miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression.
miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression.
复制标题
DOI：
10.18632/oncotarget.18664
复制
发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Leedman PJ
中科院分区：
文献类型：
--
作者：
Epis MR;Giles KM;Beveridge DJ;Richardson KL;Candy PA;Stuart LM;Bentel J;Cohen RJ;Leedman PJ
基于RNA的疗法可能代表癌症治疗的新途径。 miRNA 331-3p (miR-331-3p) 作为一种假定的肿瘤抑制因子与前列腺癌 (PCa) 相关，但其功能活性以及与其他抗肿瘤药物的协同作用在很大程度上尚不清楚。我们发现与非恶性匹配组织相比，PCa 肿瘤中 miR-331-3p 的表达显着降低。对公开的PCa基因表达数据集的分析显示，miR-331-3p表达与格里森评分、肿瘤分期、淋巴结受累和PSA值呈负相关，并且相对于正常前列腺组织，在肿瘤组织中显着下调。 miR-331-3p 的过度表达减少了 PCa 细胞的生长、迁移和集落形成，以及小鼠异种移植肿瘤的发生、增殖和存活。微阵列分析确定了前列腺癌中 miR-331-3p 的七个新靶标。 PLCγ1 和 RALA 的 3'-非翻译区被确认为 miR-331-3p 的靶标，突变分析证实 RALA 是直接靶标。 PCa 细胞中 miR-331-3p 或 RALA siRNA 的表达可减少体外 RALA 表达、增殖、迁移和集落形成。在两项独立的研究以及 PCa 组织微阵列中，RALA 表达与格里森分级呈正相关。使用 siRALA 与极光激酶抑制剂 (AKi-II) 共同治疗可减少 PCa 细胞的集落形成，而 AKi-II 与 miR-331-3p 的组合可显着减少体外 PCa 细胞增殖和体内 PCa 异种移植物生长。因此，miR-331-3p 直接靶向 RALA 通路，并且添加 AKi-II 对肿瘤生长抑制具有协同作用，表明其作为 PCa 联合治疗的潜在作用。
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.