Role of enhanced bone morphogenetic protein-endothelial cell-precursor derived regulator in hepatocellular carcinoma

The role of bone morphogenic protein (BMP) signaling in hepatocellular carcinoma (HCC) is complex. BMPs have been shown to act as tumor-suppressors but also oncogenic factors. BMP endothelial cell-precursor derived regulator (BMPER) has been shown to act as extracellular regulator of different BMPs. Depending on its concentration and the cellular environment, BMPER can enhance or attenuate BMP signalling.

The aim of this study was to investigate the expression and function of BMPER in HCC.

Methods and results BMPER mRNA and protein are significantly increased in human HCC-cells compared to primary human hepatocytes. Furthermore, enhanced BMPER-expression in HCC-tissues correlates inversely with patients’ survival. Stimulation with low concentrations of recombinant BMPER-protein (rBMPER; 1ng/ml) had no or slightly enhancing effects on the expression of inhibitor of differentiation 1 and 3 (ID1, ID3), which are well-characterized read-outs for BMP-pathway activity. At higher concentrations, rBMPER dose-dependently downregulated ID1- and ID3-expression. In line with this, smad 1/5/8 phosphorylation was induced by stimulation with low but reduced with higher BMPER-doses. Interestingly, also ERK-phosphorylation was reduced after BMPER-stimulation. Furthermore, BMPER-treatment inhibited expression of Smad7, indicating additional indirect regulation of BMP signalling by BMPER.

Summary and conclusion We newly identified enhanced BMPER expression in HCC, and its correlation with pure patients survival suggest a pro-tumorigenic role in HCC. In vitro data indicate stimulatory as well as inhibitory effects of BMPER on BMP-activity in HCC-cells. Further analyses are need to reveal BMPER's molecular mechanisms of action and its functional relevance in HCC-development and -progression.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022