Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma

Author

Yingxuan Chua, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

5-2015

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Wei Zhang, Ph.D.

Committee Member

Gregory N. Fuller, M.D., Ph.D.

Committee Member

Oliver Bogler, Ph.D.

Committee Member

Paul J. Chiao, Ph.D.

Committee Member

Frederick F. Lang Jr, M.D.

Committee Member

Zhimin Lu, M.D., Ph.D.

Abstract

Gliomas are clinically challenging brain tumors with dismal survival rates due to its infiltrative nature and ineffective standard therapy. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the contributions of intracellular IGFBP2 to tumor development and progression are poorly understood. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from the TCGA database for human glioma. A high level of all 3 proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient dataset. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by 2 distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.

Keywords

glioma, glioblastoma, IGFBP2, EGFR, STAT3, TCGA