Augmenter of Liver Regeneration inhibits angiogenesis and invasiveness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant disorders, and in some parts of the world represents the most important neoplastic cause of death. In general, HCC represents a hypervascularized cancer and its progression depends on different factors like angiogenesis and invasiveness. Several studies showed that the transcription factor Hypoxia-Inducible Factor 1-alpha plays a central role in HCC progression, angiogenesis and neovascularization. Hif-1 alpha can directly activate the expression of different pro-angiogenic factors like VEGF, VEGFR and angiopoietins. Furthermore, we have shown that Augmenter of Liver Regeneration (ALR), a hepatotrophic factor with specific liver regeneration enhancing effects, is induced in cirrotic livers and hepatocellular carcinoma. The goal of our study was to find out whether ALR modulate the tumor angiogenesis and invasiveness. Using immunohistochemistry technique, we have shown that the invasiveness of HCC in patients was inversely correlated with ALR expression. Performing Western Blot analysis, using WT and ALR-stable transfected HepG2 cells, we found that Hif1-alpha protein expression was significantly reduced in the ALR-stable transfected cells comparing to the mock control. Migration assays with modified Boyden chambers, we demonstrated that the over-expression of ALR in HepG2 cells inhibits the cancer cell motility (3,3±1,29 cells/hpf) compared to the mock control (15,5±3,85 cells/hpf). Based on these results we hypothesize that ALR might interfere with angiogenesis- and invasiveness-related pathways in hepatocellular carcinomas. Here we show for the first time that increased levels of ALR might have the potential to reduce metastasis diminishing migratory and invasive properties of HCC cells.

Augmenter of Liver Regeneration - HCC - Hif-1alpha - angiogenesis - hypoxia-inducible factor - invasiveness - metastasis