Cyclooxygenase-2–Dependent Regulation of E-Cadherin: Prostaglandin E2 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 Ecadherin, whereas treatment of COX-2-S cells with celecoxib (1 Amol/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 downregulate 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. (Cancer Res 2006; 66(10): 5338-45)

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

“…showed that PI(3) kinase contributes to TrkB signaling as well (including anoikis resistance; Douma et al, 2004), in aggregate these data suggest a model in which TrkB activates multiple pathways, some of which critically depend on Zeb1 (Figure 7). Several reports have shown a correlation between Zeb1 expression and the aggressiveness of tumors, including those of endometrial (Spoelstra et al, 2006;Singh et al, 2008), colon (Pena et al, 2005;Aigner et al, 2007b), breast (Aigner et al, 2007a), lung (Dohadwala et al, 2006), gallbladder (Adachi et al, 2009), ovarian (Bendoraite et al, 2010) and prostate origin (Graham et al, 2008). In colon cancer, Zeb1 expression is linked to loss of the basement membrane, which correlates with increased metastasis (Spaderna et al, 2006).…”

Type I collagen inhibits differentiation and promotes a stem cell-like phenotype in human colorectal carcinoma cells

“…In HCA-7 cells, E-cadherin is downregulated by constitutive expression of COX-2 and RhoA, which are associated with the disruption of adherens junctions in these cells (Chang et al, 2006). COX-2-dependent pathways upregulate ZEB1 and Snail, transcriptional suppressors of E-cadherin in lung cancer cells (Dohadwala et al, 2006). ZEB1 represses differentiation and cell -cell adhesion in human colorectal carcinoma cells (Aigner et al, 2007).…”

Elevated Levels of Urinary PGE-M Are Found in Tobacco Users and Indicate a Poor Prognosis for Oral Squamous Cell Carcinoma Patients

“…Cross-talk between EP receptors and the EGFR can also stimulate cell growth (3). PGE 2 has multiple other effects that may stimulate tumor progression including induction of matrix metalloproteinase-9 and VEGF and stimulation of epithelialmesenchymal transition (3,29,48). In addition, there is considerable evidence that COX-derived PGE 2 is a driver of tumor growth through evasion of immunity (49).…”

“…COX-2-derived PGE 2 can stimulate cell proliferation, migration, and angiogenesis while inhibiting immune surveillance and apoptosis (3,(23)(24)(25)(26)(27). PGE 2 has also been suggested to promote metastasis by stimulating cell invasiveness and an epithelialmesenchymal transition (28,29).…”