The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy.We report in this article that K ؉ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells.Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas.
Abstract. Electrical signals elicited by integrin interaction with ECM components and theft role in neurite outgrowth were studied in two clones (N1 and N7) isolated from 41A3 murine neuroblastoma cell line. Although the two clones similarly adhered to fibronectin (FN) and vitroncctin O/N), this adhesion induced neurite outgrowth in NI but not in N7 cells. Patch clamp recordings in whole cell configuration showed that, upon adhesion to FN or VN but not to platelet factor 4 (PF4), NI cells undergo a marked (---20 mV) hyperpolarization of the resting potential (Vr, t) that occurred within the first 20 min after cell contact with ECM, and persisted for •1 h before reverting to the time zero values. This hyperpolarization was totally absent in N7 cells. A detailed analysis of the molecular mechanisms involved in N1 and N7 cell adhesion to ECM substrata was performed by using antibodies raised against the FN receptor and synthetic peptides variously competing with the FN or VN binding to integrin receptors (GRGDSP and GRGESP). Antibodies, as well as GRGDSP, abolished adhesion of N1 and N7 clones to FN and VN, revealing a similar implication of integrins in the adhesion of these clones to the ECM proteins. However, these anti-adhesive treatments, while ineffective on V,~, of N7 cells, abolished in N1 cells the FN-or VN-induced hyperpolarization and neurite outgrowth, that appeared therefore strictly associated and integrin-mediated phenomena. The nature of this association was deepened through a comparative analysis of the integrin profiles and the ion channels of N1 and N7 cells. The integrin immunoprecipitation profile resulted very similarly in the two clones, with only minor differences concerning the aV containing complexes. Both clones possessed Ca 2+ and K + delayed rectifier (KDR) channels, while only N1 cells were endowed with inward rectifier K + (Kit) channels. The latter governed the Vr~, and, unlike KDR channels, were blocked by Ba 2+ and Cs +. By moving patched cells in contact with FN-coated beads, it was shown that Km channel activation was responsible for the FN-mediated hyperpolarization of V,~. Treatment with Pertuxis toxin (PTX) abolished this hyperpolarization and neurite outgrowth, indicating that a G protein is interposed between integrins and Km channels and that the activation of these channels is required for neuritogenesis. In fact, the block of Km channels by Cs ÷ abolished both hyperpolarization and neurite outgrowth, provided that the cation was supplied during the first two hours after N1 cell contact with FN. This Cs+-sensitive commitment time for neuritogenesis coincided with the time length of the FNinduced hyperpolarization.
Ion channels regulate a broad range of cellular activities. Alteration in ion channel function has been reported in different human pathologies, such as cardiac, neuromuscular, autoimmune diseases, and cancer. We investigated the expression of hERG1 K þ channels in the human upper gastrointestinal tract, focusing our attention on the lower esophagus. In particular, we analyzed by both Reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) endoscopic samples obtained from normal subjects, from patients suffering from gastroesophageal reflux, associated or not with esophagitis, and from patients affected by Barrett's esophagus (BE), that is, intestinal metaplasia. None of the normal samples, nor those from patients with gastro-esophageal reflux symptoms and reflux esophagitis expressed the hERG1 protein. On the other hand, 69% of patients with BE expressed hERG1. Since BE is a preneoplastic lesion, dysplasias (Ds) and adenocarcinomas (ADKs) arising on a previously diagnosed BE were also analyzed, and all the samples showed a high expression of the hERG1 protein. The surveillance of patients with BE showed that 89% of those who later developed ADKs displayed hERG1 expression. Data here reported, support the hypothesis that hERG1 expression marks an early step of the progression of normality to cancer in the human esophagus through a metaplastic and dysplastic stage.
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