title: 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.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Peng
authors.initials: P
authors.lastname: Tan
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Feng-Koo
authors.initials: FK
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C548170:MIRN328 microRNA, human; D035683:MicroRNAs; D013267:Stilbenes; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D000077185:Resveratrol