Novel tumor suppressor microRNA at frequently deleted chromosomal region 8p21 regulates Epidermal Growth Factor Receptor in prostate cancer
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Nathan Bucay1,*, Kirandeep Sekhon1,*, Shahana Majid1, Soichiro Yamamura1, Varahram Shahryari1, Z. Laura Tabatabai1, Kirsten Greene1, Yuichiro Tanaka1, Rajvir Dahiya1, Guoren Deng1, Sharanjot Saini1
1Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA
*These authors have contributed equally to this work
Sharanjot Saini, email: [email protected]
Keywords: prostate cancer, miR-3622b, EGFR, chr8p21, tumor suppressor
Received: May 24, 2016 Accepted: August 13, 2016 Published: September 06, 2016
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.
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