Abstract
Over the last two decades, there have been no significant changes in patient outcomes in relation to the treatment of osteosarcoma, an aggressive malignant neoplasm. It is known that vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and in osteosarcoma. Moreover, VEGF-A expression correlates with clinical stages of osteosarcoma. The adipokine resistin exhibits proinflammatory, proangiogenic and metastatic properties, and evidence suggests that resistin may serve as a prognostic biomarker linking obesity and inflammation to cancer. However, whether resistin has a role in osteosarcoma angiogenesis is unclear. This investigation shows that resistin promotes VEGF-A expression in human osteosarcoma cells and activates the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 signaling pathways, while ERK, JNK, and p38 inhibitors or their small interfering RNAs (siRNAs) inhibit resistin-induced VEGF-A expression as well as endothelial progenitor cell (EPC) migration and tube formation. We also found that resistin upregulates VEGF-A expression by enhancing activation of the transcription factor nuclear factor-kappa B (NF-κB). Finally, resistin promotes angiogenesis in the chick chorioallantoic membrane (CAM) model. Resistin appears to be a promising target for human osteosarcoma.
Highlights
Osteosarcoma accounts for 30–80% of primary skeletal sarcomas and is well-recognized for its high metastatic rates, which are believed to underline the poor survival rates in this disease
When we examined resistin expression profiles in human osteosarcoma tissue specimens, we found that higher resistin expression significantly correlated with increasing tumor stage (Figure 1A)
endothelial progenitor cell (EPC) migration and tube formation, which were induced by treatment with the indicated inhibitors or small interfering RNAs (siRNAs)-treated culture medium (CM), was abolished (Figure 3C and 3D). These results indicate that resistin promotes vascular endothelial growth factor-A (VEGF-A) expression in osteosarcoma cells and contributes to angiogenesis by activating the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 pathways
Summary
Osteosarcoma accounts for 30–80% of primary skeletal sarcomas and is well-recognized for its high metastatic rates, which are believed to underline the poor survival rates in this disease. Lung metastases are found in approximately 20% of patients at initial diagnosis; around 40% of patients develop metastases at a later stage [1]. Following the development of metastases, osteosarcoma has a 5-year survival rate of 20% [2]. Angiogenesis is key to the development of osteosarcoma, its subsequent progression and metastasis [3, 4]. Results from using differential co-expression network, finding angiogenesis is closely related to osteosarcoma progression and metastasis [5]. Antiangiogenic therapy might be feasible for osteosarcoma patients [6]
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