vtRNA2-1/nc886 Produces a Small RNA That Contributes to Its Tumor Suppression Action through the microRNA Pathway in Prostate Cancer
vtRNA2-1/nc886 Produces a Small RNA That Contributes to Its Tumor Suppression Action through the microRNA Pathway in Prostate Cancer
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DOI：
10.3390/ncrna6010007
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发表时间：
2020-03-01
期刊：
影响因子：
4.3
通讯作者：
Duhagon, Maria Ana
中科院分区：
文献类型：
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作者：
Fort, Rafael Sebastian;Garat, Beatriz;Duhagon, Maria Ana
vtRNA 2 -1是一种穹窿状RNA，最初被分类为microRNA前体hsa-mir-886，最近被提出为“nc 886”，一种参与癌症进展的新型非编码RNA，在不同组织中作为癌基因和肿瘤抑制基因发挥作用。我们已经证明，vtRNA 2 -1/nc 886在肿瘤细胞中受到表观遗传学抑制，增加了前列腺组织中的细胞增殖和侵袭。在此，我们研究了vtRNA 2 -1/nc 886在前列腺细胞中产生小RNA的能力及其生物学效应。对前列腺和其他组织的公共小RNA转录组的研究发现了两种小RNA，snc 886 - 3 p和snc 886 - 5 p，它们来源于vtRNA 2 -1/nc 886（以前称为hsa-miR-886- 3 p和hsa-miR-886- 5 p）。PAR-CLIP的重新分析和microRNA生物合成酶数据的敲除表明，这些小RNA是DICER的产物，不依赖于DROSHA，并且与Argonaute蛋白缔合，满足microRNA属性。此外，snc 886 - 3 p的过表达引起在其30-UTR中具有与其“种子”互补的序列的mRNA的下调。DU 145、LNCaP和PC 3细胞系中的微阵列和体外功能测定显示，snc 886 - 3 p与其前体vtRNA 2 -1/nc 886一样，减少细胞周期进展并增加细胞凋亡。最后，我们在PRAD-TCGA数据中发现了一系列snc 886 - 3 p上调的直接候选靶基因，这些基因与疾病状况和进展相关。总之，我们的研究结果表明，vtRNA 2 -1/nc 886及其加工产物snc 886 - 3 p在前列腺细胞中合成，发挥肿瘤抑制作用。
vtRNA2-1 is a vault RNA initially classified as microRNA precursor hsa-mir-886 and recently proposed as "nc886", a new type of non-coding RNA involved in cancer progression acting as an oncogene and tumor suppressor gene in different tissues. We have shown that vtRNA2-1/nc886 is epigenetically repressed in neoplastic cells, increasing cell proliferation and invasion in prostate tissue. Here we investigate the ability of vtRNA2-1/nc886 to produce small-RNAs and their biological e ffect in prostate cells. The interrogation of public small-RNA transcriptomes of prostate and other tissues uncovered two small RNAs, snc886-3p and snc886-5p, derived from vtRNA2-1/nc886 (previously hsa-miR-886-3p and hsa-miR-886-5p). Re-analysis of PAR-CLIP and knockout of microRNA biogenesis enzymes data showed that these small RNAs are products of DICER, independent of DROSHA, and associate with Argonaute proteins, satisfying microRNA attributes. In addition, the overexpression of snc886-3p provokes the downregulation of mRNAs bearing sequences complementary to its "seed" in their 30-UTRs. Microarray and in vitro functional assays in DU145, LNCaP and PC3 cell lines revealed that snc886-3p reduced cell cycle progression and increases apoptosis, like its precursor vtRNA2-1/nc886. Finally, we found a list of direct candidate targets genes of snc886-3p upregulated and associated with disease condition and progression in PRAD-TCGA data. Overall, our findings suggest that vtRNA2-1/nc886 and its processed product snc886-3p are synthesized in prostate cells, exerting a tumor suppressor action.