The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells
The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells
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DOI：
10.3390/cells9020354
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发表时间：
2020-02-01
期刊：
影响因子：
6
通讯作者：
Rizzo, Milena
中科院分区：
文献类型：
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作者：
Fazio, Sofia;Berti, Gabriele;Rizzo, Milena
miR-28- 5 p在一些肿瘤组织中下调，其中已证明其具有肿瘤抑制（TS）活性。在这里，我们证明了miR-28- 5 p在前列腺癌（PCa）细胞中作为TS，影响细胞增殖/存活，以及迁移和侵袭。使用miRNA pull out分析和下一代测序，我们收集了miR-28- 5 p靶标的完整库，获得了191个mRNA的数据集（miR-28- 5 p targetome）。用TargetScan 7、PITA和RNA 22筛选靶组，我们发现61%的转录物具有miR-28- 5 p结合位点。为了给捕获的转录物分配功能值，我们将miR-28- 5 p靶点分组为具有注释功能的基因家族，并显示6个转录物属于转录因子类别。其中，我们选择了SREBF 2，一个在PCa中起重要作用的基因。我们验证了miR-28- 5 p/SREBF 2相互作用，证明SREBF 2抑制影响几乎所有由miR-28- 5 p再表达改变的肿瘤过程，表明SREBF 2是miR-28- 5 p TS活性的重要介导物。我们的研究结果支持将癌症相关miRNA的靶组鉴定为发现肿瘤发展的基础基因和途径以及抗肿瘤治疗的潜在新靶点的工具。
miR-28-5p is downregulated in some tumor tissues in which it has been demonstrated to have tumor suppressor (TS) activity. Here, we demonstrate that miR-28-5p acts as a TS in prostate cancer (PCa) cells affecting cell proliferation/survival, as well as migration and invasion. Using the miRNA pull out assay and next generation sequencing, we collected the complete repertoire of miR-28-5p targets, obtaining a data set (miR-28-5p targetome) of 191 mRNAs. Filtering the targetome with TargetScan 7, PITA and RNA22, we found that 61% of the transcripts had miR-28-5p binding sites. To assign a functional value to the captured transcripts, we grouped the miR-28-5p targets into gene families with annotated function and showed that six transcripts belong to the transcription factor category. Among them we selected SREBF2, a gene with an important role in PCa. We validated miR-28-5p/SREBF2 interaction, demonstrating that SREBF2 inhibition affects almost all the tumor processes altered by miR-28-5p re-expression, suggesting that SREBF2 is an important mediator of miR-28-5p TS activity. Our findings support the identification of the targetome of cancer-related miRNAs as a tool to discover genes and pathways fundamental for tumor development, and potential new targets for anti-tumor therapy.