Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis

Kamei, Daisuke; Murakami, Makoto; Nakatani, Yoshihito; Ishikawa, Yukio; Ishii, Toshiharu; Kudo, Ichiro

doi:10.1074/jbc.m213290200

Cited by 181 publications

(181 citation statements)

References 68 publications

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“…Our previous immunohistochemical analyses demonstrated a preferential localization of mPGES-1 in MF-like cells infiltrating the stromal tissues in proximity to cancer cells (Kamei et al, 2003). As shown in Figure 2b, mPGES-1 was expressed in leukocytes invading into the stroma of the colon carcinoma region in the AOM-treated mice.…”

Section: Reduced Growth Of Intrasplenically Transplanted Tumor Cells mentioning

confidence: 55%

“…These results suggest that overproduction of mPGES-1-derived PGE 2 is not sufficient for initiating colon carcinogenesis, but is crucially involved in ACF formation. We previously reported that the forcible transfection of mPGES-1 in combination with COX-2 into HEK293 cells led to cellular transformation with a concomitant and robust increase in PGE 2 (Kamei et al, 2003). It was also shown that overexpression of COX-2 induced genomic instability in MCF10A breast cancer cells (Singh et al, 2007) and that AOM-induced colon tumors in mice were chromosomally stable and were characterized by low-level microsatellite instability (Guda et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that mPGES-1 is constitutively expressed in several cancers, most of which also express COX-2 constitutively (Kamei et al, 2003;Golijanin et al, 2004). We have reported that the forcible transfection of mPGES-1 in combination with COX-2, but not with COX-1, into HEK293 cells led to cellular transformation, with a concomitant and robust increase in PGE 2 (Kamei et al, 2003). Transgenic mice overexpressing both COX-2 and mPGES-1 developed metaplasia, hyperplasia and tumorous growth in the glandular stomach with heavy macrophage (MF) infiltration (Oshima et al, 2004(Oshima et al, , 2005.…”

Section: Introductionmentioning

confidence: 93%

“…Induction of mPGES-1 expression and its function have been observed in various diseases and systems in which COX-2-driven PGE 2 has been implicated, such as rheumatoid arthritis, febrile response, reproduction, bone metabolism, cardiovascular function, stroke and Alzheimer's disease (Kamei et al, 2004;Samuelsson et al, 2007;Hara et al, 2010). It has also been reported that mPGES-1 is constitutively expressed in several cancers, most of which also express COX-2 constitutively (Kamei et al, 2003;Golijanin et al, 2004). We have reported that the forcible transfection of mPGES-1 in combination with COX-2, but not with COX-1, into HEK293 cells led to cellular transformation, with a concomitant and robust increase in PGE 2 (Kamei et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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Section: Reduced Growth Of Intrasplenically Transplanted Tumor Cells mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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“…The overexpression of COX-2 has been linked to the development of various types of human cancers [65,66]. Several reports have indicated that COX-2 affects the invasiveness of cancer cells [67][68][69]. Gastric fibroblasts stimulate the invasiveness of scirrhous gastric cancer cells, while a selective COX-2 inhibitor, JTE-522, decreases HGF production from gastric fibroblasts by suppression of PGE2 productions, thus resulting in decreased invasion ability of gastric cancer cells [62,70].…”

Section: Therapies To Target the Cancer-stromal Interactionsmentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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Fibroblasts play an important role in the progression, growth and spread of gastric cancers. Cancer-stroma interactions have been especially evident in the scirrhous type of gastric carcinoma. Fibroblasts are associated with the cancer progression at the primary and metastatic site. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors produced by organ-specific fibroblasts. Fibroblasts are therefore a key determinant in the malignant progression of gastric cancer and represent an important target for cancer therapies.

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Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Nan

Hutter

Lin

et al. 2015

JAMA

179

108

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IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTSCase-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES Colorectal cancer.RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10 −28 ) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10 −9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10 −33 ) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10 −9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10 −30 ) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCEIn this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

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Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis

Cited by 181 publications

References 68 publications

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

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