Cyclooxygenase-2–Dependent Regulation of E-Cadherin: Prostaglandin E2 Induces Transcriptional Repressors ZEB1 and Snail in Non–Small Cell Lung Cancer
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- Mariam Dohadwala
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Seok-Chul Yang
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Jie Luo
- 2Medicine,
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- Sherven Sharma
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Raj K. Batra
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Min Huang
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Ying Lin
- 2Medicine,
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- Lee Goodglick
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Kostyantyn Krysan
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Michael C. Fishbein
- 4Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California;
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- Longsheng Hong
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Chi Lai
- 4Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California;
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- Robert B. Cameron
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
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- Robert M. Gemmill
- 6Division of Medical Oncology, University of Colorado Health Science and Cancer Centers, Denver, Colorado
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- Harry A. Drabkin
- 6Division of Medical Oncology, University of Colorado Health Science and Cancer Centers, Denver, Colorado
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- Steven M. Dubinett
- 1Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center and Departments of
抄録
<jats:title>Abstract</jats:title> <jats:p>Elevated tumor cyclooxygenase-2 (COX-2) expression is associated with tumor invasion, metastasis, and poor prognosis in non–small cell lung cancer (NSCLC). Here, we report that COX-2-dependent pathways contribute to the modulation of E-cadherin expression in NSCLC. First, whereas genetically modified COX-2-sense (COX-2-S) NSCLC cells expressed low E-cadherin and showed diminished capacity for cellular aggregation, genetic or pharmacologic inhibition of tumor COX-2 led to increased E-cadherin expression and resulted in augmented homotypic cellular aggregation among NSCLC cells in vitro. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human lung adenocarcinoma tissue sections. Second, treatment of NSCLC cells with exogenous prostaglandin E2 (PGE2) significantly decreased the expression of E-cadherin, whereas treatment of COX-2-S cells with celecoxib (1 μmol/L) led to increased E-cadherin expression. Third, the transcriptional suppressors of E-cadherin, ZEB1 and Snail, were up-regulated in COX-2-S cells or PGE2-treated NSCLC cells but decreased in COX-2-antisense cells. PGE2 exposure led to enhanced ZEB1 and Snail binding at the chromatin level as determined by chromatin immunoprecipitation assays. Small interfering RNA–mediated knockdown of ZEB1 or Snail interrupted the capacity of PGE2 to down-regulate E-cadherin. Fourth, an inverse relationship between E-cadherin and ZEB1 and a direct relationship between COX-2 and ZEB1 were shown by immunohistochemical staining of human lung adenocarcinoma tissue sections. These findings indicate that PGE2, in autocrine or paracrine fashion, modulates transcriptional repressors of E-cadherin and thereby regulates COX-2-dependent E-cadherin expression in NSCLC. Thus, blocking PGE2 production or activity may contribute to both prevention and treatment of NSCLC. (Cancer Res 2006; 66(10): 5338-45)</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 66 (10), 5338-5345, 2006-05-15
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1362262944120959232
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- ISSN
- 15387445
- 00085472
- http://id.crossref.org/issn/00085472
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- データソース種別
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- Crossref