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

ABSTRACT

Potassium channels are often dysregulated in tumours of the gastrointestinal (GI) tract. Among them, the voltage-dependent channel KV 11.1, also known as human ether-à-go-go related gene 1 (hERG1), is frequently expressed in tumours and precancerous lesions of the GI tract. In precancerous lesions, hERG1 behaves as a progression factor, contributing to identifying those patients whose lesions can progress towards true cancers. In advanced cancers, such as colorectal and pancreatic cancer, a high hERG1 expression represents a negative prognostic factor, contributing to identifying high risk patients. The only exception is represented by neuroendocrine cancers of both the ileum and the pancreas, where hERG1 represents a positive prognostic factor for survival. In GI tumours, hERG1 can function either as a true channel, allowing outward potassium ion flux and membrane repolarisation, or in a non-canonical, non-conductive way. This occurs because, in cancer, hERG1 forms complexes with different plasma membrane and cytosolic proteins, instead of classical accessory subunits. In particular, hERG1 forms a complex with the ß1 subunit of integrin receptors the hERG1-ß1 complex. Growth and chemokine receptors, small GTPases, phosphoinositide 3-kinase, as well as other ion transporters or channels, are also recruited in the hERG1-ß1 complex. The formation of multiprotein channel complexes represents an emerging mechanism allowing functional channel networking in both excitable and non-excitable cells. hERG1 represents a prototype of how multiprotein complexes operate in tumours, that is, giving rise to signalling hubs which can transmit and modulate signals arising from the tumour microenvironment, hence contributing to tumour progression and malignancy.