Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines.
ABSTRACT COX-2 and E-cadherin, involved in invasion and metastasis, are molecules critical for gastric carcinogenesis. A relationship between them is documented in non-small cell lung and prostate cancer. We present novel evidence of a relationship between COX-2 and E-cadherin expression in gastric cancer.
Using qPCR and Western blots analysis on celecoxib and PGE2 treated and untreated gastric cancer cell lines derived from tumours of the intestinal type (MKN45, MKN28, AGS3, MKN7) and immunohistochemistry of 178 gastric cancers on tissue microarrays (TMA), we examined the COX-2/E-cadherin relationship.
Down-regulation of COX-2 by celecoxib led to up-regulation of E-cadherin mRNA and protein levels in conventional gastric cancer cell lines, whereas expression was down regulated in the early-onset gastric cancer (EOGC) cell line. Immunohistochemistry on TMAs of 178 gastric cancers showed no correlation between COX-2 and E-cadherin expression in the conventional or early gastric cancer groups.
The results suggest that COX-2 has an impact on transcriptional regulation of E-cadherin in gastric cancer and our findings further highlight the intriguing nature of EOGCs which appear to have a molecular phenotype distinct from conventional gastric cancer. In addition, our findings also suggest that reduction of COX-2 using nonsteroidal anti-inflammatory drugs in gastric cancer chemoprevention may only be relevant for older patients.
- SourceAvailable from: ncbi.nlm.nih.gov[show abstract] [hide abstract]
ABSTRACT: INTRODUCTION: Emerging data suggest that human inducible regulatory T cells (Tr1) produce adenosine and prostaglandin E(2) and that these factors cooperate in mediating immune suppression. AREAS COVERED: Human Tr1 present in human tumors or blood of cancer patients express ectonucleotidases, CD39 and/or CD73, hydrolyze ATP to adenosine and are COX-2 positive. Expression of CD39 and/or CD73 on human tumors favors expansion and suppressor functions of Tr1. Adenosine and PGE(2) signal via adenosine 2A receptor (A(2A)R) and prostaglandin E(2) receptor 2 (EP(2)R) expressed on effector T (Teff) cells, suppressing their anti-tumor functions by a common mechanism involving upregulation of cytosolic cAMP levels and protein kinase A (PKA) type I activation. The frequency and activity of circulating CD4(+)CD39(+) and CD4(+)COX-2(+) Treg subsets increase in advanced disease and also following oncologic therapies. EXPERT OPINION: Pharmacologic blocking of adenosine-PGE(2) collaboration provides a clinically-feasible strategy for disarming of Treg. Used in conjunction with conventional anti-cancer drugs or immune interventions, pharmacologic inhibitors could improve outcome of oncologic therapies.Expert opinion on biological therapy 06/2011; 11(9):1203-14. · 3.22 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Inflammation is closely related to the progression of cancer as well as tumorigenesis. Here, we investigated the effect of prostaglandin E(2) (PGE(2)) and interleukin-1β (IL-1β) on E-cadherin expression in SNU719 gastric cancer cells. E-cadherin expression decreased as the dose or exposure time of PGE(2) and IL-1β increased, whereas Snail expression increased with dose or time of PGE(2) and IL-1β. E-cadherin expression reduced by PGE(2) treatment increased after the transfection of Snail siRNA. Neutralization of IL-1β using anti-IL-1β antibody blocked the expression pattern of E-cadherin and Snail occurred by IL-1β treatment. However, there was no synergic effect of IL-1β and PGE(2) on the expression pattern of E-cadherin and Snail. In conclusion, inflammatory mediators reduced E-cadherin expression by enhancing Snail expression in gastric cancer cells. Inflammation-induced transcriptional regulation of E-cadherin in gastric cancer has implications for targeted chemoprevention and therapy.Journal of Korean medical science 09/2012; 27(9):987-92. · 0.84 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques. Tissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen). Overall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p=0.085 and p=0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p=0.181 and p=0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p=0.029). A similar association was seen for HER2 IHC and histologic type (p=0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type. Even focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression.Cellular oncology (Dordrecht). 03/2011; 34(2):89-95.