Dataset Information

Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5487320 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.

Wang Zaozao Z Yang Jie J Di Jiabo J Cui Ming M Xing Jiadi J Wu Fan F Wu Wei W Yang Hong H Zhang Chenghai C Yao Zhendan Z Zhang Nan N Jiang Beihai B Su Xiangqian X

Scientific reports 20170627 1

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 SMA ...[more]

PMID: 28655924

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Project description:BackgroundAccumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behaviors of HCC.MethodsEdU, Transwell and flow cytometry were used to determine proliferation, migration, invasion and apoptosis of HCC cells in vitro. The subcutaneous tumor model and lung metastasis mouse model in nude mice was established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-16-5p to 3'UTR of ANXA11 was confirmed by luciferase reporter assay. The expression of AGAP2-AS1 and miR-16-5p in HCC specimens and cell lines were detected by real-time PCR. The correlation among AGAP2-AS1 and miR-16-5p were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay.ResultsHere, we demonstrated that AGAP2-AS1 expression was up-regulated in HCC tissues and cell lines, especially in metastatic and recurrent cases. Gain- and loss-of-function experiments indicated that AGAP2-AS1 promoted cell proliferation, migration, invasion, EMT progression and inhibited apoptosis of HCC cells in vitro and in vivo. Further studies demonstrated that AGAP2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-16-5p in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-16-5p promoted HCC progression and alteration of miR-16-5p abolished the promotive effects of AGAP2-AS1 on HCC cells. Moreover, ANXA11 was identified as direct downstream targets of miR-16-5p in HCC cells, and mediated the functional effects of miR-16-5p and AGAP2-AS1 in HCC, resulting in AKT signaling activation. Clinically, AGAP2-AS1 and miR-16-5p expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the overexpression of AGAP2-AS1 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by AGAP2-AS1 knockdown.ConclusionsTaken together, this research supports the first evidence that AGAP2-AS1 plays an oncogenic role in HCC via AGAP2-AS1/miR-16-5p/ANXA11/AKT axis pathway and represents a promising therapeutic strategy for HCC patients.

Dataset Information

Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.

Publications

Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer.

Similar Datasets

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