Abstract 4170: Oncogenic activation of LMO2 by EGFR signaling regulates STAT3 phosphorylation and transcriptional activity in human glioma

Abstract

Abstract Glioblastoma multiforme (GBM) is a highly heterogeneous disease characterized by multiple genetic abnormalities. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities occurred in over 60% of GBM. The successful application of EGFR-targeted therapy for the treatment of GBM is thus dependent on a thorough understanding of the intricate signal pathways cross-linkage that underlies the pathobiology of this disease. The LIM-domain only factor 2 (LMO2) gene is a crucial oncogene involved in hematopoietic development and leukemogenesis. Herein, we showed, from the TCGA GBM data, that LMO2 is highly expressed in EGFR-aberrant GBM samples and might serve as a downstream effector of EGFR signaling in GBM. Depletion of LMO2 expression impairs the maintenance of glioma cell proliferation in vitro and in vivo. In addition, EGFR signaling induces LMO2 nuclear translocation and enables LMO2 to form a triplex with EGFR and Signal transducer and activator of transcription 3 (STAT3). More importantly, LMO2 serves as a bridging molecule to promote the formation of EGFR/STAT3 complex and to enhance EGFR-mediated STAT3 Y705 phosphorylation upon EGF stimulation, which in turn up-regulates the expression of STAT3-responsive genes involved in the regulation of cell proliferation and tumor development. In conclusion, these findings reveal that LMO2 might serve as a critical effector of EGFR signaling in human glioma and highlight the essential function of LMO2 in EGF-stimulated STAT3 activation and tumorigenesis. Citation Format: Jun Fu, Dimpy Koul, Shaofang Wu, Siyuan Zheng, Roel G. Verhaak, W.K Yung. Oncogenic activation of LMO2 by EGFR signaling regulates STAT3 phosphorylation and transcriptional activity in human glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4170. doi:10.1158/1538-7445.AM2014-4170