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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Shun-Fa Yang1,2,*, Wei-Jiunn Lee3,*, Peng Tan4, Chih-Hsin Tang5, Michael Hsiao6, Feng-Koo Hsieh7 and Ming-Hsien Chien4,8
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
* These authors contributed equally to this work
Ming-Hsien Chien, email:
Keywords: osteosarcoma, miR-328, CREB, MMP-2, resveratrol, metastasis
Received: October 20, 2014 Accepted: December 25, 2014 Published: December 30, 2014
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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