Tumor-associated EGFR over-expression specifically activates Stat3 and Smad7 resulting in desensitization of TGF-E signaling

摘要: Transforming Growth Factor(TGF) and Epidermal Factor (EGF) signaling pathways are both independently implicated as key regulators in tumor formation progression. Here, we demonstrate that activation of the tumor-associated over-expressed EGFR desensitizes TGFsignaling its cytostatic regulation through specific Stat3 Smad7 induction. In normal human cell lines, reduction TGFmediated Smad2 phosphorylation, nuclear translocation Smad3 target gene were observed where is over-expressed, but not cells which expressed at levels. The downstream molecules phosphatidyinositol-3 Kinase (PI3K) or mitogen-activated protein kinase/ERK kinase (MEK) responsible for down-regulation since blockade them by pharmacological inhibitors LY294002 U0126 had little effects on sensitivity TGFsignaling. We identified a molecule activated specifically persistently overexpressed EGFR, Importantly, reduced TGFsensitivity, knockdown siRNA restored sensitivity. Furthermore, activates promoter activity, increasing levels, negative regulator Consequently, re-sensitized to TGFwhen expression was using siRNA. Therefore establish novel EGFR-Stat3-Smad7-TGFsignaling molecular axis over-expression epithelial results hyperactivation Stat3, expression, compromising TGF’s epithelium consequent formation. Nature Precedings : hdl:10101/npre.2008.1535.1 Posted 23 Jan 2008