Ousingsawat Jiraporn, Spitzner Melanie, Puntheeranurak Supaporn, Terracciano Luigi, Tornillo Luigi, Bubendorf Lukas, Kunzelmann Karl, Schreiber Rainer
Institut für Physiologie, Universität Regensburg, Regensburg, Germany, and Institute for Pathology, University Hospital Basel, Basel, Switzerland.
Clin Cancer Res. 2007 Feb 1;13(3):824-31. doi: 10.1158/1078-0432.CCR-06-1940.
Voltage-gated Kv potassium channels, like ether a go-go (EAG) channels, have been recognized for their oncogenic potential in breast cancer and other malignant tumors.
We examined the molecular and functional expression of Kv channels in human colonic cancers and colon of mice treated with the chemical carcinogens dimethylhydrazine and N-methyl-N-nitrosourea. The data were compared with results from control mice and animals with chemically induced DSS colitis.
Electrogenic salt transport by amiloride-sensitive Na+ channels and cyclic AMP-activated cystic fibrosis transmembrane conductance regulator Cl- channels were attenuated during tumor development and colitis, whereas Ca2+-dependent transport remained unchanged. Kv channels, in particular Eag-1, were enhanced during carcinogenesis. Multiplex reverse transcription-PCR showed increased mRNA expression for Kv1.3, Kv1.5, Kv3.1, and members of the Eag channel family, after dimethylhydrazine and N-methyl-N-nitrosourea treatment. Eag-1 protein was detected in the malignant mouse colon and human colonic cancers. Genomic amplification of Eag-1 was found in 3.4% of all human colorectal adenocarcinoma and was an independent marker of adverse prognosis.
The study predicts an oncogenic role of Kv and Eag channels for the development of colonic cancer. These channels may represent an important target for a novel pharmacotherapy of colonic cancer.
电压门控钾通道，如超快速激活延迟整流钾通道（EAG），已被公认为在乳腺癌和其他恶性肿瘤中具有致癌潜力。
我们检测了用化学致癌物二甲基肼和N-甲基-N-亚硝基脲处理的人类结肠癌和小鼠结肠中钾通道的分子和功能表达。将这些数据与对照小鼠和化学诱导的葡聚糖硫酸钠（DSS）结肠炎动物的结果进行比较。
在肿瘤发生和结肠炎期间，氨氯地平敏感的钠通道和环磷酸腺苷激活的囊性纤维化跨膜电导调节氯离子通道介导的电致盐转运减弱，而钙依赖性转运保持不变。钾通道，特别是Eag-1，在致癌过程中增强。多重逆转录-PCR显示，在二甲基肼和N-甲基-N-亚硝基脲处理后，Kv1.3、Kv1.5、Kv3.1和Eag通道家族成员的mRNA表达增加。在恶性小鼠结肠和人类结肠癌中检测到Eag-1蛋白。在所有人类结肠腺癌中，3.4%发现Eag-1基因扩增，且是不良预后的独立标志物。
该研究预测钾通道和Eag通道在结肠癌发生中具有致癌作用。这些通道可能是结肠癌新型药物治疗的重要靶点。
