F-45 Involvement of the potassium channel ERG1 in cholangiocarcinoma

Background and Aim: Due to the lack of proper biomarkers and potentially effective treatments, the management of cholangiocar- cinoma (CCA) is still challenging. Ion channels have been proven to be novel biomarkers and new targets for cancer therapy, due to their easy druggability. The voltage-gated K + channel hERG1 ex- erts pleiotropic effects in cancer cells. This study explored the role of hERG1 in the biology of intrahepatic CCA (iCCA). Methods: Validation of h ERG1 in iCCA tissues was performed in TCGA database. In vitro experiments were conducted to estimate the impact of h ERG1 inhibition on cell function in iCCA cell lines (HUCCT1, CCLP1, CCA4). Results: A significant difference in h ERG1 gene expression was observed between iCCA and normal tissue samples. Similarly, iCCA cell lines showed significantly higher protein content of hERG1 compared to normal cholangiocytes (NHC3). Treatment with E4031, a selective hERG1 inhibitor, showed a limited impact on cell growth, but a substantial reduction of the invasive capabilities of iCCA cells. Immunoprecipitation assays and immunofluorescence revealed the formation of an active macro- molecular complex with β1 integrin responsible for VEGF-A activation through AKT signaling. Treatment with a bispecific antibody (scDb: single-chain Diabody) that binds the hERG1- β1 complex, negatively impacted the invasiveness of iCCA cells as well as ex- pression of genes regulating epithelial to mesenchymal transition. In vitro co-treatment with scDb and cisplatin-gemcitabine, significantly reduced growth of iCCA cells. Conclusion: This study indicates that h ERG1 may be relevant in promoting the malignant characteristics of iCCA.