Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion.
Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion.
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DOI：
10.1158/0008-5472.can-10-1169
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Lee NH
中科院分区：
文献类型：
--
作者：
House CD;Vaske CJ;Schwartz AM;Obias V;Frank B;Luu T;Sarvazyan N;Irby R;Strausberg RL;Hales TG;Stuart JM;Lee NH
电压门控Na+通道（VGSCs）与人类乳腺癌、前列腺癌和肺癌细胞的转移潜能有关。具体来说，编码VGSC同型Nav1.5的SCN5A基因已被定义为人类癌细胞侵袭的关键驱动因素。在这项研究中，我们通过电生理记录检测了VGSCs在一组结肠癌细胞系中的表达和功能。Na+通道活性和侵袭电位可被河豚毒素或特异性靶向SCN5A的sirna从药理学上抑制。通过患者活检的免疫组化来建立临床相关性，结肠癌标本中有很强的Nav1.5蛋白染色，而配对的正常结肠组织中几乎没有染色。基于已报道的可兴奋细胞中VGSC活性与基因表达之间的联系，我们探索了VGSC介导的侵袭电位的机制。功能缺失筛查的概率建模和微阵列数据确定了VGSC SCN5A作为结肠癌侵袭网络的高水平调节剂的明确作用，该网络涉及包含Wnt信号、细胞迁移、外胚层发育、对生物刺激的反应、类固醇代谢过程和细胞周期控制的基因。sirna介导的预测下游网络组分的敲低导致了侵袭行为的丧失，证明了网络连通性及其在驱动结肠癌侵袭中的作用。
Voltage-gated Na+ channels (VGSCs) have been implicated in the metastatic potential of human breast, prostate and lung cancer cells. Specifically, the SCN5A gene encoding the VGSC isotype Nav1.5 has been defined as a key driver of human cancer cell invasion. In this study, we examined the expression and function of VGSCs in a panel of colon cancer cell lines by electrophysiological recordings. Na+ channel activity and invasive potential were inhibited pharmacologically by tetrodotoxin or genetically by siRNAs specifically targeting SCN5A. Clinical relevance was established by immunohistochemistry of patient biopsies, where there was strong Nav1.5 protein staining in colon cancer specimens but little to no staining in matched-paired normal colon tissues. We explored the mechanism of VGSC-mediated invasive potential on the basis of reported links between VGSC activity and gene expression in excitable cells. Probabilistic modeling of loss-of-function screens and microarray data established an unequivocal role of VGSC SCN5A as a high level regulator of a colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process and cell cycle control. siRNA-mediated knockdown of predicted downstream network components caused a loss of invasive behavior, demonstrating network connectivity and its function in driving colon cancer invasion.