Cancer Research The Future of Cancer Research: Science and Patient Impact  AACR Conference on Molecular Diagnostics - 2008
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Cancer Research 67, 8486-8493, September 15, 2007. doi: 10.1158/0008-5472.CAN-07-0498
© 2007 American Association for Cancer Research

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Molecular Biology, Pathobiology, and Genetics

Membrane-Bound Heparin-Binding Epidermal Growth Factor–Like Growth Factor Regulates E-Cadherin Expression in Pancreatic Carcinoma Cells

Fang Wang1, Callum Sloss1, Xiaobo Zhang2, Sam W. Lee3 and James C. Cusack1

1 Division of Surgical Oncology and 2 Gastrointestinal Unit and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts and 3 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: James C. Cusack, Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, 7th Floor, Yawkey Building, 55 Fruit Street, Boston, MA 02114. Phone: 617-724-4093; Fax: 617-724-3895; E-mail: jcusack{at}partners.org or Fang Wang, Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Jackson Building 904, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-5165; Fax: 617-726-8623; E-mail: fwang6{at}partners.org.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF growth factor family. Initially synthesized as a membrane-bound precursor (pro-HB-EGF), it is cleaved at the juxtamembrane domain to release the soluble form of HB-EGF (s-HB-EGF) by sheddases, including matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases. This is a process referred to as ectodomain shedding and is implicated in the process of all ligands of the EGF receptor (EGFR) family. The tumorigenic potential of s-HB-EGF has been studied extensively; however, the role of pro-HB-EGF in tumor progression is unknown, despite the fact that a considerable amount of pro-HB-EGF remains on the cell membrane. Our data here clearly indicated the distinct role of pro-HB-EGF in the regulation of E-cadherin expression and the epithelial-mesenchymal transition. We showed here that the expression of pro-HB-EGF was associated with the differentiation status in pancreatic tumors and cell lines. Expression of noncleaved pro-HB-EGF in pancreatic cells resulted in the up-regulation of E-cadherin through suppression of ZEB1, which is a transcriptional repressor of E-cadherin. Inhibition of HB-EGF shedding using a MMP inhibitor, GM6001, also dramatically augmented the E-cadherin expression while suppressing the EGFR activation. Moreover, up-regulation of E-cadherin by pro-HB-EGF not only resulted in cellular morphologic change but also decreased cell motility and enhanced apoptotic sensitivity in response to gemcitabine-erlotinib treatment. Collectively, our data defined a distinct role of pro-HB-EGF in the regulation of E-cadherin, suggesting that inhibition of shedding may be a novel approach to suppress pancreatic metastasis and sensitize cells to cancer therapy. [Cancer Res 2007;67(18):8486–93]







HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2007 by the American Association for Cancer Research.