Characterization of <scp>hERG1</scp> channel role in mouse colorectal carcinogenesis

Fiore, Antonella; Carraresi, Laura; Morabito, Angela; Polvani, S.; Fortunato, Angelo; Lastraioli, Elena; Femia, Angelo Pietro; Lorenzo, Emanuele De; Caderni, Giovanna

doi:10.1002/cam4.72

Cited by 23 publications

(21 citation statements)

References 47 publications

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“…As PDAC carcinogenesis progresses, as it occurs in KPC mice, mERG1 expression increases to reach high levels in adenocarcinomas of KPC mice. This not-obvious result is similar to what occurs in APC mice ( Fiore et al , 2013 ) which over-express mERG1 in the tumours they develop in the small and large intestine, and further stresses the relevance of hERG1 in tumour progression.…”

Section: Discussionsupporting

confidence: 78%

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

et al. 2015

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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 (α-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-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-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 α-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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Section: Discussionsupporting

confidence: 78%

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

et al. 2015

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“…The functional role of hERG1 channels in gastric cancer was analyzed in gastric cancer cell lines and we provided evidence that hERG1 regulates VEGF-A transcription and hence VEGF-A secretion in gastric cancer. Hence, hERG1 function in gastric cancer is similar to that discovered in brain tumors (10) and during mouse colorectal carcinogenesis (27). The regulation of VEGF-A secretion occurs exclusively in gastric cancer cells expressing hERG1 at high levels, a fact proven by both pharmacologic and biomolecular hERG1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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

Crociani

Lastraioli

Boni

et al. 2014

Clinical Cancer Research

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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. Ó2014 AACR.

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“…Several antiarrhythmic agents of the class III antiarrhythmics are known to block Kv11.1 channels. Anti-arrhythmic agents Way 123,398 and E4031 are selective blockers of Kv11.1 have been shown to impart therapeutic benefit in cancer as observed in various in vitro and pre-clinical models of cancer [ 135 , 142 , 143 ]. A major limitation that prevents the use of the Kv10.1 and Kv11.1 blockers in cancer is their adverse effects on cardiac physiology, resulting in prolonged QT intervals, which may further lead to fatal ventricular arrhythmias [ 144 ].…”

Section: Vgics As Therapeutic Targets For Cancermentioning

confidence: 99%

Voltage-Gated Ion Channels in Cancer Cell Proliferation

Rao¹,

Perez-Neut²,

Kaja³

et al. 2015

Cancers

175

160

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Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K+, Ca++, Cl−, Na+. Traditionally, voltage-gated ion channels (VGIC) are known to play fundamental roles in controlling rapid bioelectrical signaling including action potential and/or contraction. However, several investigations have revealed that these classes of proteins can also contribute significantly to cell mitotic biochemical signaling, cell cycle progression, as well as cell volume regulation. All these functions are critically important for cancer cell proliferation. Interestingly, a variety of distinct VGICs are expressed in different cancer cell types, including metastasis but not in the tissues from which these tumors were generated. Given the increasing evidence suggesting that VGIC play a major role in cancer cell biology, in this review we discuss the role of distinct VGIC in cancer cell proliferation and possible therapeutic potential of VIGC pharmacological manipulation.

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Characterization of hERG1 channel role in mouse colorectal carcinogenesis

Cited by 23 publications

References 47 publications

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

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

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

Voltage-Gated Ion Channels in Cancer Cell Proliferation

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