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.

Abstract	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.
Authors	Shun-Fa Yang, Wei-Jiunn Lee, Peng Tan, Chih-Hsin Tang, Michael Hsiao, Feng-Koo Hsieh, Ming-Hsien Chien
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 5 Pg. 2736-53 (Feb 20 2015) ISSN: 1949-2553 [Electronic] United States
PMID	25605016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	3' Untranslated Regions Antineoplastic Agents MIRN328 microRNA, human MicroRNAs Stilbenes CREB-Binding Protein CREBBP protein, human JNK Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MMP2 protein, human Matrix Metalloproteinase 2 Resveratrol
Topics	3' Untranslated Regions Adult Animals Antineoplastic Agents (pharmacology) Binding Sites Bone Neoplasms (drug therapy, enzymology, genetics, pathology) CREB-Binding Protein (genetics, metabolism) Cell Line, Tumor Cell Movement (drug effects) Dose-Response Relationship, Drug Female Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans JNK Mitogen-Activated Protein Kinases (metabolism) Lung Neoplasms (enzymology, genetics, prevention & control, secondary) Male Matrix Metalloproteinase 2 (genetics, metabolism) Mice, SCID MicroRNAs (genetics, metabolism) Neoplasm Invasiveness Osteosarcoma (drug therapy, enzymology, genetics, secondary) Resveratrol Signal Transduction (drug effects) Stilbenes (pharmacology) Time Factors Transcription, Genetic Transfection Xenograft Model Antitumor Assays Young Adult p38 Mitogen-Activated Protein Kinases (metabolism)

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