High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and young adults. Account for 80% of all OS cases, conventional OS are characterized by the presence of osteoblastic, chondroblastic and fibroblastic cell types. Despite this heterogeneity, therapeutic treatment and prognosis of OS are essentially the same for all OS subtypes. Here, we report that DEC2, a transcriptional repressor, is expressed at higher levels in chondroblastic OS compared with osteoblastic OS. This difference suggests that DEC2 is disproportionately involved in the progression of chondroblastic OS, and thus, DEC2 may represent a possible molecular target for treating this type of OS. In the human chondroblastic-like OS cell line MNNG/HOS, we found that overexpression of DEC2 affects the proliferation of the cells by activating the VEGFC/VEGFR2/KDR/Flk-1 signalling pathway. Enhanced expression of DEC2 increased VEGFR2/KDR/Flk-1 expression, as well as increased the phosphorylation levels at sites Y951 and Y1175 of VEGFR2/KDR/Flk-1. On the one hand, activation of VEGFR2/KDR/Flk-1_Y1175 enhanced cell proliferation through VEGFR2/KDR/Flk-1_Y1175-PLCγ1-PKC-SPHK-MEK-ERK signalling. On the Other hand, activation of VEGFR2/KDR/Flk-1_Y951 decreased mitochondria-dependent Apoptosis rate through VEGFR2/KDR/Flk-1_Y951-VARP-PI3K-AKT signalling. Activation of these two signalling pathways resulted in enhanced progression of chondroblastic OS. In conclusion, DEC2 plays a pivotal role in cell proliferation and apoptosis-resistance in chondroblastic OS via the VEGFC/VEGFR2/KDR/Flk-1 signalling pathway. These findings lay the groundwork for developing focused treatments that target specific types of OS.

Chondroblastic osteosarcoma; DEC2; VEGF signalling; phosphorylation.