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      The roles of microRNAs in the regulation of tumor metastasis

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          Abstract

          MicroRNAs (miRNAs) are small noncoding regulatory RNAs that regulate gene expression post-transcriptionally by either inhibiting protein translation or degrading target mRNAs. The differential expression profiles of miRNAs in different types of cancers and in the multi-step process of tumor progression indicate that miRNAs are involved in tumor onset, growth and progression. Metastasis is the most common cause of cancer-related mortality. Current evidence demonstrates that aberrant miRNA expression promotes or inhibits tumor metastasis by modulating the expression of numerous target genes. Therefore, the identification of metastasis-related miRNAs and a better understanding of the complex functions of miRNAs in tumor metastasis will provide potential diagnostic and prognostic biomarkers, as well as therapeutic targets for clinical application. Here, we review the functions of miRNAs in the control of multiple steps of tumor metastasis.

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          MicroRNA control of signal transduction.

          MicroRNAs (miRNAs) are integral elements in the post-transcriptional control of gene expression. After the identification of hundreds of miRNAs, the challenge is now to understand their specific biological function. Signalling pathways are ideal candidates for miRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Indeed, emerging evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-beta, WNT, Notch and epidermal growth factor. As such, miRNAs serve as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.
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            MicroRNA silencing for cancer therapy targeted to the tumor microenvironment

            SUMMARY PARAGRAPH MicroRNAs (miRNAs) are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, miRNAs are critical cogs in numerous biological processes 1,2 , and dysregulated miRNA expression is correlated with many human diseases. Certain miRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumors that depend on these miRNAs are said to display oncomiR addiction 3–5 . Some of the most effective anticancer therapies target oncogenes like EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (i.e. antimiRs) is an evolving therapeutic strategy 6,7 . However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells 8 . Here we introduce a novel antimiR delivery platform that targets the acidic tumor microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We found that the attachment of peptide nucleic acid (PNA) antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produced a novel construct that could target the tumor microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumors (pH ~6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new paradigm in the use of antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
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              MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.

              MicroRNAs (miRNAs) are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level. Our previous studies suggest that mir-21 functions as an oncogene and has a role in tumorigenesis, in part through regulation of the tumor suppressor gene tropomyosin 1 (TPM1). Given that TPM1 has been implicated in cell migration, in this study we further investigated the role of mir-21 in cell invasion and tumor metastasis. We found that suppression of mir-21 in metastatic breast cancer MDA-MB-231 cells significantly reduced invasion and lung metastasis. Consistent with this, ectopic expression of TPM1 remarkably reduced cell invasion. Furthermore, we identified two additional direct mir-21 targets, programmed cell death 4 (PDCD4) and maspin, both of which have been implicated in invasion and metastasis. Like TPM1, PDCD4 and maspin also reduced invasiveness of MDA-MB-231 cells. Finally, the expression of PDCD4 and maspin inversely correlated with mir-21 expression in human breast tumor specimens, indicating the potential regulation of PDCD4 and maspin by mir-21 in these tumors. Taken together, the results suggest that, as an oncogenic miRNA, mir-21 has a role not only in tumor growth but also in invasion and tumor metastasis by targeting multiple tumor/metastasis suppressor genes. Therefore, suppression of mir-21 may provide a novel approach for the treatment of advanced cancers.
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                Author and article information

                Contributors
                zhoulei@njmu.edu.cn
                liufan@xmu.edu.cn
                wxm@xmzsh.com
                oygldz@xmu.edu.cn
                Journal
                Cell Biosci
                Cell Biosci
                Cell & Bioscience
                BioMed Central (London )
                2045-3701
                20 June 2015
                20 June 2015
                2015
                : 5
                : 32
                Affiliations
                [ ]Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Medical College, Xiamen University, Xiamen, 361004 China
                [ ]Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 China
                [ ]Medical College, Xiamen University, Xiamen, 361102 China
                [ ]State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 China
                Article
                28
                10.1186/s13578-015-0028-8
                4491246
                26146543
                af5a7319-40a3-4d9d-b653-e08f67025126
                © Zhou et al. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

                History
                : 9 May 2015
                : 14 June 2015
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Cell biology
                microrna,cancer,metastasis,epithelial-mesenchymal transition,cancer stem cell
                Cell biology
                microrna, cancer, metastasis, epithelial-mesenchymal transition, cancer stem cell

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