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

TL;DR

DEC2 is highly expressed in chondroblastic osteosarcoma and promotes tumor growth through the VEGFC/VEGFR2 signaling pathway, suggesting a potential new treatment target.

Contribution

DEC2's role in promoting chondroblastic osteosarcoma growth via VEGFC/VEGFR2 signaling is newly identified as a potential therapeutic target.

Findings

DEC2 is overexpressed in chondroblastic osteosarcoma compared to osteoblastic osteosarcoma.

DEC2 activates VEGFR2 signaling through two pathways, enhancing cell proliferation and reducing apoptosis.

Targeting DEC2 or VEGFC/VEGFR2 signaling could lead to new treatments for chondroblastic osteosarcoma.

Abstract

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 signalling pathway. Enhanced expression of DEC2 increased VEGFR2 expression, as well as increased the phosphorylation levels at sites Y951 and Y1175 of VEGFR2. On the one hand, activation of VEGFR2Y1175 enhanced cell proliferation through VEGFR2Y1175‐PLCγ1‐PKC‐SPHK‐MEK‐ERK signalling. On the other hand, activation of VEGFR2Y951 decreased mitochondria‐dependent apoptosis rate through VEGFR2Y951‐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 signalling pathway. These findings lay the groundwork for developing focused treatments that target specific types of OS.

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