Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer.

Abstract

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 E(2) (PGE(2)) significantly decreased the expression of E-cadherin, whereas treatment of COX-2-S cells with celecoxib (1 mumol/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 PGE(2)-treated NSCLC cells but decreased in COX-2-antisense cells. PGE(2) 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 PGE(2) 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 PGE(2), in autocrine or paracrine fashion, modulates transcriptional repressors of E-cadherin and thereby regulates COX-2-dependent E-cadherin expression in NSCLC. Thus, blocking PGE(2) production or activity may contribute to both prevention and treatment of NSCLC.

• Authors: Mariam Dohadwala, Seok-Chul Yang, Jie Luo, Sherven Sharma, Raj K Batra, Min Huang, Ying Lin, Lee Goodglick, Kostyantyn Krysan, Michael C Fishbein, Longsheng Hong, Chi Lai, Robert B Cameron, Robert M Gemmill, Harry A Drabkin, Steven M Dubinett
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 10 Pg. 5338-45 (May 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16707460 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cadherins
• Homeodomain Proteins
• Snail Family Transcription Factors
• Transcription Factors
• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• Cyclooxygenase 2
• Dinoprostone

Topics

• Cadherins (biosynthesis, genetics)
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, metabolism)
• Cell Aggregation (physiology)
• Cell Line, Tumor
• Cyclooxygenase 2 (biosynthesis, genetics, metabolism)
• Dinoprostone (pharmacology)
• E-Box Elements
• Homeodomain Proteins (biosynthesis, genetics)
• Humans
• Immunohistochemistry
• Lung Neoplasms (enzymology, genetics, metabolism)
• Promoter Regions, Genetic
• Snail Family Transcription Factors
• Transcription Factors (biosynthesis, genetics)
• Up-Regulation
• Zinc Finger E-box-Binding Homeobox 1