Oncogenic K-Ras and loss of Smad4 mediate invasion by activating an EGFR/NF-κB Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells.
Oncogenic K-Ras and loss of Smad4 mediate invasion by activating an EGFR/NF-κB Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells.
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DOI：
10.1371/journal.pone.0082282
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Freeman JW
中科院分区：
文献类型：
--
作者：
Bera A;Zhao S;Cao L;Chiao PJ;Freeman JW
激活K-RAS基因突变和失活Smad4基因突变是胰腺导管腺癌(PDAC)发生发展过程中两种常见的基因改变。为了进一步研究这两种突变在PDAC发病机制中的单独和组合作用，对永生化的人胰腺巢蛋白阳性细胞(HPNE/K-RAS)进行了基因修饰，方法是表达癌基因K-RAS(HPNE/K-RAS)，通过shRNA敲除Smad4(HPNE/ShSmad4)，或者在同一细胞系(HPNE/K-RAS/ShSmad4)中同时产生这两种突变。我们先前发现，癌基因K-RAS的表达导致EGFR的表达增加，Smad4的缺失进一步增强了EGFR的表达上调，这种EGFR的增加足以诱导肿瘤的侵袭。在这里，我们进一步研究了突变改变和EGFR表达与侵袭性之间的联系。EGFR信号的增强与MMP9和uPA蛋白及活性上调有关。此外，EGFR信号的增加促进了NF-κB的一个亚单位RelA(P65)与MMP9和uPA启动子的核转位和结合。用EGFR抑制剂处理HPNE/K-RAS/ShSmad4细胞可减少表皮生长因子介导的NF-κB核转位，EGFR或NF-κB的抑制剂均可减少MMP9或uPA表达的增加。综上所述，本研究提供了致癌K-RAS和Smad4缺失如何导致肿瘤侵袭的机制，并为抑制转移的新策略提供了基础。
Activating K-Ras mutations and inactivating mutations of Smad4 are two common genetic alterations that occur in the development and progression of pancreatic ductal adenocarcinomas (PDAC). To further study the individual and combinatorial roles of these two mutations in the pathogenesis of PDAC, immortalized human pancreas nestin postive cells (HPNE) were genetically modified by either expressing oncogenic K-Ras (HPNE/K-Ras), by shRNA knock down of Smad4 (HPNE/ShSmad4) or by creating both alterations in the same cell line (HPNE/K-Ras/ShSmad4). We previously found that expression of oncogenic K-Ras caused an increase in expression of EGFR and loss of Smad4 further enhanced the up regulation in expression of EGFR and that this increase in EGFR was sufficient to induce invasion. Here we further investigated the mechanism that links mutational alterations and EGFR expression with invasion. The increase in EGFR signaling was associated with up regulation of MMP9 and uPA protein and activity. Moreover, the increase in EGFR signaling promoted a nuclear translocation and binding of RelA (p65), a subunit of NF-κB, to the promoters of both MMP-9 and uPA. Treatment of HPNE/K-Ras/ShSmad4 cells with an inhibitor of EGFR reduced EGF-mediated NF-κB nuclear translocation and inhibitors of either EGFR or NF-κB reduced the increase in MMP-9 or uPA expression. In conclusion, this study provides the mechanism of how a combination of oncogenic K-Ras and loss of Smad4 causes invasion and provides the basis for new strategies to inhibit metastases.
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影响因子：
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