Bone morphogenetic protein 13 is expressed by activated hepatic stellate cells and promotes tumorigenicity of hepatocellular carcinoma

Activated hepatic stellate cells (HSC) play a key role in hepatic fibrosis, and herewith, build the soil for hepatocarcinogenesis. Furthermore, HSC are known to promote the progression of hepatocellular carcinoma (HCC) but the molecular mechanisms are only incompletely understood. Following activation, HSC produce bone morphogenetic proteins (BMPs) to support liver-regeneration and some BMP-family have been shown to affect also HCC-development and progression. So far, BMP13 has mostly been studied in the context of cartilage and bone repair.

The aim of this study was to analyze the expression and function of BMP13 HCC.

Methods and Results RT-qPCR and Westernblot analyses revealed high BMP13-expression in activated human HSC but not in human HCC-cell-lines. Furthermore, analysis of human HCC-tissues showed a significant correlation between BMP13 and alpha-smooth muscle actin (alpha-sma) and immunofluorescence staining confirmed co-localization of BMP13 and alpha-sma, indicating activated HSC as cellular source of BMP13 in HCC. Stimulation of HCC-cells with recombinant BMP13 dose-dependently increased expression of Inhibitor of Differentiation 1 (ID1), a known target of BMP-signaling and cell-cycle promotor. In line with this, BMP13-stimulation caused induced Smad 1,5,9-phosphorylation as well as reduced expression of cyclin-dependent kinases (CDKs) and increased proliferation and colony size formation of HCC-cells in clonogenicity assays. Interestingly, BMP13 also induced pro-tumorigenic ERK-activation, i. e. non-canonical BMP-signaling, in HCC-cells.

Summary and conclusion This study newly identified stroma-derived BMP13 as tumor promotor in HCC and indicates this secreted growth-factor as potential novel prognostic marker and therapeutic target in HCC.

Publication History

Article published online:
26 January 2022