Abstract
Genomic loss of chromosome (chr) 8p21 region, containing prostate-specific NKX3.1 gene, is a frequent alteration of the prostate cancer (PCa) oncogenome. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is also associated with a cluster of microRNA genes- miR-3622a/b- that are lost in PCa and play an important mechanistic role in progression and metastasis. In this study, we demonstrate the role of miR-3622b in prostate cancer. Expression analyses in a cohort of PCa clinical specimens and cell lines show that miR-3622b expression is frequently lost in prostate cancer. Low miR-3622b expression was found to be associated with tumor progression and poor biochemical recurrence-free survival. Further, our analyses suggest that miR-3622b expression is a promising prostate cancer diagnostic biomarker that exhibits 100% specificity and 66% sensitivity. Restoration of miR-3622b expression in PCa cell lines led to reduced cellular viability, proliferation, invasiveness, migration and increased apoptosis. miR-3622b overexpression in vivo induced regression of established prostate tumor xenografts pointing to its therapeutic potential. Further, we found that miR-3622b directly represses Epidermal Growth Factor Receptor (EGFR). In conclusion, our study suggests that miR-3622b plays a tumor suppressive role and is frequently downregulated in prostate cancer, leading to EGFR upregulation. Importantly, miR-3622b has associated diagnostic, prognostic and therapeutic potential. Considering the association of chr8p21 loss with poor prognosis, our findings are highly significant and support a novel concept that associates a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer.
Highlights
Prostate cancer (PCa) is the most common male malignancy worldwide and a leading cause of cancer related mortality amongst men [1, 2] with an estimated 26,120 deaths predicted for 2016 within the US [2]
We previously demonstrated that miR3622a located on frequently deleted chr8p21 region plays a crucial role in prostate cancer (PCa) epithelial-to-mesenchymal transition (EMT), progression and metastasis by direct targeting of Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Snail Family Zinc Finger 2 (SNAI2) (Bucay et al, manuscript under consideration)
Loss of chromosome 8p [11,12,13,14,15,16,17]- chr8p21 subregion- [21, 22] – has been consistently reported as a frequent alteration of the PCa genome that has been associated with the loss of tumor suppressors such as prostate-specific NKX3.1 gene [20]
Summary
Prostate cancer (PCa) is the most common male malignancy worldwide and a leading cause of cancer related mortality amongst men [1, 2] with an estimated 26,120 deaths predicted for 2016 within the US [2]. Though novel therapies with marginal survival benefits have been developed for advanced disease [6, 7], its clinical management remains challenging. A major challenge is the elucidation www.impactjournals.com/oncotarget of underlying molecular pathways of PCa progression, recurrence and metastasis that holds enormous potential towards the design of effective therapeutic strategies for better clinical management of the disease
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