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.
Highlights
Hormone refractory prostate cancer is often associated with neuroendocrine differentiation (NED) [1]
MiR-652 expression correlates with increased patient prostate cancer recurrence but not metastasis
To determine whether miR-652 could be used as an independent prognostic marker for patients with localized prostate cancer, we examined a cohort of patients who underwent surgery for prostate cancer who were separate and independent from the initial Discovery Set
Summary
Hormone refractory prostate cancer is often associated with neuroendocrine differentiation (NED) [1]. Several studies suggest that activation of the Wnt pathway promotes NED of prostate cancer cells [7, 8]. Β-catenin, a component of the Wnt signaling pathway, has been found to induce NED when overexpressed in LNCaP cells [8]. Sustained extracellular signal-regulated kinase (ERK)-1/2 activation www.oncotarget.com is proposed as one of the major mechanisms in NED of prostate cancer cells, playing a critical role in converging of multiple signaling pathways for NED [10]. Upregulated activity of the Ras-Raf-mitogen-activated protein (MEK)/ ERK pathway is associated with prostate cancer progression and poor prognosis, correlating with increased tumor grade of primary or metastatic prostate cancer and tumor relapse after therapy [11,12,13,14]. ERK-1/2 and AKT activation correlate with loss of AR upon androgen deprivation, and is sufficient to regulate AR [15, 17]
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