Osteosarcoma is a highly aggressive malignant tumor of the bone that affects adolescents and young adults. Despite aggressive chemotherapy and wide resection of the tumor, many patients eventually develop pulmonary metastasis and succumb to their disease. The majority of patients with this bone tumor may harbor ‘‘micrometastases’’ at the time of diagnosis, and many develop multidrug resistance during treatment. It is difficult to improve current response rates and overcome drug resistance with dose escalation because of the associated cytotoxic effects on normal tissues and organs. In this regard, dietary supplements and phytotherapeutic agents with a high anticancer efficacy and lower toxicity to normal tissues are possible candidates to be investigated for their synergistic efficacy in combination with anticancer drugs. Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, and has been tested in clinical trials. However, the therapeutic effects of resveratrol on the invasion and metastasis of osteosarcoma and the underlying mechanisms of these effects have not yet been studied. Preliminary studies found that resveratrol at non-toxic concentrations for osteosarcoma cells can induce actin cytoskeletal rearrangement and significantly suppress the migration and invasion abilities of cells. Resveratrol also inhibits the activities of extracellular matrix (ECM)-degrading enzymes, such as matrix metalloproteinase-2, 9 (MMP-2, 9) and plasminogen activator (PA), at the same concentrations. In addition, microRNA microarray data show that a group of microRNAs is upregulated or downregulated after resveratrol treatment in osteosarcoma cells; these microRNAs modulate some genes (e.g., MMP-2 and MMP-9) that regulate cell invasion and metastasis. This study presents the molecular mechanisms involved in the resveratrol-suppressed invasion of osteosarcoma cells, including several target microRNAs of resveratrol in cancer cells, and uses in vitro and in vivo models to investigate the role of these microRNAs in resveratrol-regulated cell invasion and metastasis, respectively. This study also presents the clinical correlation between these microRNAs and their target genes in tumor specimens from osteosarcoma patients. The results of this study may yield new insights into the role of resveratrol in tumor metastasis treatment, providing novel therapeutic avenues for bone cancer.
|Effective start/end date||8/1/15 → 7/31/16|