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      LncRNA LUCAT1/miR-181a-5p axis promotes proliferation and invasion of breast cancer via targeting KLF6 and KLF15

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          Abstract

          Background

          Long non-coding RNAs (lncRNAs) are novel regulatory molecules in breast cancer development. LncRNA LUCAT1 is a potential tumor promoter in human cancers. In this study, we aimed to explore the role of LUCAT1 in human breast cancer tissues and cells.

          Methods

          A total of 31 breast cancer patients who underwent tumor resection, but without chemo- or radiotherapy or acute lung/heart/kidney diseases, provided tumor and adjacent normal tissues. Bioinformatic analysis, qRT-PCR, and luciferase reporter assay were carried out during the study.

          Results

          qRT-PCR analysis indicated that, compared with the adjacent tissues and MCF-10A normal breast epithelial cells, LUCAT1 was markedly up-regulated in the breast cancer tissues and five BC cell lines, including MDA-MB-231, MDA-MB-468, MDA-MB-435, SKBR3, and MCF-7. The knockdown of LUCAT1, through the transfection of small interfering RNA (siRNA) specific to LUCAT1, resulted in inhibition of proliferation in breast cancer cells. The expression levels of miR-181a-5p were decreased in the breast cancer tissues and five BC cell lines. Bioinformatic analysis and luciferase reporter assay suggested the interaction between miR-181a-5p and LUCAT1. In addition, the effects of LUCAT1 on promoting cell proliferation were attenuated by overexpression of miR-181a-5p through the transfection of miR-181a-5p mimic. Moreover, bioinformatics and luciferase reporter assay confirmed that miR-181a-5p targeted the 3′-UTR region of KLF6 and KLF15 mRNA, which were two tumor suppressor genes. LUCAT1/miR-181a-5p axis regulated the expression of KLF6 and KLF15 both in vitro and in vivo.

          Conclusions

          Our data indicate that LUCAT1/miR-181a-5p axis can serve as a novel therapeutic target in breast cancer.

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          Most cited references14

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          Time to Surgery and Breast Cancer Survival in the United States.

          Time to surgery (TTS) is of concern to patients and clinicians, but controversy surrounds its effect on breast cancer survival. There remains little national data evaluating the association.
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            Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells.

            MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression with functional links to tumorigenesis. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and it is heterogeneous in clinical outcomes and biological activities. Recently, we have identified a subset of highly invasive epithelial cell adhesion molecule (EpCAM)(+) HCC cells from alpha-fetoprotein (AFP)(+) tumors with cancer stem/progenitor cell features, that is, the abilities to self-renew, differentiate, and initiate aggressive tumors in vivo. Here, using a global microarray-based miRNA profiling approach followed by validation with quantitative reverse transcription polymerase chain reaction, we have demonstrated that conserved miR-181 family members were up-regulated in EpCAM(+)AFP(+) HCCs and in EpCAM(+) HCC cells isolated from AFP(+) tumors. Moreover, miR-181 family members were highly expressed in embryonic livers and in isolated hepatic stem cells. Importantly, inhibition of miR-181 led to a reduction in EpCAM(+) HCC cell quantity and tumor initiating ability, whereas exogenous miR-181 expression in HCC cells resulted in an enrichment of EpCAM(+) HCC cells. We have found that miR-181 could directly target hepatic transcriptional regulators of differentiation (for example, caudal type homeobox transcription factor 2 [CDX2] and GATA binding protein 6 [GATA6]) and an inhibitor of Wnt/beta-catenin signaling (nemo-like kinase [NLK]). Taken together, our results define a novel regulatory link between miR-181s and human EpCAM(+) liver cancer stem/progenitor cells and imply that molecular targeting of miR-181 may eradicate HCC.
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              MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes.

              GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3'UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.
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                Author and article information

                Contributors
                gcwaziablx4@163.com
                Journal
                BMC Mol Cell Biol
                BMC Mol Cell Biol
                BMC Molecular and Cell Biology
                BioMed Central (London )
                2661-8850
                30 September 2020
                30 September 2020
                2020
                : 21
                : 69
                Affiliations
                [1 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of ENT, Tongji Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan City, Hubei Province 430030 PR China
                [2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Breast and Thyroid surgery, Division of General Surgery, Tongji Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; No. 1095, Jiefang Avenue, Qiaokou District, Wuhan City, Hubei Province 430030 PR China
                Article
                310
                10.1186/s12860-020-00310-0
                7525994
                32998707
                b86a3bba-d8a0-4b44-a443-a5ac5959e62b
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 16 December 2019
                : 31 August 2020
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                lucat1,mir-181a-5p,breast cancer,klf6,klf15
                lucat1, mir-181a-5p, breast cancer, klf6, klf15

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