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Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth.

ABSTRACT: Although the Mdm2/p53 interaction has been well documented, it is not clear whether there are new microRNAs participating in this regulatory network. Here, we provide evidence that miR-509-5p, which is downregulated in a subset of newly diagnosed cervical cancer and hepatocellular carcinoma tissues compared with the adjacent nontumor tissue, can be activated by p53 through binding the promoter of miR-509-5p and it suppresses the growth and invasion/migration of cervical cancer and hepatoma cells by regulating apoptosis and the G1/S-phase transition of cell cycle. Furthermore, Mdm2 was identified to be a target of miR-509-5p by targeting its 3'-UTR. Restoration of Mdm2 abrogated the cell phenotypes induced by miR-509-5p. Moreover, ectopic expression of miR-509-5p in HeLa and QGY-7703 cells repressed the expression of Mdm2, subsequently enhancing its p53-activating effects. These results suggest that miR-509-5p is a new regulator of Mdm2/p53 pathway and may play a key role in cancer development.

SUBMITTER: Ren ZJ

PROVIDER: S-EPMC4454302 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth.

Ren Z-J ZJ Nong X-Y XY Lv Y-R YR Sun H-H HH An P-P PP Wang F F Li X X Liu M M Tang H H

Cell death & disease 20140821

Although the Mdm2/p53 interaction has been well documented, it is not clear whether there are new microRNAs participating in this regulatory network. Here, we provide evidence that miR-509-5p, which is downregulated in a subset of newly diagnosed cervical cancer and hepatocellular carcinoma tissues compared with the adjacent nontumor tissue, can be activated by p53 through binding the promoter of miR-509-5p and it suppresses the growth and invasion/migration of cervical cancer and hepatoma cells ...[more]

PMID: 25144722

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Project description:BackgroundAngiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.MethodsThe expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .ResultsWe demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.ConclusionOur data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Project description:Background: Pancreatic cancer is a malignancy with poor prognosis. Importin 7 (IPO7) is a soluble nuclear transport factor, which has been linked to the pathogenesis of several human diseases. However, its role and underlying mechanism in pancreatic cancer are still obscure. Methods: Immunohistochemical staining and quantitative real-time polymerase chain reaction (qPCR) were performed to determine IPO7 expression in pancreatic cancer tissues and adjacent tissues. Western blot was used to measure IPO7 expression at the protein level in cell lines. Cell Counting Kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), flow cytometry, and Transwell assays were employed to explore the biological functions of IPO7. Subcutaneous xenograft transplanted tumor model and caudal vein injection model in mice were also established to validate the oncogenic role of IPO7. Western blot and qPCR were utilized to detect the regulatory function of IPO7 on p53 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), respectively. Interaction between MALAT1 and miR-129-5p and interaction between miR-129-5p and IPO7 were verified by bioinformatics prediction, qPCR, dual-luciferase reporter gene experiment, RNA immunoprecipitation (RIP), and pull-down assay. Results: Upregulation of IPO7 in pancreatic cancer tissues was associated with adverse prognosis of the patients with pancreatic cancer. Knocking down IPO7 remarkably suppressed cancer cell proliferation and metastasis, while it promoted apoptosis. Overexpression of IPO7 facilitated the malignant phenotypes of pancreatic cancer cells. Mechanistically, IPO7 could repress the expression of p53 and induce the expression of MALAT1 but reduce miR-129-5p expression. Furthermore, miR-129-5p was identified as a posttranscriptional regulator for IPO7, and its inhibition led to IPO7 overexpression in pancreatic cancer cells. Conclusion: IPO7 is a novel oncogene for pancreatic cancer, and IPO7/p53/MALAT1/miR-129-5p positive feedback loop facilitates the progression of this deadly disease.

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Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth.

Publications

Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth.

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