The oncogenic potential of human ether-a-go-go-related gene (hERG) potassium channels

Human ether-a-go-go-related gene product (hERG) is a potassium channel found ubiquitously in embryonic tissue, but only in key excitable tissues in the adult. hERG is expressed in many tumours of different histological origin, and is not found in the healthy tissues from which the tumour originates. The related EAG channel has been shown to possess oncogenic potential. Having investigated the effect of stable, recombinant hERG expression in NIH-3T3 and HEK293 cell-lines, it was found that there was not significant difference in the proliferative rate or serum-dependency of growth at physiological hERG expression levels, compared to mock-transfected cells. However, hERG expression increased the ability of confluent cells to overgrow each other resulting in a significant increase in post-confluent cell density compared with wild-type cells. In contrast to the parental cell-line, hERG-expressing NIH-3T3 cells grew in soft agar, and exhibited increased rates of cell migration. hERG-mediated transformation appeared to be cell density-dependent, with effects on cell shape and cytoskeletal organization only being seen in confluent cultures. None of the effects of hERG expression were affected by the presence of hERG channel-blocking compounds, or co-expression of non-conducting, dominant-negative hERG subunits. However, hERG-mediated overgrowth seemed to be dependent on p38 MAPK, protein kinase C, phosphoinositide 3-kinase and Src signalling, and independent of MEK/ERK signalling. In addition, hERG expression permitted Src-independent cell proliferation not seen in control cell-lines.;In summary, stable expression of hERG results in NIH-3T3 and HEK293 cell-lines exhibiting some of the characteristics of a transformed phenotype. Pharmacological and molecular biological evidence suggests that this effect on cell phenotype is not dependent on a functional channel current. Instead, the hERG channel protein may interact with protein components of key cell signalling pathways, in a similar fashion to the protein-protein interactions observed for the EAG channel.