Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (alpha-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre, LSL-Kras(G12D/+), LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled alpha-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the alpha-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma / Lastraioli, E; Perrone, G.; Sette, A.; Fiore, A.; Crociani, O.; Manoli, S.; D'Amico, M.; Masselli, M.; Iorio, J.; Callea, M.; Borzomati, D.; Nappo, G.; Bartolozzi, F.; Santini, D.; Bencini, L.; Farsi, M.; Boni, L.; Di Costanzo, F.; Schwab, A.; Onetti Muda, A.; Coppola, R.; Arcangeli, A.. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - ELETTRONICO. - 112:(2015), pp. 1076-1087. [10.1038/bjc.2015.28]

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

LASTRAIOLI, ELENA;SETTE, ANGELICA;FIORE, ANTONELLA;CROCIANI, OLIVIA;MANOLI, SAGAR SHASHIDHAR;D'AMICO, MASSIMO;MASSELLI, MARIKA;IORIO, JESSICA;BENCINI, LAPO;FARSI, MARCO;BONI, LUCA;DI COSTANZO, FRANCESCO;ARCANGELI, ANNAROSA
2015

Abstract

Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (alpha-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre, LSL-Kras(G12D/+), LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled alpha-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the alpha-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.
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1076
1087
Goal 3: Good health and well-being
Lastraioli, E; Perrone, G.; Sette, A.; Fiore, A.; Crociani, O.; Manoli, S.; D'Amico, M.; Masselli, M.; Iorio, J.; Callea, M.; Borzomati, D.; Nappo, G.; Bartolozzi, F.; Santini, D.; Bencini, L.; Farsi, M.; Boni, L.; Di Costanzo, F.; Schwab, A.; Onetti Muda, A.; Coppola, R.; Arcangeli, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1022648
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