The 3'UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1
The 3'UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1
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DOI：
10.1007/s10549-015-3298-2
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发表时间：
2015-02-01
影响因子：
3.8
通讯作者：
Xi, Tao
中科院分区：
文献类型：
--
作者：
Zheng, Lufeng;Li, Xiaoman;Xi, Tao
现在已知假基因调节它们的蛋白质编码对应物。此外，3 'UTR的紊乱可能通过作为基因表达的调节剂而增加癌症易感性的风险。本研究旨在探讨假基因CYP 4 Z2 P-3 'UTR和功能基因CYP 4 Z1 - 3' UTR在乳腺癌血管生成过程中的作用。通过qRT-PCR在与非癌样品配对的22个癌组织中测量CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR以及感兴趣的miRNA的水平。通过体外和离体过表达和RNA干扰方法研究了CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR的影响。通过生物信息学分析、荧光素酶测定和蛋白质印迹分析，获得了对竞争性内源RNA的机制的见解。通过qRT-PCR分析和双变量相关性分析确定预测的miRNA与CYP 4 Z2 P/CYP 4 Z1的正相互作用和与CYP 4 Z2 P或CYP 4 Z1的负相互作用。CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR共享几个miRNA结合位点，包括miR-211、miR-125 a-3 p、miR-197、miR-1226和miR-204。CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR阻止了这些miRNA引起的干扰，导致CYP 4 Z1的翻译增加。此外，CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR的异位表达通过诱导ERK 1/2和PI 3 K/Akt的磷酸化而共同在乳腺癌中表现出肿瘤血管生成促进特性。与Dicer siRNA共转染逆转了CYP 4 Z2 P 3 'UTR介导的变化。此外，PI 3 K或ERK抑制剂逆转了CYP 4 Z2 P和CYP 4 Z1 - 3 'UTR介导的VEGF-A表达变化。CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR表达增加促进乳腺癌中肿瘤血管生成，部分通过miRNA依赖性激活PI 3 K/Akt和ERK 1/2。因此，CYP 4 Z2 P-和CYP 4 Z1 - 3 'UTR可用作组合miRNA抑制剂。
Pseudogenes are now known to regulate their protein-coding counterparts. Additionally, disturbances of 3'UTRs could increase the risk of cancer susceptibility by acting as modulators of gene expression. The aim of this study was to investigate the roles of the pseudogene CYP4Z2P-3'UTR and functional gene CYP4Z1-3'UTR in breast cancer angiogenesis process. The levels of CYP4Z2P- and CYP4Z1-3'UTR and miRNA of interests were measured in 22 cancerous tissues paired with non-cancerous samples by qRT-PCR. The effects of CYP4Z2P- and CYP4Z1-3'UTR were studied by overexpression and RNA interference approaches in vitro and ex vivo. Insights of the mechanism of competitive endogenous RNAs were gained from bioinformatic analysis, luciferase assays, and western blot. The positive CYP4Z2P/CYP4Z1 interaction and negative interaction between predicted miRNAs and CYP4Z2P or CYP4Z1 were identified via qRT-PCR assay and bivariate correlation analysis. CYP4Z2P- and CYP4Z1-3'UTR share several miRNA-binding sites, including miR-211, miR-125a-3p, miR-197, miR-1226, and miR-204. The CYP4Z2P- and CYP4Z1-3'UTRs arrest the interference caused by of these miRNAs, resulting in increased translation of CYP4Z1. Moreover, ectopic expression of the CYP4Z2P- and CYP4Z1-3'UTRs exhibit tumor angiogenesis-promoting properties in breast cancer collectively by inducing the phosphorylation of ERK1/2 and PI3K/Akt. Co-transfection with Dicer siRNA reversed the CYP4Z2P 3'UTR-mediated changes. Additionally, PI3K or ERK inhibitors reversed CYP4Z2P- and CYP4Z1-3'UTR-mediated changes in VEGF-A expression. Increased CYP4Z2P- and CYP4Z1-3'UTR expression promotes tumor angiogenesis in breast cancer partly via miRNA-dependent activation of PI3K/Akt and ERK1/2. The CYP4Z2P- and CYP4Z1-3'UTRs could thus be used as combinatorial miRNA inhibitors.