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


METHODS
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.


CONCLUSIONS
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.
Authors' 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, Forlì, Italy.
Olivia
O
Crociani
Elena
E
Lastraioli
Luca
L
Boni
Serena
S
Pillozzi
Maria Raffaella
MR
Romoli
Massimo
M
D'Amico
Matteo
M
Stefanini
Silvia
S
Crescioli
Alessio
A
Masi
Antonio
A
Taddei
Lapo
L
Bencini
Marco
M
Bernini
Marco
M
Farsi
Stefania
S
Beghelli
Aldo
A
Scarpa
Luca
L
Messerini
Anna
A
Tomezzoli
Carla
C
Vindigni
Paolo
P
Morgagni
Luca
L
Saragoni
Elisa
E
Giommoni
Silvia
S
Gasperoni
Francesco
F
Di Costanzo
Franco
F
Roviello
Giovanni
G
De Manzoni
Paolo
P
Bechi
Annarosa
A
Arcangeli
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D000072237:ERG1 Potassium Channel; D004797:Enzyme-Linked Immunosorbent Assay; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A