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      Upregulation of miR-328 and inhibition of CREB-DNA-binding activity are critical for resveratrol-mediated suppression of matrix metalloproteinase-2 and subsequent metastatic ability in human osteosarcomas


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          Osteosarcomas, the most common malignant bone tumors, show a potent capacity for local invasion and pulmonary metastasis. Resveratrol (RESV), a phytochemical, exhibits multiple tumor-suppressing activities and has been tested in clinical trials. However, the antitumor activities of RESV in osteosarcomas are not yet completely defined. In osteosarcoma cells, we found that RESV inhibited the migration/invasion in vitro and lung metastasis in vivo by suppressing matrix metalloproteinase (MMP)-2. We identified that RESV exhibited a transcriptional inhibitory effect on MMP-2 through reducing CREB-DNA-binding activity. Moreover, a microRNA (miR) analysis showed that miR-328 was predominantly upregulated after RESV treatment. Inhibition of miR-328 significantly relieved MMP-2 and motility suppression imposed by RESV treatment. Furthermore, ectopic miR-328 expression in highly invasive cells decreased MMP-2 expression and invasive abilities. Mechanistic investigations found that JNK and p38 MAPK signaling pathways were involved in RESV-regulated CREB-DNA-binding activity, miR328 expression, and cell motility. Clinical samples indicated inverse expression between MMP-2 and miR-328 in normal bone and osteosarcoma tissues. The inverse correlation of MMP-2 and miR-328 was also observed in tumor specimens, and MMP-2 expression was linked to tumor metastasis. Taken together, our results provide new insights into the role of RESV-induced molecular and epigenetic regulation in suppressing tumor metastasis.

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          Most cited references39

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          Targeting microRNAs in cancer: rationale, strategies and challenges.

          MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.
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            Molecular mechanisms of glioma invasiveness: the role of proteases.

            Jasti Rao (2003)
            The invasive nature of brain-tumour cells makes an important contribution to the ineffectiveness of current treatment modalities, as the remaining tumour cells inevitably infiltrate the surrounding normal brain tissue, which leads to tumour recurrence. Such local invasion remains an important cause of mortality and underscores the need to understand in more detail the mechanisms of tumour invasiveness. Several proteases influence the malignant characteristics of gliomas--could their inhibition prove to be a useful therapeutic strategy?
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              CREB is a regulatory target for the protein kinase Akt/PKB.

              The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. Recent studies showing that CREB and its paralog CREM are required for survival of certain cell types prompted us to examine whether CREB is a nuclear target for activation via the growth factor-dependent Ser/Thr kinase Akt/PKB. When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. Akt/PKB induced CREB activity only in response to serum stimulation, and this effect was suppressed by the phosphatidylinositol 3-kinase inhibitor LY 294002. Our results support the notion that Akt/PKB promotes cell survival, at least in part, by stimulating the expression of cellular genes via the CREB/CBP nuclear transduction pathway.

                Author and article information

                Impact Journals LLC
                February 2015
                30 December 2014
                : 6
                : 5
                : 2736-2753
                1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
                2 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
                3 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
                4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                5 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
                6 The Genomics Research Center, Academia Sinica, Taipei, Taiwan
                7 Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians University, Munich, Germany
                8 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
                Author notes
                Correspondence to: Ming-Hsien Chien, mhchien1976@ 123456gmail.com
                Copyright: © 2015 Yang et al.

                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.

                : 20 October 2014
                : 25 December 2014
                Research Paper

                Oncology & Radiotherapy
                Oncology & Radiotherapy
                osteosarcoma, mir-328, creb, mmp-2, resveratrol, metastasis


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