HERG ENCODES A K- A SELECTIVE ADVANTAGE FOR CANCER-CELLS( CURRENT HIGHLY CONSERVED IN TUMORS OF DIFFERENT HISTOGENESIS )

The human ether a-go-go-related gene (herg) encodes a K+ currnt (I-HER G) that plays a fundamental role in heart excitability by regulating t he action potential repolarization (I-Kr); mutations of this gene are responsible for the chromosome 7-linked long QT syndrome (LQT2). In th is report, we show that in a variety (n = 17) of tumor cell lines of d ifferent species (human and murine) and distinct histogenesis (neurobl astoma, rhabdomyosarcoma, adenocarcinoma, lung microcytoma, pituitary tumors, insulinoma beta-cells, and monoblastic leukemia), a novel K+ i nward-rectifier current (I-IR), which is biophysically and pharmacolog ically similar to I-HERG, can be recorded with the patch-clamp techniq ue. Northern blot experiments with a human herg cDNA probe revealed th at both in human and murine clones the very high expression of herg tr anscripts can be quantified in at least three clearly identifiable ban ds, suggesting an alternative splicing of HERG mRNA. Moreover, se clon ed a cDNA encoding for I-IR the SH-SY5Y human neuroblastoma, The seque nce of this cDNA result was practically identical to that already repo rted for herg, indicating a high conservation of this gene in tumors. Consistently, the expression of this clone in Xenopus oocytes showed t hat the encoded K+ channel had substantially all of the biophysical an d pharmacological properties of the native I(IR)ibed for tumor cells. In addition, in the tumor clones studied, I-IR governs the resting pot ential, whereas it could not be detected either by the patch clamp or the Northern blot techniques in cells obtained from primary cell cultu res of parental tissues (sensory neurons and myotubes), whose resting potential is controlled by the classical K+ anomalous rectifier curren t, This current substitution had a profound impact on the resting pote ntial, which was markedly depolarized in tumors as compared with norma l cells. These results suggest that I, is normally only expressed duri ng the early stages of cell differentiation frozen by neoplastic trans formation, playing an important pathophysiological role in the regulat ory mechanisms of neoplastic cell survival, In fact, because of its bi ophysical features, I-IR,s keeping the resting potential within the de polarized values required for unlimited tumor growth, could also appea r suitable to afford a selective advantage in an ischemic environment.