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

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications / Crociani O; Lastraioli E; Boni L; Pillozzi S; Romoli MR; D'Amico M; Stefanini M; Crescioli S; Taddei A; Bencini L; Bernini M; Farsi M; Beghelli S; Scarpa A; Messerini L; Tomezzoli A; Vindigni C; Morgagni P; Saragoni L; Giommoni E; Gasperoni S; Di Costanzo F; Roviello F; De Manzoni G; Bechi P; Arcangeli A.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - (2014), pp. 1502-1512. [10.1158/1078-0432.CCR-13-2633]

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

CROCIANI, OLIVIA;LASTRAIOLI, ELENA;BONI, LUCA;PILLOZZI, SERENA;D'AMICO, MASSIMO;CRESCIOLI, SILVIA;TADDEI, ANTONIO;BERNINI, MARCO;MESSERINI, LUCA;BECHI, PAOLO;ARCANGELI, ANNAROSA
2014

Abstract

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
1502
1512
Crociani O; Lastraioli E; Boni L; Pillozzi S; Romoli MR; D'Amico M; Stefanini M; Crescioli S; Taddei A; Bencini L; Bernini M; Farsi M; Beghelli S; Scarpa A; Messerini L; Tomezzoli A; Vindigni C; Morgagni P; Saragoni L; Giommoni E; Gasperoni S; Di Costanzo F; Roviello F; De Manzoni G; Bechi P; Arcangeli A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/969321
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