The tumor suppressive role of TIMP3 in the human osteosarcoma cells |
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| Institution: | 1. Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Japan;2. Department of Pharmacy, Saga University Hospital, Saga, Japan;3. Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe, Japan;4. Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan;1. The Department of Orthopaedic Surgery, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan;2. Emergency Medicine, Acute Critical Care Center, University of Miyazaki Hospital, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan;3. The Department of Orthopaedic Surgery, Miyazaki Prefectural Nobeoka Hospital, 2-1-10 Shinkouji, Nobeoka, 882-0835, Japan;4. The Department of Orthopaedic Surgery, Miyazaki Prefectural Nichinan Hospital, 1-9-5 Kiyama, Nichinan, 887-0013, Japan;1. Department of Paediatric Surgery, Tianjin Medical University General Hospital, 154 An-Shan Road, Heping District, Tianjin 300052, PR China;2. Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, PR China;1. Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, 2630, Sugitani, Toyama-City, Toyama, 930-0194, Japan;2. Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Japan;1. Department of Orthopaedic Surgery, Tohoku University School of Medicine, Japan;2. Department of Orthopaedic Surgery, Tohoku Medical and Pharmaceutical University School of Medicine, Japan |
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| Abstract: | BackgroundTissue inhibitor of metalloproteinase 3 (TIMP3) regulates a variety of cellular activities such as proliferation, viability, apoptosis, and motility. Functional loss of TIMP3 is reported in several human cancers. However, its role in osteosarcoma (OS) remains largely unclear.MethodsIn this study, we explored the mechanism underlying the modulation of TIMP3 in the growth and aggressiveness of U2OS and 143B human OS cells at both cellular and molecular levels.ResultsOur results show that overexpression of TIMP3 inhibits endogenous MMP activity and represses a series of oncogenic phenotypes of tumor cells independent of MMP inhibition, including reduced proliferation and survival, induced apoptosis, as well as improved sensitivity of tumor cells in response to cisplatin chemotherapy. TIMP3 overexpression also suppresses tumor cell invasion via its MMP inhibitory capacity. Importantly, TIMP3 modulates tumor cell oncogenesis via its induction of PTEN and subsequent inactivation of the PI3K/AKT pathway.ConclusionOur results suggest that TIMP3 is an oncosuppressor in human OS cells. Reactivation of TIMP3 function may be considered as a potential therapy for the treatment of this bone cancer. |
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