Protective effect of nonsteroidal anti-inflammatory drugs on colorectal adenomas is modified by a polymorphism in peroxisome proliferator-activated receptor δ

Siezen, Christine L. E.; Tijhuis, Marja; Kram, Nicolien; Soest, Eva M. van; Jong, Dirk J. de; Fodde, Riccardo; Kranen, Henk J. van; Kampman, Ellen

doi:10.1097/01.fpc.0000182778.03180.f3

Cited by 35 publications

(31 citation statements)

References 24 publications

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“…In spite of these indications, however, whether PPARd is a good target for chemoprevention and/or treatment of CRC remains controversial. It has been reported that a polymorphism in PPARd modifies the protective effects of nonsteroidal anti-inflammatory drugs on colorectal adenomas (Siezen et al, 2006), but other investigators have not reached the same conclusions in the context of CRC (McGreavey et al, 2005). As mentioned in the Introduction, PPARd was found to be unnecessary for small intestinal polyp formation (Barak et al, 2002), but PPARd attenuated polyp formation in chemical and genetic models (Harman et al, 2004;Reed et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

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Whether peroxisome proliferator-activated receptor (PPAR) d is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARd expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARd in CRC. Immunohistochemical analysis indicated that PPARd expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARd protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARd-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARd-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARd in CRC samples. Based on Western blot analysis and quantitative RT -PCR, high PPARd protein expression correlated with high PPARd mRNA levels. Peroxisome proliferator-activated receptor d may have a supporting role in tumorigenesis, and the close association between PPARd expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.

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Section: Discussionmentioning

confidence: 98%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

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“…The conflicting result of the association between rs2910164 and PAH could be attributed to the distinct genotype frequency in different ethnic populations (e.g., the rs2910164 G allele in Caucasians: 76.58 vs Asians: 47.88%) [30]. Several other polymorphisms within the pathway of COX-2 production, including rs20417, rs20432, rs5275 and rs4648310, have been proven to be functional and are associated with a risk of various human diseases [31,32,33,34,35,36,37,38]. They might also be responsible for the development of PAH.…”

Section: Discussionmentioning

confidence: 99%

rs2910164 Polymorphism Confers a Decreased Risk for Pulmonary Hypertension by Compromising the Processing of microRNA-146a

Liu

Chen²,

Wu³

et al. 2015

Cell Physiol Biochem

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Objective: To identify the association between rs2910164 polymorphism and development of pulmonary hypertension, as well as underlying molecular mechanism. Methods and Results: 281 patients diagnosed with pulmonary hypertension and 325 normal controls were recruited, and rs2910164 genotype was determined in each participant: As a result, the rs2910164 polymorphism was significantly associated with the development of pulmonary hypertension after adjusting some potential confounding factors. Additionally, lung tissue samples were obtained from 39 patients who received surgical intervention for lung cancer, and mRNA and protein expression levels of miR-146a, COX-2 and PGI₂ production were examined. Furthermore, we confirmed COX-2 is a target of miR-146a in pulmonary smooth muscle cells, and identified a differentially expressed miR-146a and COX-2 in each rs2910164 genotype group. We observed a significant association between rs2910164 polymorphism and the levels of either COX-2 or PGI₂ using real-time PCR and western blot. In conclusion, the results of this study demonstrate that the rs2910164 CC and GC genotype is associated with a decreased risk of pulmonary hypertension, which could be attributed to defective miRNA processing and compromised ability to inhibit production of COX-2 and PGI₂.

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“…Aspirin has an added advantage of being readily available and inexpensive. Some epidemiologic studies have found an association between the consumption of aspirin and a reduced risk of many cancers, including EOC (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Signal-Regulated Kinase Is a Target of Cyclooxygenase-1-Peroxisome Proliferator-Activated Receptor-δ Signaling in Epithelial Ovarian Cancer

Daikoku¹,

Tranguch²,

Chakrabarty³

et al. 2007

Cancer Research

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The underlying causes of epithelial ovarian cancer (EOC) are unclear, and treatment options for patients with advanced disease are limited. There is evidence that the use of nonsteroidal anti-inflammatory drugs is associated with decreased risk of developing EOC. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX)-1 and COX-2, which catalyze prostaglandin biosynthesis. We previously showed that mouse and human EOCs have increased levels of COX-1, but not COX-2, and a COX-1-selective inhibitor, SC-560, attenuates prostaglandin production and tumor growth. However, the downstream targets of COX-1 signaling in EOC are not yet known. To address this question, we evaluated peroxisome proliferator-activated receptor D (PPARD) expression and function in EOC. We found that EOC cells express high levels of PPARD, and neutralizing PPARD function reduces tumor growth in vivo. More interestingly, aspirin, a nonsteroidal anti-inflammatory drug that preferentially inhibits COX-1, compromises PPARD function and cell growth by inhibiting extracellular signal-regulated kinases 1/2, members of the mitogen-activated protein kinase family. Our study, for the first time, shows that whereas PPARD can be a target of COX-1, extracellular signal-regulated kinase is a potential target of PPARD. The ability of aspirin to inhibit EOC growth in vivo is an exciting finding because of its low cost, lack of cardiovascular side effects, and availability. [Cancer Res 2007;67(11):5285-92]

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Protective effect of nonsteroidal anti-inflammatory drugs on colorectal adenomas is modified by a polymorphism in peroxisome proliferator-activated receptor δ

Abstract: This study confirms the protective effect of NSAIDs and suggests a modulating effect of a SNP in the promoter of PPARdelta.

Cited by 35 publications

References 24 publications

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

rs2910164 Polymorphism Confers a Decreased Risk for Pulmonary Hypertension by Compromising the Processing of microRNA-146a

Extracellular Signal-Regulated Kinase Is a Target of Cyclooxygenase-1-Peroxisome Proliferator-Activated Receptor-δ Signaling in Epithelial Ovarian Cancer

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