Prognostic role of hERG1 Potassium Channels in Neuroendocrine Tumours of the Ileum and Pancreas

Abstract

hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/β1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation.

Combination Therapy with a Bispecific Antibody Targeting the hERG1/β1 Integrin Complex and Gemcitabine in Pancreatic Ductal Adenocarcinoma

“…Furthermore, through IHC analysis, we provide evidence that a strong correlation exists between the expression of the hERG1 protein and the expression levels of the hERG1/β1 integrin complex. Applying the same antibodies to a smaller cohort of tissue samples, we also recently showed a good correlation between the co-expression of the two proteins in pancreatic neuroendocrine tumours [ 35 ]. The latter result is significant since it strengthens the case for the hERG1-β1 complex being a cancer-specific phenomenon, paving the way for clinical applications.…”

“…Cell viability was measured by the trypan blue (Sigma, Darmstad, Germany) exclusion test as in [ 35 ]. After incubation with the drug and the scDb-hERG1-β1 antibody, the trypan blue dye was added to the cells and live cells were counted using LUNA-II™ Automated Cell Counter (Logos Biosystems, Villeneuve d’Ascq France).…”

The role of potassium channels in tumours of the gastrointestinal tract: a focus on the human ether‐à‐go‐go related gene 1 channels

“…In normal pancreas hERG1 is absent in epithelial duct and acinar cells, while expressed at good levels in insulin secreting β-cells, where the channel is functional and negatively regulates cell firing and insulin secretion (Rosati et al, 2000). hERG1 expression is highly upregulated in human PCs, both the neuroendocrine (pNET) (Iorio et al, 2022) Figure 1. hERG1 expression in representative images of human oesophageal and gastric samples A, healthy oesophageal epithelium.…”

“…In normal pancreas hERG1 is absent in epithelial duct and acinar cells, while expressed at good levels in insulin secreting β‐cells, where the channel is functional and negatively regulates cell firing and insulin secretion (Rosati et al., 2000). hERG1 expression is highly upregulated in human PCs, both the neuroendocrine (pNET) (Iorio et al., 2022) and PDAC (Feng et al., 2014; Lastraioli, Perrone et al., 2015). In PDAC, hERG1 positivity occurs at high levels in roughly 60% of the samples and correlates with a high proliferation index, tumour grading and epidermal growth factor receptor (EGF‐R) expression (Lastraioli, Perrone et al., 2015).…”

“…Furthermore, hERG1 positivity represents an independent negative prognostic factor, in addition to the TNM tumour stage (Lastraioli, Perrone et al., 2015). In contrast, in pNETs hERG1 is mainly overexpressed in low grade and stage tumours, and represents a positive prognostic factor (Iorio et al., 2022). While hERG1 was not studied in human pancreatic preneoplastic lesions, the analysis conducted in KPC transgenic mice, a widely used model of PDAC, showed that the channel is expressed in PanIN, with expression scores increasing along with the progression from less to more severe lesions (Lastraioli, Perrone et al., 2015).…”