Bone Morphogenetic Protein (BMP)-9: a hepatic cytokine with potentially tumour-suppressive function in hepatocellular carcinoma (HCC)

Introduction BMP-9 is a hepatic cytokine belonging to the TGF-β superfamily. Recent studies have shown that the role of BMP-9 in HCC is rather controversial. BMP-9 was described to promote cell proliferation and epithelial-to-mesenchymal transition (EMT) in some studies, whereas in others it acted anti-proliferative and decreased mesenchymal markers in HCC cells. It seems that BMP-9 can be both, a pro- as well as anti-fibrogenic factor and it can act pro- or anti-proliferative on cancer cells. HCC is still the third leading cause of cancer death worldwide and new therapeutic targets to improve therapeutic strategies are urgently needed. Aim of this study was therefore to better understand BMP-9 signalling in HCC.

Methods Public databases such as The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas (TCPA) were used to extensively analyse available expression data for BMP-9 signalling pathway components. Cellular responses upon BMP-9 stimulation were determined in two human HCC cell lines (HLE and Hep3B) by Western blot, real-time PCR, proliferation- and wound closure assays. Freshly collected samples from 6 HCC patients were additionally analysed for validation of the in silico findings.

Results In silico analyses show that Alk1 is significantly upregulated in HCC patient samples and that presence of Alk1 is associated with attributes of cancer progression. In line with this, BMP-9 induced proliferation, migration and EMT in HLE cells, which display high levels of Alk1. This was inversed after knocking-down Alk1. In epithelial Hep3B cells with low Alk1 expression BMP-9 reduced proliferation and induced anti-tumorigenice expression signatures. This was inverted by Alk1-overexpression. In human liver Alk1 is highly expressed on sinusoidal endothelial cells and Kupffer cells/macrophages but not hepatocytes (HC). In healthy HC BMP-9 therefore signals via alternative type I receptors, like Alk2, and mediates maintenance of a differentiated, non-proliferative cellular phenotype via activation of the Smad-1 pathway. In HCC cells with high Alk1 (like HLE) BMP-9 does not efficiently activate the Smad-1 pathway anymore and ID1 induction is strongly dampened. It seems that in such cancer cells Alk1 acts like a ligand trap, preventing the anti-cancerous BMP-9 signalling via Alk2.

Conclusion In conclusion, BMP-9 targeted therapy acting via specific blockage of the BMP-9/Alk1 interaction but leaving BMP-9/Alk2 signalling intact, could be a promising new approach to treat HCC patients.

Publikationsverlauf

Artikel online veröffentlicht:
19. August 2022