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      Downregulation of microRNA-23a suppresses prostate cancer metastasis by targeting the PAK6-LIMK1 signaling pathway

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          Abstract

          Here we found that levels of miR-23a were decreased in prostate cancer cell lines and tumor tissues. These low levels were associated with poor patients' prognosis. MiR-23a inhibited migration and invasion of prostate cancer in vivo and in orthotopic prostate cancer mice model. MiR-23a decreased levels of p21-activated kinase 6 (PAK6). Expression of miR-23a inhibited phosphorylation of LIM kinase 1 (LIMK1) and cofilin, in turn suppressing formation of stress fibers and actin filaments, which was required for cell motility and invasion. PAK6 bound to LIMK1 and activated it via phosphorylation at Thr-508. Also, PAK6 and LIMK1 were colocalized in the cytoplasma. Thus, miR-23a regulated cytoskeleton by affecting LIMK1 and cofilin. In summary, we have identified the miR-23a-PAK6-LIMK1 pathway of prostate cancer metastasis. Potential therapeutic approach by targeting miR-23 is suggested.

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          Tumor metastasis: molecular insights and evolving paradigms.

          Scott Valastyan, Robert A Weinberg (2011)
          Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting. Copyright © 2011 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 1423 times – based on 0 reviews     Review now
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            Functions of cofilin in cell locomotion and invasion.

            Jose Bravo-Cordero, Marco A O Magalhaes, Robert Eddy … (2013)
            Recently, a consensus has emerged that cofilin severing activity can generate free actin filament ends that are accessible for F-actin polymerization and depolymerization without changing the rate of G-actin association and dissociation at either filament end. The structural basis of actin filament severing by cofilin is now better understood. These results have been integrated with recently discovered mechanisms for cofilin activation in migrating cells, which led to new models for cofilin function that provide insights into how cofilin regulation determines the temporal and spatial control of cell behaviour.
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              The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2.

              Fang Zheng, Yi-Ji Liao, Mu-Yan Cai … (2012)
              Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-124) in hepatocellular carcinoma (HCC). To determine the status of miR-124 expression and its underlying mechanisms in the pathogenesis of HCC. The expression levels of miR-124 were first examined in HCC cell lines and tumour tissues by real-time PCR. The in vitro and in vivo functional effect of miR-124 was examined further. A luciferase reporter assay was conducted to confirm target associations. The expression levels of miR-124 were frequently reduced in HCC cells and tissues, and low-level expression of miR-124 was significantly associated with a more aggressive and/or poor prognostic phenotype of patients with HCC (p<0.05). In HCC cell lines, stable overexpression of miR-124 was sufficient to inhibit cell motility and invasion in vitro, and suppress intrahepatic and pulmonary metastasis in vivo. In addition, ectopic overexpression of miR-124 in HCC cells inhibited epithelial-mesenchymal cell transition, formation of stress fibres, filopodia and lamellipodia. Further studies showed that miR-124 could directly target the 3'-untranslated region (3'-UTR) of both ROCK2 and EZH2 mRNAs, and suppress their mRNA and protein expressions. These findings suggest that miR-124 plays a critical role in regulating cytoskeletal events and epithelial-mesenchymal cell transition and, ultimately, inhibits the invasive and/or metastatic potential of HCC, probably by its direct target on ROCK2 and EZH2 genes. These results provide functional and mechanistic links between the tumour suppressor miRNA-124 and the two oncogenes ROCK2 and EZH2 on the aggressive nature of HCC. These data highlight an important role for miR-124 in the regulation of invasion and metastasis in the molecular aetiology of HCC, and suggest a potential application of miR-124 in prognosis prediction and cancer treatment.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: February 2015
                Publication date (Electronic): 16 January 2015
                Volume: 6
                Issue: 6
                Pages: 3904-3917
                Affiliations
                1 Department of Cardiothoracic Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
                2 Department of Emergency, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
                3 Department of Health Care, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
                4 Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
                5 Department of Dermatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
                6 Department of Urology, Zhongshan People's Hospital, Zhongshan City, Guangdong, China
                7 Department of Urology, Qingyuan People's Hospital, Qingyuan City, Guangdong, China
                8 Department of Urology, Taishan People's Hospital, Taishan City, Guangdong, China
                9 Department of Urology, The First People's Hospital of Foshan City, Foshan City, Guangdong, China
                Author notes
                Correspondence to: Xingqiao Wen, wenxq@ 123456mail.sysu.edu.cn
                Article
                PMC ID: 4414162
                PubMed ID: 25714010
                SO-VID: e43ca774-914b-449b-ba3e-81ba1cc40d1e
                Copyright © Copyright: © 2015 Cai et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 12 August 2014
                Date accepted : 8 December 2014
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: microrna,mir23a,prostate cancer,metastasis,cytoskeleton
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: microrna, mir23a, prostate cancer, metastasis, cytoskeleton

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