hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behaviour. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer (GC) is still lacking. Experimental design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected GC patients, by immunohistochemistry (IHC) and Real Time Quantitative- (RQ) PCR. The functional link between hERG1 and the Vascular Endothelial Growth Factor-A (VEGF-A) was studied in different GC cell lines. The effects of hERG1 and VEGF-A inhibition was evaluated in vivo in xenograft mouse models.

hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II TNM stage and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the Hypoxia Inducible Factor (HIF). Treatment of immunodeficient mice xenografted with human GC cells, with a combination of hERG1 blockers and anti VEGF-A antibodies, impaired tumor growth more than single drug treatments.

Our results show that hERG1 (i) is aberrantly expressed in human GC since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a GC patients' group where a combined treatment with anti-angiogenic drugs and non cardiotoxic hERG1 inhibitors could be proposed.