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Epidermal growth factor down-regulates the expression of neutrophil gelatinase-associated lipocalin (NGAL) through E-cadherin in pancreatic cancer cells
Article first published online: 29 DEC 2010
Copyright © 2010 American Cancer Society
Volume 117, Issue 11, pages 2408–2418, 1 June 2011
How to Cite
Tong, Z., Chakraborty, S., Sung, B., Koolwal, P., Kaur, S., Aggarwal, B. B., Mani, S. A., Bresalier, R. S., Batra, S. K. and Guha, S. (2011), Epidermal growth factor down-regulates the expression of neutrophil gelatinase-associated lipocalin (NGAL) through E-cadherin in pancreatic cancer cells. Cancer, 117: 2408–2418. doi: 10.1002/cncr.25803
- Issue published online: 19 MAY 2011
- Article first published online: 29 DEC 2010
- Manuscript Accepted: 25 OCT 2010
- Manuscript Revised: 5 OCT 2010
- Manuscript Received: 18 AUG 2010
- neutrophil gelatinase associated lipocalin;
- epidermal growth factor;
- nuclear factor κB;
- pancreatic cancer
The authors previously reported that neutrophil gelatinase-associated lipocalin (NGAL) overexpression significantly blocked invasion and angiogenesis of pancreatic ductal adenocarcinoma (PDAC). They also demonstrated a loss of NGAL expression in the advanced stages of PDAC. However, little is known regarding the mechanisms of NGAL regulation in PDAC. Because the epidermal growth factor (EGF)-EGF receptor (EGFR) axis is up-regulated significantly in PDAC, they examined EGF-mediated NGAL regulation in these cells.
The NGAL-positive cell lines AsPC-1 and BxPC-3 were used as a model system. Quantitative real-time polymerase chain reaction (RT-PCR), Western blot analysis, and immunofluorescence studies were used to investigate EGF-mediated effects on NGAL expression. E-cadherin expression was manipulated using lentiviral overexpression or small hairpin RNA constructs. NGAL promoter activity was assessed by luciferase-reporter assay and electrophoretic mobility shift assay.
NGAL expression was positively associated with tumor differentiation and was down-regulated significantly after EGF treatment along with a concomitant reduction of E-cadherin expression in PDAC cells. E-cadherin down-regulation was partly through the EGFR-dependent mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) (MEK-ERK) signaling pathway. In addition, E-cadherin down-regulation reduced NGAL expression in PDAC cells, whereas overexpression of E-cadherin led to increased NGAL expression and partly rescued the inhibition of NGAL expression by EGF. Furthermore, EGF, in part through E-cadherin, reduced NGAL promoter activity by blocking nuclear factor κB (NF-κB) activation.
The current study demonstrated for the first time that EGF potently blocked NGAL expression in PDAC cells. This effect was mediated in part through activation of the EGFR-MEK-ERK signaling pathway, which, in turn, down-regulated E-cadherin with a subsequent reduction in NF-κB activation. These findings illustrate a novel mechanism by which EGF regulates NGAL expression in PDAC. Cancer 2011;. © 2010 American Cancer Society.