR-4287 distinguishes prostate cancer from normal with a specificity of 88.24% and with an Area under the curve (AUC) of 0.66. Further, we found that miR-4287 levels correlate inversely with patients’ serum prostate-specific antigen levels. Ectopic over-expression of miR-4287 in PCa cell lines showed that miR-4287 plays a tumor suppressor role. miR-4287 led to an increase in G2/M phase of cell cycle in PCa cell lines. Further, ectopic miR-4287 inhibited PCa epithelial-to-mesenchymal transition (EMT) by directly repressing SLUG and stem cell marker CD44. Since miR-4287 specifically targets metastasis pathway mediators, miR-4287 has potential diagnostic and therapeutic significance in preventing advanced, metastatic disease.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer related deaths among men in the United States
We studied the function of a novel miRNA, miR-4287, another miRNA that falls on chromosome 8p 21.1 (GRCh38.p13) within intron of gene scavenger receptor class A member 5 (SCARA5), in prostate cancer cell lines
A trend was observed with increasing Gleason score with percentage of patients with low miR-4287 expression increasing from 62.5% in Gleason 4–6 to 70% and 89% in Gleason 7 and 8–10, respectively
Summary
Prostate cancer (PCa) is the second leading cause of cancer related deaths among men in the United States. PSA is not a very specific PCa biomarker and is found to be elevated in patients with benign prostatic hyperplasia (BPH), that often leads to over-diagnosis and false positive results [3,4,5] This has led the for more specific biomarkers that can diagnose the disease but can successfully predict disease outcome and stratify the disease severity [5, 6]. Significant advances have been made to better understand www.oncotarget.com prostate cancer biology, including identification of genomic rearrangements and alterations, chromosomal translocations and deletions that are associated with prostate cancer [7,8,9] These genetic anomalies are being identified as a very specific indicator of disease severity and can predict the clinical course of the disease with a much higher accuracy [10]
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