IGFBP2 Activates the NF-κB Pathway to Drive Epithelial–Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma

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 PDAC patients. 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.

Oncogenic transformation of normal breast epithelial cells co-cultured with cancer cells

“…Our results showed that IGFBP-2 was significantly upregulated in MCF10A.NeuT (C3 cells). IGFBP-2 has previously been reported to drive EMT and invasiveness in pancreatic ductal adenocarcinoma through activating the NF-κB pathway [33]. Consistent with this, NF-κB pathway receptors and downstream effectors, i.e.…”

AREG mediates the epithelial‑mesenchymal transition in pancreatic cancer cells via the EGFR/ERK/NF‑κB signalling pathway

“…Previous studies have suggested that NF-κB plays an essential role in the induction and maintenance of EMT (19,20). We proposed that the role of AREG-induced pancreatic cancer cell migration, invasion and EMT may be through regulation of the NF-κB signalling pathway.…”

IGFBP5 increases cell invasion and inhibits cell proliferation by EMT and Akt signaling pathway in Glioblastoma multiforme cells

“…Many previous studies indicate that IGFBPs can promote tumor growth but can also function as anti-oncogenes [17]. IGFBP2 has been demonstrated to show promoted tumorigenicity in various cancer types [1,23,24]. And in high quality glioma studies, IGFBP-2 showed non conflicting results in predictive biomarkers [25].…”