The Expression of Both Peroxisome Proliferator-Activated Receptor Delta and Cyclooxygenase-2 in Tissues Is Associated with Poor Prognosis in Colorectal Cancer Patients

Yoshinaga, Masahiro; Taki, Kentaro; Somada, Shinichi; Sakiyama, Yumiko; Kubo, Nobuhide; Kaku, Toyoma; Tsuruta, Satoru; Kusumoto, Tetsuya; Sakai, Hironori; Nakamura, Kazuhiko; Takayanagi, Ryoichi

doi:10.1007/s10620-010-1389-9

Cited by 34 publications

(37 citation statements)

References 28 publications

(30 reference statements)

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“…Moreover, we found a novel function of COX-2-derived PGE 2 signaling in mediating crosstalk between colonic tumor epithelial cells and macrophages. Our results indicate that both PPARδ and COX-2-derived PGE 2 signaling coordinately promotes colonic inflammation and colitis-associate tumorigenesis and is likely to be clinically relevant because the elevation of both PPARδ and COX-2 in tumor tissues correlates with a poor prognosis in CRC patients (43).…”

Section: Discussionmentioning

confidence: 76%

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Wang¹,

Fu²,

Wei³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E 2 (PGE 2 ), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE 2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE 2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.colorectal cancer | COX-2/PGE 2

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Section: Discussionmentioning

confidence: 76%

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Wang¹,

Fu²,

Wei³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies have suggested that PPAR-δ expression has prognostic value for cancer patients including those with colorectal cancer (54, 55). However, there are inconsistencies in the reported PPAR-δ expression levels of different human tumors compared to normal tissue as well as how PPAR-δ expression correlates with prognosis.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway

Beyaz

Yılmaz

2016

Clinical Cancer Research

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Peroxisome Proliferator-Activated Receptor delta (PPAR-δ) is a nuclear receptor transcription factor that regulates gene expression during development and disease states such as cancer. However, the precise role of PPAR-δ during tumorigenesis is not well understood. Recent data suggest that PPAR-δ may have context specific oncogenic and tumor suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example in the intestine, pro-obesity diets, like a high fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of a HFD in the stem and progenitor cell compartment are driven by a robust PPAR-δ program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-δ pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that particularly arise in obese patients. Although potent PPAR-δ agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-δ mediates tumorigenesis in diverse tissues and cell-types as well as in response to diet.

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“…First, PPAR / expression is elevated in colon cancer cells, and its endogenous activation has been proposed to mediate the pro-tumorigenic effect of PGs in the colon [370]. Importantly, tissue expression of PPAR / has been associated with poor prognosis in CRC patients [371], and its genetic disruption decreases the tumorigenicity of human colon cancer cells [372]. Moreover, repression of PPAR / by NSAIDs has been shown to mediate the tumor suppressor activity of these agents in CRC [373] and ovarian cancer [374] by a mechanism that includes a decrease of COX-dependent PG production and a direct inhibition of the DNA-binding activity of PPAR / .…”

Section: Ppar /mentioning

confidence: 99%

Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors

Menéndez-Gutierrez

Röszer²,

Ricote

2012

CTMC

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Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/ differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer.

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The Expression of Both Peroxisome Proliferator-Activated Receptor Delta and Cyclooxygenase-2 in Tissues Is Associated with Poor Prognosis in Colorectal Cancer Patients

Abstract: The expression of both PPAR δ and COX-2 in tissues may lead to liver metastasis and consequent poor prognosis in CRC patients.

Cited by 34 publications

References 28 publications

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway

Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors

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