Bakkar Ashraf, Alshalalfa Mohammed, Petersen Lars F, Abou-Ouf Hatem, Al-Mami Amal, Hegazy Samar A, Feng Felix, Alhajj Reda, Bijian Krikor, Alaoui-Jamali Moulay A, Bismar Tarek A
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, T2V 1P9, Canada.
Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza, Egypt.
Mol Biol Rep. 2016 Apr;43(4):229-40. doi: 10.1007/s11033-016-3948-4. Epub 2016 Feb 23.
MicroRNAs (miRNAs) are small non-coding RNAs that function in transcriptional and post-transcriptional regulation of gene expression. Several miRNAs have been implicated in regulating prostate cancer (PCa) progression. Deregulations of miRNA regulatory networks have been reported in ERG positive PCa, which accounts for ~50 % of PCa and have been suggested to affect tumor aggressiveness. The function of miR338-3p, its prognostic significance, and its association with ERG positive PCa has not been fully investigated. Using microarray expression profiling, we identified miRNA338-3p as among the top deregulated miRNAs associated with ERG status in PCa. We investigated miR338-3p function using in vitro and in vivo experimental models and its expression was assessed and validated in clinical samples and a public cohort of localized and metastatic prostate cancer. miR338-3p was significantly down-regulated with disease progression from benign prostate tissue to primary and metastatic lesions. In localized disease, patients with lower miR338-3p expression levels showed increased association to biochemical recurrence and several adverse pathological parameters compared to patients with higher miRNA338-3p tissue expression levels. Using in vitro PCa cell models, overexpression of miR338-3p resulted in a decrease in cell invasion and expression of chemokine signalling genes CXCL12, CXCR4, and CXCR7. In vivo, orthotropic implantation of PC3 cells stably expressing miR338-3p was associated with a significant decrease in tumor weights compared to control cells. miR338-3p has anti-proliferative and anti-invasive properties. It affects CXCR4 axis, and its down-regulation is associated with adverse clinical outcomes in PCa patients.
微小RNA（miRNA）是一类小的非编码RNA，在基因表达的转录和转录后调控中发挥作用。几种miRNA已被证明与前列腺癌（PCa）进展相关。在ERG阳性的PCa中，miRNA调控网络失调的情况已有报道，ERG阳性的PCa约占PCa的50%，并被认为会影响肿瘤侵袭性。miR338 - 3p的功能、其预后意义及其与ERG阳性PCa的关系尚未得到充分研究。通过微阵列表达谱分析，我们确定miRNA338 - 3p是与PCa中ERG状态相关的失调最严重的miRNA之一。我们使用体外和体内实验模型研究了miR338 - 3p的功能，并在临床样本以及局部和转移性前列腺癌的公共队列中评估和验证了其表达。随着疾病从良性前列腺组织发展到原发性和转移性病变，miR338 - 3p显著下调。在局限性疾病中，与miRNA338 - 3p组织表达水平较高的患者相比，miR338 - 3p表达水平较低的患者生化复发及一些不良病理参数的相关性增加。使用体外PCa细胞模型，miR338 - 3p的过表达导致细胞侵袭以及趋化因子信号基因CXCL12、CXCR4和CXCR7的表达降低。在体内，与对照细胞相比，稳定表达miR338 - 3p的PC3细胞原位植入后肿瘤重量显著降低。miR338 - 3p具有抗增殖和抗侵袭特性。它影响CXCR4轴，其下调与PCa患者的不良临床结局相关。
