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 CellsReportar como inadecuado




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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.



Autor: Alakesh Bera, Shujie Zhao, Lin Cao, Paul J. Chiao, James W. Freeman

Fuente: http://plos.srce.hr/



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