Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.
Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.
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下调的USP3 mRNA通过海绵miR-224作为SMAD4的竞争性内源RNA发挥作用并促进结直肠癌的转移
DOI：
10.1038/s41598-017-04368-3
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发表时间：
2017-06-27
影响因子：
4.6
通讯作者：
Su X
中科院分区：
文献类型：
--
作者：
Wang Z;Yang J;Di J;Cui M;Xing J;Wu F;Wu W;Yang H;Zhang C;Yao Z;Zhang N;Jiang B;Su X
越来越多的证据表明，竞争性内源性RNA（ceRNA）可以通过螯合常见的microRNA（miRNAs）影响其他转录物的表达，从而参与肿瘤的发生。SMAD 4是结直肠癌（CRC）中一种有效的肿瘤抑制因子，受多种miRNAs调控。然而，SMAD 4通过ceRNA的调节从未被研究过。在本研究中，我们发现USP 3以miRNA依赖性和蛋白质编码基因非依赖性的方式调节SMAD 4的表达。miR-224可直接靶向USP 3和SMAD 4，过表达USP 3 3 3′UTR可抑制USP 3缺失引起的转移。在结直肠癌标本中进一步验证了USP 3、SMAD 4和miR-224表达的相关性。此外，USP 3的丢失与远端转移和预后不良相关。总之，我们的研究证明USP 3是真正的SMAD 4 ceRNA。这项研究的结果可能为CRC的预防和治疗提供新的见解。
Increasing evidence shows that competitive endogenous RNAs (ceRNAs) can affect the expression of other transcripts by sequestering common microRNAs (miRNAs), and participate in tumourigenesis. As a potent tumour suppressor in colorectal cancer (CRC), SMAD4 is regulated by many miRNAs. However, the regulation of SMAD4 by ceRNAs has never been examined. In the present study, we found that USP3 modulated SMAD4 expression in a miRNA dependent, and protein-coding gene independent manner. USP3 and SMAD4 were directly targeted by miR-224, and overexpression of the USP3 3′UTR could inhibit metastasis caused by the loss of USP3. The correlation of USP3, SMAD4 and miR-224 expression was further verified in CRC specimens. Additionally, the loss of USP3 was associated with distal metastasis and a poor prognosis. Altogether, our study demonstrates USP3 as a bona fide SMAD4 ceRNA. The results from this study may provide new insights into the prevention and treatment of CRC.