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Negative regulation of miR-145 by C/EBP-? through the Akt pathway in cancer cells.

ABSTRACT: MicroRNAs are master gene regulators that can also be under the control of transcriptional regulation. We have previously shown that miR-145 is a tumor suppressor capable of silencing c-Myc and the tumor suppressor p53 induces miR-145 by directly binding to the miR-145 promoter, demonstrating the role of miR-145 in p53-mediated c-Myc repression. However, little is known as to why miR-145 is often downregulated in tumors. In this study, we identify CCAAT/enhancer binding protein beta (C/EBP-?) as a negative regulator for miR-145 expression by direct interaction with the putative C/EBP-? binding site in the miR-145 promoter. In the wild-type p53 background, C/EBP-? counteracts the ability of p53 to induce miR-145. Moreover, C/EBP-? is able to suppress miR-145 in the mutant p53 background, suggesting the p53 independent regulation of miR-145. Of interest, both the large isoform (LAP-2) and the small isoform (LIP) of C/EBP-? can exert suppressive function for miR-145. Finally, we further show that, like serum starvation and PI3K inhibitor LY29, the antioxidant resveratrol suppresses pAkt and phosphorylation of C/EBP-? and at the same time, it induces miR-145. Together, these results suggest a miR-145 regulatory system involving the Akt and C/EBP-?, which may contribute to the downregulation of miR-145 in cancer cells.

SUBMITTER: Sachdeva M

PROVIDER: S-EPMC3413133 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Negative regulation of miR-145 by C/EBP-β through the Akt pathway in cancer cells.

Sachdeva Mohit M Liu Qian Q Cao Julia J Lu Zhaohui Z Mo Yin-Yuan YY

Nucleic acids research 20120411 14

MicroRNAs are master gene regulators that can also be under the control of transcriptional regulation. We have previously shown that miR-145 is a tumor suppressor capable of silencing c-Myc and the tumor suppressor p53 induces miR-145 by directly binding to the miR-145 promoter, demonstrating the role of miR-145 in p53-mediated c-Myc repression. However, little is known as to why miR-145 is often downregulated in tumors. In this study, we identify CCAAT/enhancer binding protein beta (C/EBP-β) as ...[more]

PMID: 22495929

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Project description:BackgroundLong-non-coding RNA PVT1 (lncRNA PVT1) can be used as an oncogenic regulatory non-coding RNA (ncRNA) for many cancers. However, its function and mechanism in breast cancer (BRCA) are still not clearly elucidated.ObjectiveWe attempt to explain the mechanism of PVT1's role in breast cancer from different perspectives.MethodsWe analyzed the expression of PVT1 and its correlation with the breast cancer related clinical data in the The Cancer Genome Atlas (TCGA) database. We used PVT1 overexpression and knockdown lentivirus to infect breast cancer MDA-MB-231 cell line for cell function verification, in vitro using CCK-8 to measure proliferation, flow cytometry to measure apoptosis, transwell test to measure invasion and migration ability, detecting cell extracellular acidification rate (ECAR) to assess glycolysis metabolism and explore the biological functions of PVT1 in breast cancer cells. Transcriptome sequencing was used to analyze the changes of related genes in cells after overexpression of PVT1. In vivo we used a xenograft model to study the effect of PVT1 on breast cancer.ResultsPVT1 was up-regulated in breast cancer tissues and was positively correlated with the clinical stage of breast cancer patients. Overexpression of PVT1 in vitro promoted cell proliferation, migration and invasion, and promoted tumor growth in vivo. Knockdown of PVT1 led to the opposite biological consequence. Further bioinformatics analysis showed that PVT1 changes the glycolysis metabolism of tumors through regulation of glycolysis-related genes. In addition, the expression of miR-145-5p is negatively correlated with PVT1. We consider the possibility of PVT1 promoting cell proliferation and metastasis by regulating the aerobic glucose metabolism in breast cancer cells through sponging the miR-145-5p.ConclusionOur results reveal a potential pathway for competing endogenous RNA to regulate breast cancer glucose metabolism. PVT1 regulates glycolysis related genes expression by competitively binding to endogenous miR-145-5p in breast cancer cells to change the metabolic phenotype. This may Provide new ideas for precise molecular therapy targets for breast cancer.

Dataset Information

Negative regulation of miR-145 by C/EBP-? through the Akt pathway in cancer cells.

Publications

Negative regulation of miR-145 by C/EBP-β through the Akt pathway in cancer cells.

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