C/EBPα Mediated Transcriptional Regulation of Human ADAMTS-3 Gene and Collagen Expression in Osteosarcoma Cells

Abstract

ADAMTS-3 is a procollagen amino proteinase mainly expressed in type II collagen-rich tissues and its primary function is to maturate amino ends of the type II collagen precursors. This maturation process allows correct fibril formation. ADAMTS-3 also has a tumor-suppressive function by regulating the fibronectin expression in the ECM. C/EBPα is a transcription factor playing a pivotal role in the cell cycle regulation. Dysregulations in the C/EBPα expression have been reported in solid tumors. C/EBPα expression has been identified to be associated with the metabolism and prognosis of a malignant bone tumor, osteosarcoma (OS). High heterogeneity, metastasis capability, and recurrence lead to poor prognosis and survival rates in OS. Multiple genetic and epigenetic factors affect OS development. Alterations in the ECM elements are closely related to OS development and progression. According to the in-silico analyses, the ADAMTS-3 promoter includes multiple C/EBPα binding sites suggesting that C/EBPα could have a regulatory effect on ADAMTS-3 transcriptional regulation. In the present study, over-expression of the C/EBPα decreased ADAMTS-3 mRNA and protein levels in Saos-2 and MG-63 osteosarcoma models. Ectopic expression of the C/EBPα also led to alterations in some fibrillar collagen expression levels. Enhanced C/EBPα levels resulted in an increase in the type I and II collagen expression levels but didn’t change the type III collagen expression level in Saos-2 cells.