Role of ganglioside GD2 in the stem-like compartment of intrahepatic cholangiocarcinoma

Background and Aims Due to the lack of proper biomarkers and potentially effective treatments, the management of cholangiocarcinoma (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 exerts pleiotropic effects in cancer cells. This study explored the role of hERG1 in the biology of intrahepatic CCA (iCCA). Method Validation of hERG1 in iCCA tissues was performed in TCGA database. In vitro experiments were conducted to estimate the impact of hERG1 inhibition on cell function in iCCA cell lines (HUCCT1, CCLP1, CCA4). Results A significant difference in hERG1 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 macromolecular 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 expression 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 hERG1 may be relevant in promoting the malignant characteristics of iCCA.