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Clin Cancer Res. 2014 Mar 15;20(6):1502-12. doi: 10.1158/1078-0432.CCR-13-2633. Epub 2014 Jan 21.

hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications.

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  • 1Authors' Affiliations: Department of Clinical and Experimental Medicine; Surgery and Translational Medicine, University of Florence; Clinical Trials Coordinating Center; General Surgery and Surgical Oncology; Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence; Department of Pathology and Diagnostics, Division of Surgery, University of Verona; Pathology Division, Borgo Trento Hospital, Verona; Pathology Division, Azienda Ospedaliero-Universitaria Senese, Department of General Surgery and Oncology, University of Siena, Siena; and General Surgery and Division of Pathology, Morgagni-Pierantoni Hospital, Forl√¨, Italy.

Erratum in

  • Clin Cancer Res. 2014 May 1;20(9):2501. Masi, Alessio [added].
  • Clin Cancer Res. 2014 Aug 1;20(15):4168-9.

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.

PMID:
24449824
DOI:
10.1158/1078-0432.CCR-13-2633
[PubMed - indexed for MEDLINE]
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