DEC2 expression is positively correlated with HIF-1 activation and the invasiveness of human osteosarcomas

Background: osteosarcoma is the most common malignancy of bone. hif-1 (hypoxia-inducible factor 1) activation is critical for the metabolic reprogramming and progression of solid tumors,and dec2 (differentiated embryonic chondrocyte gene 2) has been recently reported to suppress hif-1 in human breast and endometrial cancers. however,the roles of hif-1 and dec2 in human osteosarcomas remain unclear. methods: we evaluated the correlation of dec2 and hif-1 expression to the prognosis,and studied the roles of dec2 and hif-1 activation in the invasiveness of osteosarcoma. multiple approaches including immunohistochemical staining of clinical osteosarcoma tissues,sirna-based knockdown and other molecular biology techniques were used. particularly,by using a repetitive trans-well culture-based in vitro evolution system,we selected a more invasive subpopulation (u2os-m) of osteosarcoma cells from u2os and used it as a model to study the roles of dec2 and hif-1 in the invasiveness of osteosarcoma. results: we found that the expression of dec2 was positively correlated with hif-1α levels,and hif-1α expression positively correlated with poor prognosis in osteosarcomas. dec2 knockdown in osteosarcoma cell lines (u2os,mnng and 143b) attenuated hif-1α accumulation and impaired the up-regulation of hif-1 target genes in response to hypoxia. compared with the low invasive parental u2os,u2os-m showed higher levels of dec2 expression which were confirmed at both mrna and protein levels. importantly,we found that the increased dec2 expression resulted in a more rapid accumulation of hif-1α in u2os-m cells in response to hypoxia. finally,we found that hif-1 activation is sufficient to upregulate dec2 expression in osteosarcoma cells. conclusion: taken together,whereas dec2 was found to promote hif-1α degradation in other types of tumors,our data indicate that dec2 facilitates hif-1α stabilization and promotes hif-1 activation in osteosarcoma. this implies that dec2 may contribute to the progression and metastasis of human osteosarcoma by sensitizing tumor cells to hypoxia. on the other hand,hif-1 activation may contribute to the expression of dec2 in osteosarcoma. this is the first demonstration of a novel dec2-hif-1 vicious cycle in osteosarcoma and a tumor-type specific role for dec2. © 2015 hu et al.; licensee biomed central.