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posted on 2023-03-31, 00:21 authored by Song Gao, Yan Sun, Xuebin Zhang, Limei Hu, Yuexin Liu, Corrine Yingxuan Chua, Lynette M. Phillips, He Ren, Jason B. Fleming, Huamin Wang, Paul J. Chiao, Jihui Hao, Wei Zhang Expression of IGFBP1, IGFBP3, IGFBP4, and IGFBP5 in tumors from PDAC patients and relationship of IGFBP3 and IGFBP5 expression to patient survival.
Funding
NIH
MD Anderson Cancer Center
National Foundation for Cancer Research
National Natural Science Foundation of China
Wake Forest Baptist Medical Center
History
ARTICLE ABSTRACT
The molecular basis underlying the particularly aggressive nature of pancreatic ductal adenocarcinoma (PDAC) still remains unclear. Here we report evidence that the insulin-like growth factor–binding protein IGFBP2 acts as a potent oncogene to drive its extremely malignant character. We found that elevated IGFBP2 expression in primary tumors was associated with lymph node metastasis and shorter survival in patients with PDAC. Enforced expression of IGFBP2 promoted invasion and metastasis of PDAC cells in vitro and in vivo by inducing NF-κB–dependent epithelial–mesenchymal transition (EMT). Mechanistic investigations revealed that IGFBP2 induced the nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKβ pathway. Conversely, enforced expression of PTEN blunted this signaling pathway and restored an epithelial phenotype to PDAC cells in the presence of overexpressed IGFBP2. Overall, our results identify IGFBP2 as a pivotal regulator of an EMT axis in PDAC, the activation of which is sufficient to confer the characteristically aggressive clinical features of this disease. Cancer Res; 76(22); 6543–54. ©2016 AACR.
