miR-199a-3p Inhibits Aurora Kinase A and Attenuates Prostate Cancer Growth

Abstract

Copyright: Epis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3'-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa.

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

“…We are the first to show a strong correlation between high active b-catenin immunohistochemical expression and high Gleason score prostate tumors. Many studies have linked overexpression of AurKA with progression and malignant phenotype of prostate cancers (41)(42)(43)(44), although there are controversial results with respect to its correlation with the Gleason score (45,46). We observed a significant correlation between high expression of AurKA and high Gleason score tumors.…”

Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A

“…Recently, miRNAs are now recognized as key post-transcriptional regulators of gene expression. Although miR-199a-3p has been reported to attenuate xenograft tumor growth of prostate carcinoma by targeting Aurora-A [38], the expression of miR-199a-3p showed no difference between HCC tissues with or without LNM from our miRNA array data and by qRT-PCR (data not shown). A single gene can be regulated by several miRNAs, while a single miRNA can regulate multiple target genes within the same or different tissues.…”

Gene interference strategies as a new tool for the treatment of prostate cancer

“…Tao et al studies have shown that miR-133 inhibits cell proliferation, migration, and invasion in PCa cells by targeting the epidermal growth factor receptor [122]. The ability of let-7 to inhibit tumor initiation was first demonstrated in a murine CD44-positive xenograft model, where overexpression and therapeutic injection of let-7 retarded tumor growth [123][124][125]. Intratumoral administration of miR-199a-3p mimics into a murine PCa-xenograft model led to decreased expression of the oncogene Aurora kinase A (AurkA), which is associated with a malignant PCa phenotype [125].…”

“…The ability of let-7 to inhibit tumor initiation was first demonstrated in a murine CD44-positive xenograft model, where overexpression and therapeutic injection of let-7 retarded tumor growth [123][124][125]. Intratumoral administration of miR-199a-3p mimics into a murine PCa-xenograft model led to decreased expression of the oncogene Aurora kinase A (AurkA), which is associated with a malignant PCa phenotype [125]. In another murine xenograft model, using transfected PCa cell lines [124], miR-128 showed antiproliferative as well as proapoptotic effects and negatively regulated PCa stem cells by directly targeting the stem cell-related genes Bmi-1 and Nanog (Nanog homeobox).…”