Journal
CANCER RESEARCH
Volume 76, Issue 22, Pages 6543-6554Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-0438
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Funding
- U.S. NIH [U24CA143835]
- MD Anderson Cancer Center support grant [P30CA016672]
- National Foundation for Cancer Research
- National Natural Science Foundation of China [81302082, 81172355, 31301151]
- Hanes and Willies Family Professorship in Cancer at Wake Forest Baptist Medical Center
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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-kappa B-dependent epithelial-mesenchymal transi-tion (EMT). Mechanistic investigations revealed that IGFBP2 induced the nuclear translocation and phosphorylation of the p65 NF-kappa B subunit through the PI3K/Akt/IKK beta 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. (C) 2016 AACR.
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