1. hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications
- Author
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Olivia, Crociani, Elena, Lastraioli, Luca, Boni, Serena, Pillozzi, Maria Raffaella, Romoli, Massimo, D'Amico, Matteo, Stefanini, Silvia, Crescioli, Alessio, Masi, Antonio, Taddei, Lapo, Bencini, Marco, Bernini, Marco, Farsi, Stefania, Beghelli, Aldo, Scarpa, Luca, Messerini, Anna, Tomezzoli, Carla, Vindigni, Paolo, Morgagni, Luca, Saragoni, Elisa, Giommoni, Silvia, Gasperoni, Francesco, Di Costanzo, Franco, Roviello, Giovanni, De Manzoni, Paolo, Bechi, and Annarosa, Arcangeli
- Subjects
hERG1 Channels ,VEGF-A Secretion ,GASTRIC CANCER ,Vascular Endothelial Growth Factor A ,ERG1 Potassium Channel ,Pathology ,medicine.medical_specialty ,Cancer Research ,Nude ,Mice, Nude ,Enzyme-Linked Immunosorbent Assay ,Biology ,Adenocarcinoma ,bevacizumab ,Real-Time Polymerase Chain Reaction ,Transfection ,Cell Line ,1 [2 (6 methyl 2 pyridyl)ethyl] 4 (4 methylsulfonylaminobenzoyl)piperidine ,Mice ,In vivo ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Secretion ,Grading (tumors) ,Ether-A-Go-Go Potassium Channels ,Heterografts ,Immunohistochemistry ,Reverse Transcriptase Polymerase Chain Reaction ,Oncology ,Medicine (all) ,Tumor ,bevacizumab, potassium channel HERG, potassium channel HERG1, unclassified drug, vasculotropin A ,medicine.disease ,potassium channel HERG1 ,potassium channel HERG ,unclassified drug ,Vascular endothelial growth factor A ,Real-time polymerase chain reaction ,vasculotropin A ,Cancer cell ,Cancer research - Abstract
Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: 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 tumor—node—metastasis 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. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. Clin Cancer Res; 20(6); 1502–12. ©2014 AACR.
- Published
- 2014