A co-op of EGFR and EphA4 promotes the progression of NSCLC through EGF-Grb7-Stat3 mediated transcriptional regulation of EphA4 gene expression
Resource
Cancer Res., 72,
Journal
Cancer Res.
Journal Issue
72
Pages
-
Date Issued
2012
Date
2012
Author(s)
Chu, Pei-Yu
Li, Tsai-Kun
Chou, Kai-Ming
Shen, Tang-Long
Abstract
Abstract Growth factor receptor bound protein-7 (Grb7) regulates diverse cellular functions as a result of its multi-domain functionality in protein-protein interactions. A number of reports have indicated that Grb7 is essential for EGFR-mediated tumorigenesis and cancer progression. However, it remains unclear how Grb7 potentiates tumor progression. To understand the underlying mechanisms by which Grb7 participates in EGFR-mediated tumorigenesis, we utilized microarray analyses and yeast two-hybrid screening to explore Grb7-mediated signaling. Of which, a migration related protein, EphA4, was markedly up-regulated in associated with Grb7 overexpression but down-regulated while knocking down Grb7. Eventually, in response to EGF stimulation, we found that Grb7 was trans-located into the nucleus from the cytoplasm, which in turn promoted STAT3 transcriptional activity on EphA4 gene expression. The significance of this finding is further highlighted by the co-upregulation of Grb7 and EphA4 is concurrent with the highly invasive capability of lung adenocarcinoma. Moreover, we found that EphA4 could also potentiate EGF-induced reorganization of cytoskeleton, ERK1/2 phosphorylation, and cancer cell functions such as proliferation, migration and anchorage-independent growth. Based on these findings, we hypothesize that EphA4 can act as an amplifier involved EGF-mediated cancer progression in an EGF/Grb7/Stat3-mediated transcriptional manner. This study reveals a novel mechanism by which Grb7 regulates tumor progression through the EGF- by triggering EphA4 expression and then prolonging EGFR signaling in regulation of diverse cellular functions involved in cancer progression, thereby highlighting the potential strategy to target Grb7 for anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-28. doi:1538-7445.AM2012-LB-28
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