Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.
Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.
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DOI：
10.1038/labinvest.2016.109
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发表时间：
2016-12
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影响因子：
--
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NF-κB在胰腺癌的发生、发展中起重要作用，并特异性介导上皮-间质转化和侵袭。在这项研究中，我们证明了活化的NF-κB信号在EMT诱导、淋巴管转移和神经侵袭中的重要性。NF-κB活性的调节通过特异性NF-κB抑制剂（BAY 11-7085）、雷公藤内酯醇和Minnelide处理以及IKBα阻遏物和IKK激活物质粒的过表达来实现。在经典的淋巴血管转移级联反应中，NF-κB的抑制降低了几种EMT转录因子（SNAI 1、SNAI 2、ZEB 1）和间充质标志物（Vim和CDH 2）的表达，并降低了体外侵袭，这是由IKK激活所挽救的。这在胰腺癌的原位模型中通过BAY 11-7085治疗在体内进一步证明。体内NF-κB抑制可减小肿瘤体积;降低肿瘤EMT基因表达，同时恢复细胞-细胞连接;并降低总体转移。此外，我们证明了NF-κB信号在神经侵袭中的重要性。雷公藤内酯醇治疗通过破坏肿瘤-神经串扰抑制NGF介导的和神经-肿瘤共培养的体外侵袭和背根神经节（DRG）神经生长。在体内，Minnelide治疗减少神经营养因子的表达，神经密度，和坐骨神经侵袭。综上所述，本研究证实了NF-κB信号通过调节EMT诱导、淋巴管浸润和神经浸润在胰腺癌进展中的重要性。
NF-κB plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.
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CD133+肿瘤在胰腺癌的合成鼠模型中启动细胞对Minnelide有反应。
DOI：
10.1158/1078-0432.ccr-13-2947
发表时间：
2014-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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通讯作者：
Saluja A
影响因子：
8
作者：
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通讯作者：
Chiao, PJ
影响因子：
3.8
作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
29.4
作者：
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