Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha.
Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha.
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DOI：
10.1038/onc.2009.410
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发表时间：
2010-02-25
期刊：
影响因子：
8
通讯作者：
Baldwin, A. S.
中科院分区：
文献类型：
--
作者：
Merkhofer, E. C.;Cogswell, P.;Baldwin, A. S.
膜结合受体酪氨酸激酶Her2在大约30%的人类乳腺癌中过度表达，这与预后不良有关。HER2诱导的信号通路包括MAPK和PI3K/Akt，后者已被证明对Her2+乳腺癌细胞的生长和生存至关重要。此外，核因子-κB通路在HER2过表达的下游被激活，但导致这种激活的机制目前尚不清楚。使用Her2+/ER-乳腺癌细胞，我们发现Her2通过规范的途径激活了NF-κB，令人惊讶的是，该途径涉及IKKα。IKKα被敲除后，多种受NF-κB调控的细胞因子和趋化因子基因的转录水平显著降低。SiRNA介导的IKKα基因敲除可降低癌细胞侵袭能力，但对细胞增殖无影响。抑制PI3K/AKT通路对NF-κB的激活无影响，但显著抑制细胞的增殖。我们的研究表明，HER2下游的NF-κB和PI3K通路在导致乳腺癌细胞侵袭和增殖的变化方面发挥了不同的作用。此外，这项工作表明了IKKα作为HER2诱导的肿瘤进展的媒介的重要性。
The membrane bound receptor tyrosine kinase Her2 is overexpressed in approximately 30% of human breast cancers which correlates with poor prognosis. Her2-induced signaling pathways include MAPK and PI3K/Akt, of which the latter has been shown to be critical for Her2+ breast cancer cell growth and survival. Additionally, the NF-κB pathway has been shown to be activated downstream of Her2 overexpression, however the mechanisms leading to this activation are not currently clear. Using Her2+/ER- breast cancer cells, we show that Her2 activates NF-κB through the canonical pathway which, surprisingly, involves IKKα. Knockdown of IKKα led to a significant decrease in transcription levels of multiple NF-κB-regulated cytokine and chemokine genes. siRNA-mediated knockdown of IKKα resulted in a decrease in cancer cell invasion, but had no effect on cell proliferation. Inhibition of the PI3K/Akt pathway had no effect on NF-κB activation, but significantly inhibited cell proliferation. Our study suggests different roles for the NF-κB and PI3K pathways downstream of Her2, leading to changes in invasion and proliferation of breast cancer cells. Additionally this work indicates the importance of IKKα as a mediator of Her2-induced tumor progression.
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影响因子：
8
作者：
Arora, P.;Cuevas, B. D.;Trejo, J.
通讯作者：
Trejo, J.
DOI：
10.1073/pnas.0403621101
发表时间：
2004-07-06
影响因子：
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作者：
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