Augmenter of Liver Regeneration has a potential role in tumour resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the fourth leading cause of cancer-related death worldwide. In most cases, HCC is only diagnosed at a later stage when surgical resection is no longer feasible and the only treatment possible is chemotherapy. Although chemotherapeutical agents are widely used in the attempt to treat HCC, new approaches need to be considered as tumours can be resistant to chemotherapy. A key protein in liver regeneration known as the Augmenter of Liver Regeneration (ALR) is known to be highly expressed in certain forms of HCC and previous investigations showed that ALR has anti-apoptotic properties. This study aimed to characterise whether ALR could be a therapeutical target towards a treatment against HCC. BEL7402, a HCC cell line, has been genetically modified in order to overexpress ALR. The BEL7402-ALR cells along with a mock transfected cell line (control) were treated with 15 ug/ml cisplatin. Following cisplatin treatment for 24h, BEL7402-ALR showed a significant decrease in caspase 3 activity (88.2+/-5.4 ugAMC.min-1.g-1protein) compared to the control (142.1+/-12.5 ugAMC.min-1.g-1protein). To determine the molecular mechanism by which ALR can prevent tumour cells from undergoing apoptosis, western blot analysis were performed following 3h treatment of cells with cisplatin. The results demonstrated that an increase by 2 folds in the phosphorylation status of AKT was observed in BEL7402-ALR compared to the control. However, the phosphorylation of ERK1/2 did not show any significant changes between the BEL7402-ALR and control. Thus, ALR is able to prevent apoptosis through the activation of AKT, which promotes cell survival. The difficulty in treating certain HCC tumours could therefore be explained by high expression levels of ALR, which will prevent tumour cell death following chemotherapeutical treatment. Therefore, in the future, ALR could be seen as the next therapeutical target for the treatment of HCC.