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Oncogenic potential of EAG K(+) channels.

ABSTRACT: We have investigated the possible implication of the cell cycle-regulated K(+) channel ether à go-go (EAG) in cell proliferation and transformation. We show that transfection of EAG into mammalian cells confers a transformed phenotype. In addition, human EAG mRNA is detected in several somatic cancer cell lines, despite being preferentially expressed in brain among normal tissues. Inhibition of EAG expression in several of these cancer cell lines causes a significant reduction of cell proliferation. Moreover, the expression of EAG favours tumour progression when transfected cells are injected into immune-depressed mice. These data provide evidence for the oncogenic potential of EAG.

SUBMITTER: Pardo LA

PROVIDER: S-EPMC1171622 | biostudies-other | 1999 Oct

REPOSITORIES: biostudies-other

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Oncogenic potential of EAG K(+) channels.

Pardo L A LA del Camino D D Sánchez A A Alves F F Brüggemann A A Beckh S S Stühmer W W

The EMBO journal 19991001 20

We have investigated the possible implication of the cell cycle-regulated K(+) channel ether à go-go (EAG) in cell proliferation and transformation. We show that transfection of EAG into mammalian cells confers a transformed phenotype. In addition, human EAG mRNA is detected in several somatic cancer cell lines, despite being preferentially expressed in brain among normal tissues. Inhibition of EAG expression in several of these cancer cell lines causes a significant reduction of cell proliferat ...[more]

PMID: 10523298

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Project description:To investigate whether IDH1R132C mutant in combination with loss of p53 and activated Notch signaling promotes intrahepatic cholangiocarcinoma (ICC) development.We applied hydrodynamic injection and sleeping beauty mediated somatic integration to induce loss of p53 (via shP53), activation of Notch [via intracellular domain of Notch1 (NICD)] and/or overexpression of IDH1R132C mutant together with the sleeping beauty transposase into the mouse liver. Specifically, we co-expressed shP53 and NICD (shP53/NICD, n = 4), shP53 and IDH1R132C (shP53/IDH1R132C, n = 3), NICD and IDH1R132C (NICD/IDH1R132C, n = 4), as well as NICD, shP53 and IDH1R132C (NICD/shP53/IDH1R132C, n = 9) in mice. Mice were monitored for liver tumor development and euthanized at various time points. Liver histology was analyzed by hematoxylin and eosin staining. Molecular features of NICD/shP53/IDH1R132C ICC tumor cells were characterized by Myc tag, Flag tag, Ki-67, p-Erk and p-AKT immunohistochemical staining. Desmoplastic reaction in tumor tissues was studied by Picro-Sirius red staining.We found that co-expression of shP53/NICD, shP53/IDH1R132C or NICD/IDH1R132C did not lead to liver tumor formation. In striking contrast, co-expression of NICD/shP53/IDH1R132C resulted in ICC development in mice (P < 0.01). The tumors could be identified as early as 12 wk post hydrodynamic injection. Tumors rapidly progressed, and by 18 wk post hydrodynamic injection, multiple cystic lesions could be identified on the liver surface. NICD/shP53/IDH1R132C liver tumors shared multiple histological features of human ICCs, including hyperplasia of irregular glands. Importantly, all tumor cells were positive for the biliary epithelial cell marker cytokeratin 19. Extensive collagen fibers could be visualized in tumor tissues using Sirus red staining, duplicating the desmoplastic reaction observed in human ICC. Tumors were highly proliferative and expressed ectopically injected genes. Together these studies supported that NICD/shP53/IDH1R132C liver tumors were indeed ICCs. Finally, no p-AKT or p-ERK positive staining was observed, suggesting that NICD/shP53/IDH1R132C driven ICC development was independent of AKT/mTOR and Ras/MAPK signaling cascades.We have generated a simple, non-germline murine ICC model with activated Notch, loss of p53 and IDH1R132C mutant. The study supported the oncogenic potential of IDH1R132C.

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Oncogenic potential of EAG K(+) channels.

Publications

Oncogenic potential of EAG K(+) channels.

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