Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer.
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.
Dohadwala
Mariam
M
Lung Cancer Research Program of the University of California at Los Angeles Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
Yang
Seok-Chul
SC
Luo
Jie
J
Sharma
Sherven
S
Batra
Raj K
RK
Huang
Min
M
Lin
Ying
Y
Goodglick
Lee
L
Krysan
Kostyantyn
K
Fishbein
Michael C
MC
Hong
Longsheng
L
Lai
Chi
C
Cameron
Robert B
RB
Gemmill
Robert M
RM
Drabkin
Harry A
HA
Dubinett
Steven M
SM
D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002449:Cell Aggregation / Q000502:physiology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D024721:E-Box Elements; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone