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hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications
- Publication Year :
- 2014
-
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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....0b7b0449e7466873277e6fddf6e95ce6