Estrogens and Human Papilloma Virus Oncogenes Regulate Human Ether-a-go-go-1 Potassium Channel Expression
Estrogens and Human Papilloma Virus Oncogenes Regulate Human Ether-a-go-go-1 Potassium Channel Expression
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DOI：
10.1158/0008-5472.can-08-2036
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Camacho, Javier
中科院分区：
文献类型：
--
作者：
Diaz, Lorenza;Ceja-Ochoa, Irais;Camacho, Javier
Ether-a-go-go-1 (Eag1) 钾通道是检测和治疗多种癌症的潜在工具。在这里，我们展示了癌症相关因素对人类 Eag1 (hEag1) 的调节。我们研究了 Magi 基因表达及其对雌二醇、抗雌激素和人乳头瘤病毒 (HPV) 癌基因 (E6/E7) 的调节。来自正常胎盘和宫颈癌组织的原代培养物；来自子宫颈、绒毛膜癌、角质形成细胞和肺的肿瘤细胞系；使用来自血管内皮、角质形成细胞和肺的正常细胞系。逆转录 PCR (RT-PCR) 实验和 Southern blot 分析显示，与正常角质形成细胞和肺细胞相比，Eag1 在所有癌细胞类型、正常滋养层细胞和血管内皮细胞中表达。雌二醇和抗雌激素药物以细胞类型依赖性方式调节 Eag1。 HeLa 细胞中的实时 RT-PCR 实验表明，Eag1 雌激素调节与雌激素受体 α 的表达密切相关。单克隆抗体在正常胎盘和胎盘血管中检测到Eag1蛋白。用雌二醇处理的正常滋养层细胞的膜片钳记录显示出类似于 Eag1 通道活性的钾电流。角质形成细胞中的 Eag1 基因表达取决于细胞永生化或 HPV 癌基因的存在。在转染 E6/E7 HPV 癌基因的角质形成细胞中发现了 Eag1 蛋白。抑制通道活性的 Eag1 抗体以及非特异性 Eag1 抑制剂丙咪嗪和阿司咪唑可减少 E6/E7 角质形成细胞的细胞增殖；后者也增加了细胞凋亡。我们的研究结果提出了雌激素/抗雌激素的使用和 HPV 感染的新致癌机制。我们还建议 Eag1 作为导致恶性肿瘤的细胞增殖的早期指标，以及细胞过度增殖早期阶段的治疗靶点。 [癌症研究 2009;69(8):3300-7]
Ether-a-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eag1 (hEag1) regulation by cancer-associated factors. We studied Magi gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type-dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-alpha. Eag1 protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eag1 channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eag1 antibodies inhibiting channel activity and by the nonspecific Eag1 inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/antiestrogen use and HPV infection. We also suggest Eag1 as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation. [Cancer Res 2009;69(8):3300-7]