miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression

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.

LncRNA XLOC_006390 facilitates cervical cancer tumorigenesis and metastasis as a ceRNA against miR-331-3p and miR-338-3p

“…MiR-331-3p and miR-338-3p were reported to regulate multiple cancer tumorigenesis and metastasis by targeting many genes in human cells (listed in Supplementary Table 1 , Supplementary Figs. 1 , and 2 ) [ 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 ]. Therefore, miR-331-3p and miR-338-3p were chosen for further studies.…”

Long Non-Coding RNA GATA6-AS1 Inhibits Proliferation and Promotes Apoptosis of Lung Adenocarcinoma Through Sponging miR-331-3p and Regulating SOCS1/JAK2/STAT3 Pathway

“…Similarly, miR-331-3p is able to target RCC2 to inhibit the cell proliferation, migration and invasion of ovarian cancer [20]. Up-regulation of miR-331-3p reduces prostate cancer cell growth, migration and colony formation [21]. Based on above three examples, we could get a conclusion that miR-331-3p has double characters-oncogen and tumor-inhibitor gene.…”

Overexpression of miR-331 Indicates Poor Prognosis and Promotes Progression of Breast Cancer

“…miR-455-5p and miR-1255a were upregulated with poor overall survival, while the overexpression of their target genes was related to a good overall survival, which indicated the potential roles of mir-455-5p and miR-1255a in the therapy of breast cancer [10]. miR-331 is upregulated in breast cancer, and it has been demonstrated to be dysregulated in many other cancers, such as lung cancer, gastric cancer, and prostate cancer [11][12][13][14][15]. In gastric cancer, miR-331 was downregulated, which inhibited the cell proliferation, metastasis, and tumor growth of gastric cancer [12].…”