MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells
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Robert K. Nam1,*, Tania Benatar2,*, Yutaka Amemiya3, Christopher J.D. Wallis1, Joan Miguel Romero2, Melina Tsagaris2, Christopher Sherman4,5, Linda Sugar4,5 and Arun Seth2,3,4,5
1Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
2Platform Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada
3Genomics Facility, Sunnybrook Research Institute, Toronto, ON, Canada
4Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
5Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
*These authors contributed equally to the work
Tania Benatar, email: [email protected]
Arun Seth, email: [email protected]
Keywords: miR-652-3p; miRNA; prostate cancer; NED; EMT
Received: June 15, 2017 Accepted: March 06, 2018 Published: April 10, 2018
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.
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