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Abstract

Hepatocellular carcinoma (HCC) is a complex disease with a poor prognosis which has increased the survival rates on account to the improvement in patient stratification and the introduction of new targeted therapies. However, there is still an urgent need for early diagnostic markers and personalized treatments in order to enhance the survival and reduce HCC´s recurrence. BAMBI, a transmembrane glycoprotein that regulates several biological activities through TGF-β signalling inhibition, was shown to have increased expression levels in colorectal, gastric and ovarian cancers where it correlated with metastasis, invasion and poor prognosis. Although in HCC BAMBI was reported to be upregulated, no molecular and functional studies were done so far to unravel its participation in hepatocarcinogenesis. Our meta-analysis in publicly available HCC data cohorts confirmed BAMBI overexpression in 78% of HCC patients (n=803) being upregulated and also present in cirrhotic samples and the tumour stroma. Further, BAMBI expression was also confirmed in MDR2-KO and DEN mice. Parallel to these results, the immunohistochemical (IHC) staining of a human HCC tissue microarray revealed the upregulation in 76% of patients with positive staining for BAMBI in the surrounding tissues. In HCC cell lines, BAMBI expression appeared only in the cells that present early TGF-β signature (Hep3B, HepG2 and HUH7), which corresponds to an epithelial phenotype and less aggressiveness. BAMBI knockdown in Hep3B cells produced a strong TGF-β-mediated apoptosis and reduced cell proliferation. In less differentiated HLE cells with low intrinsic BAMBI expression, BAMBI overexpression enhanced proliferation, migration and invasion in vitro. Immunoblot assays additionally show BAMBI expression dependent modulation of ERK1/2, NFκB, Wnt/β-catenin, AKT and JNK/p38 MAPK pathways. In conclusion, we report that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is upregulated in livers of HCC patients and differently expressed in HCC cell models. High BAMBI expression is blocking TGFβ-mediated apoptosis and increases proliferation in epithelial HCC cells, and reduces proliferation, migration and invasion with impact on Wnt/β-catenin, ERK1/2, AKT, NFκB and JNK/p38 MAPK pathways in mesenchymal HCC. The activation of these functions depends on the TGF-β signature stage and cell context. We postulate BAMBI as a potential target in personalized therapies for human hepatocellular carcinoma.