RNA-Binding Protein Dnd1 Promotes Breast Cancer Apoptosis by Stabilizing the Bim mRNA in a miR-221 Binding Site.
RNA-Binding Protein Dnd1 Promotes Breast Cancer Apoptosis by Stabilizing the Bim mRNA in a miR-221 Binding Site.
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RNA结合蛋白DND1通过在miR-221结合位点稳定BIM mRNA来促进乳腺癌的凋亡。
DOI：
10.1155/2017/9596152
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发表时间：
2017
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Cheng F;Pan Y;Lu YM;Zhu L;Chen S
RNA结合蛋白（RBP）和miRNA能够控制正常发育和癌症的过程。这两种基因都可以决定RNA转录本从合成到降解的命运。其中一种RBP，死端（Dnd 1），对于调节生殖细胞活力和抑制生殖细胞肿瘤的发展至关重要，但它如何在乳腺癌中发挥作用仍然没有解决。采用qRT-PCR方法检测21例胃癌组织及癌旁正常组织中Dnd 1的表达水平。我们进一步注释了TCGA（The Cancer Genome Atlas）mRNA表达谱，发现Dnd 1和Bim的表达呈正相关（p = 0.04）。通过KM Plotter工具，Dnd 1表达水平较高的患者的总生存期较长（p = 0.0014）。在MCF-7细胞中敲低Dnd 1可降低Bim表达水平并抑制凋亡。敲低Dnd 1基因可促进Bim mRNA 3′UTR的降解，但不影响Bim-5′UTR的稳定性。此外，Bim-3′UTR中miR-221结合位点的突变可抵消Dnd 1对Bim mRNA表达的影响。在MCF-7细胞中敲低Dnd 1证实了Dnd 1拮抗miR-221对Bim表达的抑制作用。总之，我们的研究结果表明，Dnd 1通过与Bim-3′UTR中的miR-221竞争性结合，增加Bim的表达，从而促进细胞凋亡。Dnd 1的新功能可能有助于乳腺癌发展的重要作用。
RNA-binding proteins (RBPs) and miRNAs are capable of controlling processes in normal development and cancer. Both of them could determine RNA transcripts fate from synthesis to decay. One such RBP, Dead end (Dnd1), is essential for regulating germ-cell viability and suppresses the germ-cell tumors development, yet how it exerts its functions in breast cancer has remained unresolved. The level of Dnd1 was detected in 21 cancerous tissues paired with neighboring normal tissues by qRT-PCR. We further annotated TCGA (The Cancer Genome Atlas) mRNA expression profiles and found that the expression of Dnd1 and Bim is positively correlated (p = 0.04). Patients with higher Dnd1 expression level had longer overall survival (p = 0.0014) by KM Plotter tool. Dnd1 knockdown in MCF-7 cells decreased Bim expression levels and inhibited apoptosis. While knockdown of Dnd1 promoted the decay of Bim mRNA 3′UTR, the stability of Bim-5′UTR was not affected. In addition, mutation of miR-221-binding site in Bim-3′UTR canceled the effect of Dnd1 on Bim mRNA. Knockdown of Dnd1 in MCF-7 cells confirmed that Dnd1 antagonized miR-221-inhibitory effects on Bim expression. Overall, our findings indicate that Dnd1 facilitates apoptosis by increasing the expression of Bim via its competitive combining with miR-221 in Bim-3′UTR. The new function of Dnd1 may contribute to a vital role in breast cancer development.