Effect And Mechanism Of Leptin And SIRT1 Promoting Osteosarcoma Cell Proliferation, Metastasis

Objective:Osteosarcoma(OS) is a malignant tumor of mesenchymal origin with high metastatic potential at early disease stage. Despite major advances have been made in the therapeutic approaches, the overall 5-year survival rate for the OS patients remains only 20%, making it urgent for discovery of more molecules that can provide mechanistic clues, prognostic values, or therapeutic potential.Leptin and the downstream protein Sirutin-1(SIRT1) have recently been evidenced to be up-regulated in breast, prostate, colon, and other tissue cancers, and their expression levels are correlated with proliferation and metastasis in the pathology of these tumor tissues. This prompted us to find whether these two proteins are similarly altered in OS tumors and possibly account for the malignancy of this type of cancer. Methods:Leptin and SIRT1 were determined by immunohistochemical staining on the paraffinized tissue sections from each patient, and the correlation between their expression levels and the pathological grade and the patient’s survival rate was statistically analyzed.The functional study of Leptin and SIRT1 was performed in the human osteosarcoma MG-63 cells, including the cellular proliferation, metastasis and protein expression by MTT, Scratch-wound and Transwell assays, and Western blotting. Results:Expression of Leptin and SIRT1 was increased in OS tissue, and was correlated with tumor distant metastasis and Enneking stage in pathology. Patients with higher expression of these two proteins generally had shorter survival duration, regardless of whether they receivedneoadjuvant chemotherapies or not.Leptin overexpression promoted angiogenesis in MG-63 osteosarcoma cells by upregulating the expression of VEGF. It also enhanced proliferation, inhibited apoptosis, and promoted adhesion and invasion of osteosarcoma cells.SIRT1 overexpression also stimulated angiogenesis, survival, and invasion through VEGF signaling pathway, possibly via increased expression of MMP2, MMP8 and MMP9.Leptin induced the upregulated expression of SIRT1 in osteosarcoma cells, and inhibition of SIRT1 can abolishedLeptin’stumor-promoting effect on proliferation and metastasis. Conclusions:Expression of Leptin and SIRT1 was upregulated in OS tissues.High expression of Leptin and SIRT1 in OS tissues correlates with aggressive tumor pathology including proliferation and metastasis, and predicts poor patient survival.Leptin has a tumor-promoting effect in cultured osteosarcoma cells, and this effect is through regulation of SIRT1, VEGF, MMP proteins.In this study, we examined the expression of Leptin and SIRT1 in OS tumor tissues, and found their positive correlation with its malignancy. We further demonstrated that these two proteins had tumor-promoting effect in the cultured human osteosarcoma cell system, and investigated the potential mechanistic proteins involved in this effect. Our study has revealed that proteins Leptin and SIRT1 are potentially involved as novel players in the pathogenesis of human OS tumor, and their pathway might be considered for therapeutic intervention to treat this challenging disease.