Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling.
Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling.
复制标题
DOI：
10.1038/srep11541
复制
发表时间：
2015-06-22
影响因子：
4.6
通讯作者：
Lee NH
中科院分区：
文献类型：
--
作者：
House CD;Wang BD;Ceniccola K;Williams R;Simaan M;Olender J;Patel V;Baptista-Hon DT;Annunziata CM;Gutkind JS;Hales TG;Lee NH
电压门控 Na+ 通道 (VGSC) 的功能性表达已在多种癌细胞类型中得到证实，其中通道活性可诱导侵袭活性。 VGSC 促进肿瘤发生的信号机制仍知之甚少。我们根据将通道活动与可兴奋细胞中基因表达变化联系起来的报告，探索了对 VGSC 介导的入侵至关重要的信号转导过程。巧合的是，结肠癌中许多受 SCN5A 同工型转录调控的基因具有过多的 ERK1/2 MAPK 磷酸化转录因子的顺式作用位点。我们假设 VGSC 活性促进 MAPK 激活，从而诱导侵袭相关基因的转录变化。使用药理学抑制剂/激活剂和 siRNA 介导的基因敲低，我们将 SW620 人结肠癌细胞系中通道活性与 Rap1 依赖性持续 MAPK 激活相关联。我们进一步证明，VGSC 活性通过 PKA/ERK/c-JUN/ELK-1/ETS-1 转录途径诱导侵袭相关基因表达的下游变化。这是第一项研究将 VGSC 的功能活性与入侵相关基因的转录激活联系起来的分子机制。
Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.
登录
查看更多内容
DOI：
10.1084/jem.180.4.1547
发表时间：
1994-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cifone MG;De Maria R;Roncaioli P;Rippo MR;Azuma M;Lanier LL;Santoni A;Testi R
通讯作者：
Testi R
DOI：
10.1016/j.molbrainres.2003.08.020
发表时间：
2003-11-06
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Baldassa, S;Zippel, R;Sturani, E
通讯作者：
Sturani, E
影响因子：
4.8
作者：
Andrikopoulos, Petros;Fraser, Scott P.;Djamgoz, Mustafa B. A.
通讯作者：
Djamgoz, Mustafa B. A.
影响因子：
4.5
作者：
Bennett, ES;Smith, BA;Harper, JM
通讯作者：
Harper, JM
影响因子：
5.6
作者：
Juretic, Nevenka;Urzua, Ulises;Riveros, Nora
通讯作者：
Riveros, Nora