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J. Biol. Chem., Vol. 282, Issue 9, 6001-6011, March 2, 2007

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Keratinocyte Growth Factor/Fibroblast Growth Factor-7-regulated Cell Migration and Invasion through Activation of NF-B Transcription Factors^*

Jiangong Niu¹², Zhe Chang¹, Bailu Peng, Qianghua Xia, Weiqin Lu^¶, Peng Huang^¶, Ming-Sound Tsao^||, and Paul J. Chiao^**3

From the Departments of Surgical Oncology, ^¶Molecular Pathology, and ^**Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Program of Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas-Houston Health Science Center, Houston, Texas 77030, and the ^||Departments of Laboratory Medicine and Pathobiology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario M5G 2M9, Canada

Keratinocyte growth factor (KGF)/fibroblast growth factor-7 (FGF-7) is a paracrine- and epithelium-specific growth factor produced by cells of mesenchymal origin. It acts exclusively through FGF-7 receptor (FGFR2/IIIb), which is expressed predominantly by epithelial cells, but not by fibroblasts, suggesting that it might function as a paracrine mediator of mesenchymal-epithelial interactions. KGF/FGF-7 plays an essential role in the growth of epithelial cells and is frequently overexpressed in cancers of epithelial origin such as pancreatic cancer, switching paracrine stimulation of KGF/FGF-7 to an autocrine loop. Less is known, however, about the signaling pathways by which KGF/FGF-7 regulates the response of epithelial cells. To delineate the signaling pathways activated by KGF/FGF-7 and examine cellular response to KGF/FGF-7 stimulation, we performed functional analysis of KGF/FGF-7 action. In this report, we show that KGF/FGF-7 activated nuclear factor B (NF-B), which in turn induced expression of VEGF, MMP-9, and urokinase-type plasminogen activator and increased migration and invasion of KGF/FGF-7-stimulated human pancreatic ductal epithelial cells. Expression of phosphorylation-defective IB (IBS32A,S36A), which blocked NF-B activation, inhibited KGF/FGF-7-induced gene expression and cell migration and invasion. Our results demonstrate for the first time that KGF/FGF-7 induces NF-B activation and that NF-B plays an essential role in regulation of KGF/FGF-7-inducible gene expression and KGF/FGF-7-initiated cellular responses. Thus, these findings identify one signaling pathway for KGF/FGF-7-regulated cell migration and invasion and suggest that paracrine sources of KGF/FGF-7 are one of the malignancy-contributing factors from tumor stroma.

Received for publication, July 19, 2006 , and in revised form, December 13, 2006.

^* This work was supported in part by NCI, National Institutes of Health Grants CA097159 and CA109405 and by grants from the Lockton Fund for Pancreatic Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² An Odyssey fellow supported by the Odyssey Program and The H-E-B Award for Scientific Achievement at M. D. Anderson Cancer Center.

³ To whom correspondence should be addressed: Dept. of Surgical Oncology/Molecular and Cellular Oncology, Unit 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-794-1030; Fax: 713-794-4830; E-mail: pjchiao{at}mdanderson.org.

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