XIAP 3'-untranslated region as a ceRNA promotes FSCN1 function in inducing the progression of breast cancer by binding endogenous miR-29a-5p.
XIAP 3'-untranslated region as a ceRNA promotes FSCN1 function in inducing the progression of breast cancer by binding endogenous miR-29a-5p.
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DOI：
10.18632/oncotarget.15159
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发表时间：
2017-03-07
期刊：
影响因子：
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通讯作者：
Wu ZS
中科院分区：
文献类型：
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作者：
Wu Q;Yan H;Tao SQ;Wang XN;Mou L;Chen P;Cheng XW;Wu WY;Wu ZS
基因的非编码3‘非翻译区(UTR)可以结合和失活多个miRNAs，在microRNA(MiRNA)功能的调节中起着重要作用。在此，我们报道了XIAP 3‘非编码区的异位表达促进了人乳腺癌细胞的增殖、集落形成、迁移、侵袭和异种移植瘤的生长，并抑制了肿瘤细胞的死亡。为了研究这一过程，我们进一步将全基因组转录图谱与XIAP 3‘非编码区在MCF-7细胞中的基因表达变化相关联。我们发现了一种强大的、全基因组的细胞迁移、运动和上皮向间充质转化的机制，通过这种机制，先前描述的细胞成分运动因子FSCN1介导了细胞迁移、运动和上皮向间充质转化。XIAP 3‘非编码区在体内外均协同上调XIAP和FSCN1的表达。XIAP和FSCN1之间的相互作用似乎是这些过程的关键决定因素。与DICER siRNA共转染可逆转XIAP 3‘非编码区介导的致瘤性，提示miRNAs可能参与了该过程。此外，我们还证明了一种miRNA miR-29a-5p可以与XIAP和FSCN1 3‘UTRs结合，并在相互作用中发挥重要作用。我们发现XIAP的3‘非编码区能够拮抗miR-29a-5p，并导致XIAP和FSCN1的翻译增加。因此，我们的发现揭示了对XIAP 3‘UTR如何工作的重要新见解，表明非编码的XIAP 3’UTR是miRNA结合的竞争对手，从而使miRNA功能失活，从而使XIAP 3‘UTR从抑制中解放出来。
The non-coding 3′-untranslated region (UTR) of genes play an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Herein, we report that ectopic expression of XIAP 3′UTR increased human breast cancer cells proliferation, colony formation, migration, invasion and xenograft tumor growth and suppressed tumor cell death. To investigate this process, we further correlated the genome-wide transcriptional profiling with the gene expression alterations after transfecting XIAP 3′UTR in MCF-7 cells. We identified a robust, genome-wide mechanism of cell migration, motility and epithelial to mesenchymal transition by which mediated by a previously described cellular component movement factor FSCN1. Expression of XIAP and FSCN1 were up-regulated synergistically after transfecting XIAP 3′UTR in vitro and in vivo. Interactions between XIAP and FSCN1 appear to be a key determinant of these processes. Co-transfection with Dicer siRNA reversed the XIAP 3′UTR-mediated oncogenicity, suggesting the miRNAs might be involved in that process. Furthermore, we demonstrated that one miRNA, miR-29a-5p, can bind to both the XIAP and FSCN1 3′UTRs and play an important role in that interactions. We showed that the 3′UTR of XIAP was able to antagonize miR-29a-5p, and resulted in the increased translation of XIAP and FSCN1. Thus, our findings reveal important new insights into how XIAP 3′UTR works, suggesting that the non-coding XIAP 3′UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by which XIAP 3′UTR frees the target mRNAs from being repressed.