Abstract
Resistin is a recently discovered adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. Chondrosarcoma is a highly malignant tumor known to frequently metastasize; however, the role of resistin in the metastasis of human chondrosarcoma is largely unknown. Here, we found that the expression of resistin was higher in chondrosarcoma biopsy tissues than in normal cartilage. Moreover, treatment with resistin increased matrix metalloproteinase (MMP)-2 expression and promoted cell migration in human chondrosarcoma cells. Co-transfection with microRNA (miR)-519d mimic resulted in reversed resistin-mediated cell migration and MMP-2 expression. Additionally, AMP-activated protein kinase (AMPK) and p38 inhibitors or siRNAs reduced the resistin-increased cell migration and miR-519d suppression, and inhibition of resistin expression resulted in suppression of MMP-2 expression and lung metastasis in vivo. Taken together, our results indicate that resistin promotes chondrosarcoma metastasis and MMP-2 expression through activation of the AMPK/p38 signaling pathway and down-regulation of miR-519d expression. Therefore, resistin may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis.
Highlights
Chondrosarcoma is a cartilage forming neoplasm, and the second most common primary bone malignancy, representing approximately 40% of all primary bone cancers
Our results indicate that resistin promotes chondrosarcoma metastasis and matrix metalloproteinase (MMP)-2 expression through activation of the AMPK/p38 signaling pathway and down-regulation of miR-519d expression
We found that resistin increased the protein and mRNA expressions of MMP-2, as measured by western blot, zymography assay, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR) (Fig. 1C-E)
Summary
Chondrosarcoma is a cartilage forming neoplasm, and the second most common primary bone malignancy, representing approximately 40% of all primary bone cancers. Chondrosarcoma is resistant to both chemotherapy and radiation, and no specific standardized therapy has been developed for this malignancy, making wide local excision the only treatment option available [3]. Many studies have focused on developing new targeted therapies, which include targeting the hedgehog pathway, inhibition of B-cell lymphoma-2 expression, and inhibition of inflammation responses, among others. Inflammation has been demonstrated to play a pathogenic role in cancer [5]. Resistin expression has been found to gradually increase along with the progression of certain tumors, including breast, prostate, colon, gastric, and endometrial cancers [6, 7]. Previous studies have demonstrated that resistin is involved in the metastasis of breast and lung cancers [8, 9]; the role of resistin in chondrosarcoma is currently largely unknown
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