MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells

// Robert K. Nam 1, * , Tania Benatar 2, * , Yutaka Amemiya 3 , Christopher J.D. Wallis 1 , Joan Miguel Romero 2 , Melina Tsagaris 2 , Christopher Sherman 4, 5 , Linda Sugar 4, 5 and Arun Seth 2, 3, 4, 5 1 Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada 2 Platform Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada 3 Genomics Facility, Sunnybrook Research Institute, Toronto, ON, Canada 4 Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada 5 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada * These authors contributed equally to the work Correspondence to: Tania Benatar, email: tbenatar@rogers.com Arun Seth, email: arun.seth@utoronto.ca Keywords: miR-652-3p; miRNA; prostate cancer; NED; EMT Received: June 15, 2017      Accepted: March 06, 2018      Published: April 10, 2018 ABSTRACT MicroRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. Dysregulation of miRNAs is frequently associated with disease and, in particular, is involved in prostate cancer progression. Next generation miRNA sequencing identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. High expression of one of these five miRNAs, miR-652, correlated significantly with an increased rate of prostate cancer biochemical recurrence. Overexpression of miR-652 in prostate cancer cells, PC3 and LNCaP, resulted in increased growth, migration and invasion. Prostate cancer cell xenografts overexpressing miR-652 showed increased tumorigenicity and metastases. We found that miR-652 directly targets the B” regulatory subunit, PPP2R3A, of the tumor suppressor PP2A, inducing epithelial-mesenchymal transition (EMT) in PC3 cells and neuroendocrine-like differentiation (NED) in LNCaP cells. The mesenchymal marker N-cadherin increased and epithelial marker E-cadherin decreased in PC3 cells overexpressing miR-652. In LNCaP cells and xenografted tumors, overexpression of miR-652 increased markers of NED, including chromogranin A, neuron specific enolase, and synaptophysin. MiR-652 may contribute to prostate tumor progression by promoting NED through decreased PP2A function. MiR-652 expression could serve as a biomarker for aggressive prostate cancer, as well as provide an opportunity for novel therapy in prostate cancer.