Review Article | Open Access
Hedi Harizi, "Epigenetic Regulations of Inflammatory Cyclooxygenase-Derived Prostanoids: Molecular Basis and Pathophysiological Consequences", Mediators of Inflammation, vol. 2015, Article ID 841097, 9 pages, 2015. https://doi.org/10.1155/2015/841097
Epigenetic Regulations of Inflammatory Cyclooxygenase-Derived Prostanoids: Molecular Basis and Pathophysiological Consequences
The potential relevance of prostanoid signaling in immunity and immunological disorders, or disease susceptibility and individual variations in drug responses, is an important area for investigation. The deregulation of Cyclooxygenase- (COX-) derived prostanoids has been reported in several immunoinflammatory disorders such as asthma, rheumatoid arthritis, cancer, and autoimmune diseases. In addition to the environmental factors and the genetic background to diseases, epigenetic mechanisms involved in the fine regulation of prostanoid biosynthesis and/or receptor signaling appeared to be an additional level of complexity in the understanding of prostanoid biology and crucial in controlling the different components of the COX pathways. Epigenetic alterations targeting inflammatory components of prostanoid biosynthesis and signaling pathways may be important in the process of neoplasia, depending on the tissue microenvironment and target genes. Here, we focused on the epigenetic modifications of inflammatory prostanoids in physiological immune response and immunological disorders. We described how major prostanoids and their receptors can be functionally regulated epigenetically and consequently the impact of these processes in the pathogenesis inflammatory diseases and the development of therapeutic approaches that may have important clinical applications.
The proinflammatory environment induced by prostanoids is increasingly being recognized as a critical element for both inflammatory diseases and cancer . The molecular and cellular basis of the immune regulation by prostanoids in physiological and pathological situations remain a topic of great interest. Biosynthesis of arachidonic-derived metabolites and receptors for major prostanoids are widely expressed throughout the immune system  and function at multiple levels in immune and inflammatory regulations . Many cellular functions that are critical in the pathological processes such as carcinogenesis chronic inflammation pathologies and asthma are regulated by various prostanoids that are metabolites of Cyclooxygenase (COX) pathways, especially prostaglandin E2 (PGE2) . This inflammatory bioactive lipid mediator is the best known and most well studied COX metabolite . It has been reported that the endogenously released PGE2, the major metabolite of the COX pathway, suppresses multiple immune functions acting on most types of immune cells . Among COX-derived prostanoids, PGE2 is one of the best characterized in terms of immunomodulation. It is a very attractive molecule in that it by itself exhibits both pro- and anti-inflammatory effects, particularly on dendritic cells (DCs). For example, in physiological conditions, PGE2 critically regulates the inflammatory phenotype and function of DCs , the most potent antigen-presenting cells (APC) of the immune system and known by their ability to stimulate naive, memory, and effector T cells . COX-2-derived prostanoids are also involved in regulating various aspects of the T cell biology, including proliferation, apoptosis, cytokine secretion, differentiation, and chemotaxis [1, 9, 10].
In pathological conditions, overexpression of COX enzymes and abnormal production of COX-derived PGE2 [11, 12] have been reported to be linked to all carcinogenesis stages ranging from initiation to tumor progression . Growing bodies of evidence have shown that COX-2-issued PGE2 markedly affects tumor angiogenesis [14–16]. When overexpressed, COX-2-synthesized PGE2 acts as a tumor promoter, regulates tumor angiogenesis , and potently alters the phenotype and function of circulating and tumor infiltrating cells, resulting in cancer-associated immunodeficiency . Moreover, many tumors are associated with high levels of immunosuppressive PGE2 and an impaired differentiation and antigen-presenting function of DCs with an immature phenotype [18, 19]. In cancer, COX-2-derived PGE2 has also been reported to play crucial roles in the immunosuppressive function of Treg cells . For these reasons and because of its inducible property, COX-2 expression must be tightly regulated and must be subjected to fine regulations.
COX-2 expression and PGE2 production can be induced by several inflammatory stimuli including growth factors and cytokines . Proinflammatory cytokines, such as TNF- [22, 23], IL-1 , and IFN- , have the potential to induce COX-2 gene expression, whereas anti-inflammatory cytokines, in particular IL-4 , IL-13 [27, 28], and IL-10 , can inhibit COX-2 gene induction and prostanoid biosynthesis. In addition to the environmental factors and the genetic background to inflammation, epigenetic acetylation of histone and nonhistone proteins by histone acetyltransferases plays a pivotal role in the expression of the proinflammatory COX-2/PGE2/EP receptor axis and its downstream signalling pathways.
2. Prostanoid Biosynthesis and Signaling Pathways
Prostanoids are inflammatory lipid signaling molecules synthesized by COX enzymes from phospholipase A2-released arachidonic acid, a 20 carbon polyunsaturated fatty acid present in most mammalian cell membranes and a major component of animal fats. Arachidonic acid is released by phospholipase A2 from the cell membrane and is converted to PGG2 and then reduced to PGH2 by COX enzymes. Two isoforms of COX enzyme are involved in the biosynthesis of prostanoids, COX-1 (also known as Prostaglandin-endoperoxide synthase, PTGS1) and COX-2 (also known as PTGS2). COX-2 is a membrane-bound and heme-containing enzyme which is a member of the mammalian heme-dependent peroxidase family. Although the expression profiles of both isoforms varies from tissue to tissue, COX-1, a housekeeping gene, is generally considered the constitutive form, being responsible for the homeostatic production of prostanoids and highly expressed in most tissues, including platelets, lung, prostate, brain, gastrointestinal tract, kidney, liver, and spleen . However, COX-2, often referred to as the inducible or rate-limiting isoform, is usually undetectable in most normal tissues, being responsible for most of the prostanoid production during inflammation and markedly upregulated in various types of cancer, as well as in other diseases [1, 17, 31]. COX-2 gene can also be constitutively expressed in some tissues, such as the endothelium, kidney, gastrointestinal mucosa, and brain [32–34], and the constitutive expression of COX-2 gene may be a contributing factor promoting tumoral pathologies, such as colorectal cancer .
Despite their different physiological functions, COX-1 and COX-2 enzymes are known by their different susceptibilities to inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) used for symptomatic treatment of inflammatory diseases, particularly due to their potent analgesic effect . The common mechanism by which NSAIDs mediate their action is the inhibition of COX activity. Because COX-2 is thought to be the predominant isoform involved in the inflammatory response , most of the new research on anti-inflammatory drugs has been aimed at targeting the COX-2-inducible enzyme. Newly developed drugs that have high selectivity against COX-2, such as celecoxib, have been proved to be potent anti-inflammatory compounds without causing gastric toxicity.
PGE2 exerts its diverse and often antagonistic effects on target cells by various designated EP receptors (EP1–4) differentially expressed on many cell types and have been shown to differ in their signal transduction pathways [2, 38]. The use of agonists inducing changes in the levels of second messenger including, cAMP and free Ca2+ and the identification of G protein coupling by a variety of methods have allowed studying the signal transduction pathways of PGE2 receptors. The four EP receptors showed differential patterns of tissue distribution. EP1 mRNA is ubiquitously expressed in murine tissues, while high levels of EP3 receptor mRNA are found in adipose tissues, pancreas, kidney, and vena cava. EP4 mRNA is mainly expressed in the gastrointestinal tract, uterus, hematopoietic tissues, and skin, whereas EP2 receptor mRNA was found to be least abundant among EP receptors, with the highest expression occurring in the airways, ovary, bone marrow, and olfactory epithelium . In addition to their differential patterns of tissue distribution, EP receptors have been shown to differ in their signal transduction pathways . The EP1 receptor activates phospholipase C and phosphatidylinositol turnover and stimulates the release of intracellular calcium. The EP2 and EP4 receptors signal by stimulating adenylate cyclase, which increases the intracellular levels of cAMP. Signaling by the EP3 receptor is more complex because of multiple EP3 receptor isoforms generated by alternative splicing from a single EP3 gene. Because of these various signaling pathways, PGE2 can exert different and sometimes opposite effects on target cells . Among the four PGE2 receptors, EP2 and EP4 mediate most, if not all, of the PGE2 effects on immune regulation [42–45].
Although, predominantly produced by APC, including DCs and macrophages [46, 47], PGE2 is known by its ubiquitous function because of the expression of various PGE2 EP receptors subtypes on immune and nonimmune cells [2, 7, 48]. In addition to environmental factors and genetic background to inflammation and immune disorders, prostanoid biosynthetic pathways and signaling can be regulated by epigenetic mechanisms.
3. Epigenetic Modifications of COX Genes
Many advances in our understanding of chromatin structure, histone modification, transcriptional activity, gene silencing, and DNA methylation have resulted in an increasingly integrated view of epigenetics and its impact in normal and pathological physiology. Inflammatory genes of the prostanoid pathways can be functionally regulated epigenetically. Dynamic epigenetic changes of prostanoid pathways can affect the biosynthesis of COX metabolites and/or the EP receptor signaling. Several epigenetic mechanisms, including DNA methylation, modification of histones, and noncoding RNAs [49, 50] are involved in these processes. It has been reported that histone acetylation is an important modification affecting gene transcription and is controlled by the action of histone acetyltransferase and deacetylase .
In mammals, changes in DNA methylation status and alterations in chromatin structure by histone modification represent the major epigenetic mechanisms involved in the regulation of gene transcription [52–54]. In fact, mammal’s DNA is subjected to covalent modification that alters the chemical information content displayed in the major groove. This molecular process is classically associated with functions in genome defense and in genomic imprinting . Described for the first time in calf thymus , methylation of cytosine is the most abundant DNA modification and occurs mainly during cellular differentiation . DNA methylation is catalyzed by a well characterized family of enzymes, termed DNA methyltransferases . In human cells, 60–80% of all CpG sites are highly methylated with some variation by cell type [59, 60].
Prostanoids are biologically active lipid mediators involved in several biological processes such as pain, fever, regulation of vascular tone, renal function, mucosal integrity, inflammation, angiogenesis apoptosis, and tumor growth. They are very attractive signaling molecules known by their critical role in regulating immune cell function [4, 7, 61]. These numerous biological processes are regulated by prostanoids through acting on secretion of various proteins, proteolysis, transcriptional activation, and epigenetic control. The biology of prostanoids has been extensively studied in cancer, and COX-2 pathway has emerged as a potential therapeutic target in some tumors [62, 63].
Genes encoding for inflammatory prostanoids and their receptors are subjected to epigenetic modifications by acetylation of core histone. Substantial evidences reported that COX-2 is an important epigenetically controlled gene inflammatory gene in many pathological processes [63, 64]. Immune disorders, such as asthma and cancer, are characterized by the expression of various inflammatory genes that can be epigenetically regulated by acetylation of core histone. For example, increased activity of histone acetyltransferase and reduced activity of histone deacetylase have been observed in asthmatic patients . The increased activity of histone acetyltransferase and the decreased activity of histone deacetylase resulted in the induction of inflammatory gene expression [65, 66]. Corticosteroids used as antiasthmatic treatment can exert their anti-inflammatory effects by regulating histone acetyltransferase or histone deacetylase activity . Histone deacetylases are histone modifying enzymes identified as critical regulators of proinflammatory cascade, especially by acting on NF-B signaling pathway . Recent study reported that epigenetic regulation is an important mechanism by which iloprost, a PGI2 analog, modulates asthma-related chemokines expression in monocytes . Used as a potential candidate for treating asthma, PGI2 analog acts as an anti-inflammatory molecule inhibiting TNF expression via MAPK signaling pathway and the downregulation of histone H3K4 trimethylation .
COX-2 is also an epigenetically controlled gene in various cellular processes including the development, differentiation, and function of many immune cells, such as T regulatory (Treg) cells involved in the cancer-mediated immune suppression, and play a key role in immune regulations [71, 72]. Tumor-infiltrating Treg cells are able to suppress tumor-specific T cell immunity and contribute to the growth of tumors in a COX-2-dependent manner in mouse and human [64, 73, 74]. In cancer, COX-2-derived PGE2 plays essential roles in the immunosuppressive function of Treg cells in an autocrine and paracrine manner. These immunosuppressive cells express COX-2 and produce PGE2 upon differentiation . The endogenously produced PGE2 released in the tumor microenvironment can inhibit T cell-mediated antitumor responses [75–77] and enhance the suppressive capacity of CD4+ CD25+ Treg cells . These immunosuppressive cells are characterized by their specific molecular marker Foxp3 (Forkhead box protein P3), which is also an epigenetically modulated transcription factor involved in the development, differentiation, and function of Treg cells [79, 80]. Deficiency or spontaneous mutations of Foxp3 gene leads to fatal autoimmune lymphoproliferation and autoimmune diseases caused by inactive Treg cells. In lung cancer, Foxp3 expression and Treg cell activity can be induced by COX-2-derived PGE2, and these effects can be reversed by COX-2 inhibitors and PGE2 receptor antagonists . Taken together, these data suggested that targeting COX-2/PGE2 axis may have crucial roles in immune regulations in cancer microenvironment.
In addition to its indirect action, COX-2-derived PGE2 can exert direct effects on tumor cells. Several lines of evidence reported that PGE2 exhibits antiapoptotic and invasion-promoting effects thus supporting protumoral roles in some cancers [82, 83]. Evidence from epidemiological studies and clinical trials clearly indicates that aspirin, which is one of the most widely used drugs in the world, can protect against different types of cancer . The COX-dependent mechanisms for the antitumoral effects of low dose aspirin have been clearly demonstrated especially in colorectal cancer  and the possible contribution of individual genetic cancer susceptibility to aspirin response  should be taken into consideration as an additional level of complexity in the understanding of the antitumor effects aspirin. Despite the individual genetic cancer susceptibility to aspirin, epigenetic control of some target genes appeared to play a crucial role in the antiproliferation of salicylates and NSAIDs. Accumulating data reported that targeting the epigenome may play a key role in cancer chemoprevention [87, 88].
Since the cancer genome usually contains both hyper- and hypomethylated genes to increase invasion, proliferation, and metastasis, it is not surprising that COX-2 gene can be upregulated or downregulated by epigenetic mechanisms. Several lines of evidence reported that COX-2 expression and prostanoid biosynthesis may be affected by various perturbations that are present in most cancer types. For example, silencing of COX-2 gene by hypermethylation has been reported in human colon cancer [89, 90]. Many data from epidemiological and clinical studies reported that COX-2 expression and prostanoid biosynthesis are frequently overexpressed in many cancer types [11, 91, 92]. The general consensus is that the elevated expression of COX-2 protein is commonly observed in many chronic inflammatory diseases and cancer . However, other studies clearly reported that COX-2 protein may be downregulated in tumors of a subset of colorectal and gastric cancer patients, and the downregulation of the COX-2 gene appeared to be strongly correlated with CpG island DNA methylation [90, 94]. These conflicting data suggested that other factors may contribute to the regulation of COX-2 gene in chronic inflammatory diseases and cancer. Kikuchi et al.,  reported that the downregulation of the COX-2 gene is mediated by histone deacetylation in gastric cancer, whereas COX-1 gene has only been found epigenetically silenced by promoter hypermethylation in pancreatic tumors . The hypermethylation of COX-2 gene by histone deacetylation has been described in several tumor types such as gastric , pancreatic , breast [97, 98], hepatic [99–101], nasopharyngeal , prostate [103, 104], esophageal [105, 106], and cervical tumors [107, 108]. Collectively, these data clearly showed that epigenetic alterations play a critical role in the deregulation and aberrant expression of the genes of the COX pathway in different types of cancer.
PGE2 regulates numerous biological processes by modulating transcriptional activation, proteolysis, secretion of various proteins, and epigenetic control. This lipid mediator could not only be regulated epigenetically but also act by itself as a potential epigenetic regulator of the transcriptional mechanisms of other inflammatory processes. In fact, given its increased production in chronic inflammatory diseases and cancer, it is not surprising that PGE2 could act as a potential regulator of other inflammatory genes. For example, it has been reported that PGE2 activates IL-8 transcription gene through specific demethylation of the CpG site and abnormal acetylation of histone H3 in the IL-8 promoter gene in human astrocytoma .
4. Epigenetic Modifications Targeting EP Receptor Signaling
PGE2 exerts its effects on target cells by binding on four EP receptors with seven transmembrane domains to trigger various intracellular signal transduction cascades, impacting cell growth, survival, apoptosis, and immune responsiveness . The existence of four subtypes of PGE2 receptors is remarkable given that each of the other prostanoids each has only a single receptor. This complex family of EP receptors coupled to distinct intracellular signals provides a molecular basis for the diverse physiological and sometimes opposing actions of PGE2 . Differential expression of these EP receptors mediates the diverse and often antagonistic effects of PGE2 on a variety of cell types . Like many inflammatory signaling molecules, genes encoding for all of the PGE2 receptors are subjected to fine regulations by various mechanisms. Growing bodies of evidence indicate that epigenetic modifications play a critical role in the deregulation of the genes of the EP receptors with critical consequences on downstream signaling [112, 113]. DNA CpG methylation and histone posttranslational modifications have been reported to be major epigenetic mechanisms affecting EP receptor expression and synthesis in most cancer types . It has been reported that histone acetylation was found to be a critical regulator of EP receptor expression in cancer . For example, EP receptor expression appeared to be frequently dysregulated in non-small lung cancer (NSLC), via DNA CpG methylation and histone posttranslational modifications . The EP1 receptor signaling, which is involved in PGE2-mediated activation of MAPK/ERK-induced cellular proliferation , was found to be downregulated by histone deacetylase inhibitors in NSCLC cell lines. The EP2 expression appeared to be predominantly downregulated by DNA CpG methylation and may have an important role in the pathogenesis of NSLC . The epigenetic downregulation of the EP2 gene by DNA CpG methylation was also observed to be associated with progression of neuroblastomas . In addition, EP2 gene has been found to be hypermethylated in lung  and gastric [118, 119] cancers. In idiopathic pulmonary fibrosis, DNA hypermethylation appeared to be responsible for diminished EP2 expression levels and PGE2 resistance . The use of DNA methylation inhibitors 5-aza-2′-deoxycytidine and zebularine as well as DNA methyltransferase-specific siRNA increased EP2 mRNA and protein expression levels and restored PGE2 responsiveness in fibrotic fibroblasts. Shoji et al.  have reported that the PGE2 receptor subtype EP3 plays a critical role in suppression of cell growth and that its downregulation enhances colon carcinogenesis at a later stage. DNA methylation of the EP3 receptor gene has been demonstrated in both colon cancer and oesophageal cancer and the use of a DNA demethylating agent restored EP3 receptor expression in various cell lines [112, 121]. Hypermethylated EP3  and EP4  genes have been reported in colorectal and gastric tumors, respectively. Moreover, it has been demonstrated that DNA methyltransferase inhibitors and histone deacetylase inhibitors upregulate EP3 and EP4 receptor expression in cancer lung . Collectively, these data clearly demonstrate that EP receptor signaling can be functionally regulated epigenetically and may represent a potential targets for epigenetic therapies in the treatment of inflammatory disorders, such as cancer, autoimmune diseases, and asthma.
5. Concluding Remarks
The inflammatory COX-derived prostanoids are increasingly being recognized as critical regulators for both immunity and immunological diseases. Substantial data clearly showed that prostanoid biosynthesis and signaling pathways are altered in these pathological processes. Pharmacological targeting of prostanoid biosynthesis and/or signaling with NSAIDs, COX-2 selective inhibitors, and EP receptor antagonists has been investigated for many years with promising results at both preventive and therapeutic levels. There are many fascinating accumulating data on the biology of inflammatory prostanoids in normal and pathological settings. Numerous studies reported that epigenetic control is an important mechanism by which COX/PGE2/EP receptor axis can be markedly modulated. Epigenetic modifications emerged as additional levels of complexity to the understanding of the regulation and functionalities of the COX pathway and prostanoid signaling in physiological and pathological settings. Investigating the epigenetic alterations that impact both COX enzymes and prostanoid receptors may inform on pathological events that characterize the immunomodulatory functions of these inflammatory lipid mediators in various immune disorders and may be relevant for the efficient clinical use of NSAIDs, COX-2 selective inhibitors, and EP receptor antagonists at both preventive and therapeutic levels. Thus, besides NSAIDs and EP receptor antagonists, epigenetic therapies, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, should be considered in studying cellular proliferation and invasiveness in immune disorders and in the development of therapeutic approaches aimed at targeting inflammatory prostanoid biosynthesis and/or signaling. Epigenetic regulations, especially alterations in DNA methylation, are intimately linked to the development of various human tumors. Because the cancer genome usually contains both hyper- and hypomethylated genes to increase invasion, proliferation, and metastasis, epigenetic control of inflammatory genes such as COX-2 should be taken into consideration as a potential therapeutic target in tumoral pathology. Thus, the epigenetic regulation of prostanoids is extremely interesting and deserves further investigations.
Conflict of Interests
There is no conflict of interests regarding the publication of this paper.
- H. Harizi, J.-B. Corcuff, and N. Gualde, “Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology,” Trends in Molecular Medicine, vol. 14, no. 10, pp. 461–469, 2008.
- S. Narumiya, Y. Sugimoto, and F. Ushikubi, “Prostanoid receptors: structures, properties, and functions,” Physiological Reviews, vol. 79, no. 4, pp. 1193–1226, 1999.
- C. D. Funk, “Prostaglandins and leukotrienes: advances in eicosanoid biology,” Science, vol. 294, no. 5548, pp. 1871–1875, 2001.
- S. L. Tilley, T. M. Coffman, and B. H. Koller, “Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes,” The Journal of Clinical Investigation, vol. 108, no. 1, pp. 15–23, 2001.
- N. Gualde and H. Harizi, “Prostanoids and their receptors that modulate dendritic cell-mediated immunity,” Immunology and Cell Biology, vol. 82, no. 4, pp. 353–360, 2004.
- S. G. Harris, J. Padilla, L. Koumas, D. Ray, and R. P. Phipps, “Prostaglandins as modulators of immunity,” Trends in Immunology, vol. 23, no. 3, pp. 144–150, 2002.
- H. Harizi, C. Grosset, and N. Gualde, “Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes,” Journal of Leukocyte Biology, vol. 73, no. 6, pp. 756–763, 2003.
- C. Münz, R. M. Steinman, and S.-I. Fujii, “Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity,” Journal of Experimental Medicine, vol. 202, no. 2, pp. 203–207, 2005.
- M. Betz and B. S. Fox, “Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines,” Journal of Immunology, vol. 146, no. 1, pp. 108–113, 1991.
- E. M. Aandahl, W. J. Moretto, P. A. Haslett et al., “Inhibition of antigen-specific T cell proliferation and cytokine production by protein kinase A type I,” Journal of Immunology, vol. 169, no. 2, pp. 802–808, 2002.
- S. M. Prescott and F. A. Fitzpatrick, “Cyclooxygenase-2 and carcinogenesis,” Biochimica Biophysica Acta, vol. 1470, pp. 69–78, 2000.
- S. Chell, A. Kadi, A. C. Williams, and C. Paraskeva, “Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer,” Biochimica et Biophysica Acta—Reviews on Cancer, vol. 1766, no. 1, pp. 104–119, 2006.
- S. Gately, “The contributions of cyclooxygenase-2 to tumor angiogenesis,” Cancer and Metastasis Reviews, vol. 19, no. 1-2, pp. 19–27, 2000.
- M. Tsujii, S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, and R. N. DuBois, “Cyclooxygenase regulates angiogenesis induced by colon cancer cells,” Cell, vol. 29, no. 5, pp. 705–716, 1998.
- J. G. Rozic, C. Chakraborty, and P. K. Lala, “Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis,” International Journal of Cancer, vol. 93, no. 4, pp. 497–506, 2001.
- M. Sonoshita, K. Takaku, N. Sasaki et al., “Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice,” Nature Medicine, vol. 7, no. 9, pp. 1048–1051, 2001.
- L. Yang, N. Yamagata, R. Yadav et al., “Cancer-associated immunodefidency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor,” Journal of Clinical Investigation, vol. 111, no. 5, pp. 727–735, 2003.
- S. Kusmartsev and D. I. Gabrilovich, “Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer,” Cancer and Metastasis Reviews, vol. 25, no. 3, pp. 323–331, 2006.
- A. Pinzon-Charry, T. Maxwell, and J. A. López, “Dendritic cell dysfunction in cancer: a mechanism for immunosuppression,” Immunology and Cell Biology, vol. 83, no. 5, pp. 451–461, 2005.
- M. Mahic, S. Yaqub, C. C. Johansson, K. Taskén, and E. M. Aandahl, “FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism,” The Journal of Immunology, vol. 177, no. 1, pp. 246–254, 2006.
- D. S. Whittaker, K. S. Bahjat, L. L. Moldawer, and M. J. Clare-Salzler, “Autoregulation of human monocyte-derived dendritic cell maturation and IL-12 production by cyclooxygenase-2-mediated prostanoid production,” Journal of Immunology, vol. 165, no. 8, pp. 4298–4304, 2000.
- L. Minghetti, D. T. Walsh, G. Levi, and V. H. Perry, “In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines,” Journal of Neuropathology & Experimental Neurology, vol. 58, no. 11, pp. 1184–1191, 1999.
- R. Vlahos and A. G. Stewart, “Interleukin-1α and tumour necrosis factor-α modulate airway smooth muscle DNA synthesis by induction of cyclo-oxygenase-2: inhibition by dexamethasone and fluticasone propionate,” British Journal of Pharmacology, vol. 126, no. 6, pp. 1315–1324, 1999.
- Z.-F. Huang, J. B. Massey, and D. P. Via, “Differential regulation of cyclooxygenase-2 (COX-2) mRNA stability by interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in human in vitro differentiated macrophages,” Biochemical Pharmacology, vol. 59, no. 2, pp. 187–194, 2000.
- H. Matsuura, M. Sakaue, K. Subbaramaiah et al., “Regulation of cyclooxygenase-2 by interferon γ and transforming growth factor α in normal human epidermal keratinocytes and squamous carcinoma cells. Role of mitogen-activated protein kinases,” Journal of Biological Chemistry, vol. 274, no. 41, pp. 29138–29148, 1999.
- H. Niiro, T. Otsuka, K. Izuhara et al., “Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils,” Blood, vol. 89, no. 5, pp. 1621–1628, 1997.
- M. Díaz-Cazorla, D. Pérez-Sala, J. Ros, W. Jiménez, M. Fresno, and S. Lamas, “Regulation of cyclooxygenase-2 expression in human mesangial cells—transcriptional inhibition by IL-13,” European Journal of Biochemistry, vol. 260, no. 1, pp. 268–274, 1999.
- N. Alaaeddine, J. A. Di Battista, J. Pelletier, K. Kiansa, J. Cloutier, and J. Martel-Pelletier, “Inhibition of tumor necrosis factor α-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways,” Arthritis & Rheumatism, vol. 42, no. 4, pp. 710–718, 1999.
- H. Niiro, T. Otsuka, T. Tanabe et al., “Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4,” Blood, vol. 85, no. 12, pp. 3736–3745, 1995.
- T. Tanabe and N. Tohnai, “Cyclooxygenase isozymes and their gene structures and expression,” Prostaglandins & Other Lipid Mediators, vol. 68-69, pp. 95–114, 2002.
- E. M. Smyth, T. Grosser, M. Wang, Y. Yu, and G. A. FitzGerald, “Prostanoids in health and disease,” Journal of Lipid Research, vol. 50, pp. S423–S428, 2009.
- M. K. O'Banion, “Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology,” Critical Reviews in Neurobiology, vol. 13, no. 1, pp. 45–82, 1999.
- N. Zidar, K. Odar, D. Glavac, M. Jerse, T. Zupanc, and D. Stajer, “Cyclooxygenase in normal human tissues—is COX-1 really a constitutive isoform, and COX-2 an inducible isoform?” Journal of Cellular and Molecular Medicine, vol. 13, no. 9, pp. 3753–3763, 2009.
- T. Grosser, S. Fries, and G. A. FitzGerald, “Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities,” Journal of Clinical Investigation, vol. 116, no. 1, pp. 4–15, 2006.
- D. A. Dixon, F. F. Blanco, A. Bruno, and P. Patrignani, “Mechanistic aspects of COX-2 expression in colorectal neoplasia,” Recent Results in Cancer Research, vol. 191, pp. 7–37, 2013.
- W. L. Smith and D. L. DeWitt, “Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs,” Seminars in Nephrology, vol. 15, no. 3, pp. 179–194, 1995.
- R. N. DuBois, S. B. Abramson, L. Crofford et al., “Cyclooxygenase in biology and disease,” The FASEB Journal, vol. 12, no. 12, pp. 1063–1073, 1998.
- R. M. Breyer, C. K. Bagdassarian, S. A. Myers, and M. D. Breyer, “Prostanoid receptors: subtypes and signaling,” Annual Review of Pharmacology and Toxicology, vol. 41, pp. 661–690, 2001.
- J. B. Regard, I. T. Sato, and S. R. Coughlin, “Anatomical profiling of G protein-coupled receptor expression,” Cell, vol. 135, no. 3, pp. 561–571, 2008.
- A. Alfranca, M. A. Iñiguez, M. Fresno, and J. M. Redondo, “Prostanoid signal transduction and gene expression in the endothelium: role in cardiovascular diseases,” Cardiovascular Research, vol. 70, no. 3, pp. 446–456, 2006.
- C. Rieser, G. Böck, H. Klocker, G. Bartsch, and M. Thurnher, “Prostaglandin E2 and tumor necrosis factor α cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production,” Journal of Experimental Medicine, vol. 186, no. 9, pp. 1603–1608, 1997.
- T. Kambayashi, R. P. A. Wallin, and H.-G. Ljunggren, “cAMP-elevating agents suppress dendritic cell function,” Journal of Leukocyte Biology, vol. 70, no. 6, pp. 903–910, 2001.
- K. Kabashima, D. Sakata, M. Nagamachi, Y. Miyachi, K. Inaba, and S. Narumiya, “Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells,” Nature Medicine, vol. 9, no. 6, pp. 744–749, 2003.
- C. Nataraj, D. W. Thomas, S. L. Tilley et al., “Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse,” The Journal of Clinical Investigation, vol. 108, no. 8, pp. 1229–1235, 2001.
- E. Kuroda, T. Sugiura, K. Zeki, Y. Yoshida, and U. Yamashita, “Sensitivity difference to the suppressive effect of prostaglandin E2 among mouse strains: a possible mechanism to polarize Th2 type response in BALB/c mice,” Journal of Immunology, vol. 164, no. 5, pp. 2386–2395, 2000.
- S. W. Russell and J. L. Pace, “Both the kind and magnitude of stimulus are important in overcoming the negative regulation of macrophage activation by PGE2,” Journal of Leukocyte Biology, vol. 35, no. 3, pp. 291–301, 1984.
- H. Harizi, M. Juzan, C. Grosset, M. Rashedi, and N. Gualde, “Dendritic cells issued in vitro from bone marrow produce PGE2 that contributes to the immunomodulation induced by antigen-presenting cells,” Cellular Immunology, vol. 209, no. 1, pp. 19–28, 2001.
- Y. Sugimoto, S. Narumiya, and A. Ichikawa, “Distribution and function of prostanoid receptors: studies from knockout mice,” Progress in Lipid Research, vol. 39, no. 4, pp. 289–314, 2000.
- A. D. Goldberg, C. D. Allis, and E. Bernstein, “Epigenetics: a lands cape takes shape,” Cell, vol. 128, no. 4, pp. 635–638, 2007.
- M. Esteller, “Cancer epigenomics: DNA methylomes and histone-modification maps,” Nature Reviews Genetics, vol. 8, no. 4, pp. 286–298, 2007.
- S. L. Berger, “The complex language of chromatin regulation during transcription,” Nature, vol. 447, no. 7143, pp. 407–412, 2007.
- A. P. Wolffe and M. A. Matzke, “Epigenetics: regulation through repression,” Science, vol. 286, no. 5439, pp. 481–486, 1999.
- T. Jenuwein and C. D. Allis, “Translating the histone code,” Science, vol. 293, no. 5532, pp. 1074–1080, 2001.
- G. Egger, G. Liang, A. Aparicio, and P. A. Jones, “Epigenetics in human disease and prospects for epigenetic therapy,” Nature, vol. 429, no. 6990, pp. 457–463, 2004.
- R. Z. Jurkowska, T. P. Jurkowski, and A. Jeltsch, “Structure and function of mammalian DNA methyltransferases,” ChemBioChem, vol. 12, no. 2, pp. 206–222, 2011.
- R. D. Hotchkiss, “The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography,” The Journal of Biological Chemistry, vol. 175, pp. 315–332, 1948.
- B. Richardson, “Impact of aging on DNA methylation,” Ageing Research Reviews, vol. 2, no. 3, pp. 245–261, 2003.
- S. Klimasauskas, S. Kumar, R. J. Roberts, and X. Cheng, “Hhal methyltransferase flips its target base out of the DNA helix,” Cell, vol. 76, no. 2, pp. 357–369, 1994.
- E. Hodges, A. Molaro, C. O. Dos Santos et al., “Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment,” Molecular Cell, vol. 44, no. 1, pp. 17–28, 2011.
- R. Lister, M. Pelizzola, R. H. Dowen et al., “Human DNA methylomes at base resolution show widespread epigenomic differences,” Nature, vol. 462, no. 7271, pp. 315–322, 2009.
- H. Harizi, M. Juzan, V. Pitard, J.-F. Moreau, and N. Gualde, “Cyclooxygenase-2-issued prostaglandin E2 enhances the production of endogenous IL-10, which down-regulates dendritic cell functions,” Journal of Immunology, vol. 168, no. 5, pp. 2255–2263, 2002.
- R. E. Harris, “Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung,” Inflammopharmacology, vol. 17, no. 2, pp. 55–67, 2009.
- I. Cebola and M. A. Peinado, “Epigenetic deregulation of the COX pathway in cancer,” Progress in Lipid Research, vol. 51, no. 4, pp. 301–313, 2012.
- M. Sahin, E. Sahin, and S. Koksoy, “Regulatory T cells in cancer: an overview and perspectives on Cyclooxygenase-2 and Foxp3 DNA methylation,” Human Immunology, vol. 74, no. 9, pp. 1061–1068, 2013.
- B. G. Cosío, B. Mann, K. Ito et al., “Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 170, no. 2, pp. 141–147, 2004.
- K. Ito, G. Caramori, S. Lim et al., “Expression and activity of histone deacetylases in human asthmatic airways,” The American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 3, pp. 392–396, 2002.
- P. J. Barnes, I. M. Adcock, and K. Ito, “Histone acetylation and deacetylation: importance in inflammatory lung diseases,” European Respiratory Journal, vol. 25, no. 3, pp. 552–563, 2005.
- F. Yeung, J. E. Hoberg, C. S. Ramsey et al., “Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase,” The EMBO Journal, vol. 23, no. 12, pp. 2369–2380, 2004.
- C.-H. Kuo, Y.-C. Ko, S.-N. Yang et al., “Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation,” Journal of Molecular Medicine, vol. 89, no. 1, pp. 29–41, 2011.
- C. H. Kuo, C. H. Lin, S. N. Yang et al., “Effect of prostaglandin I2 analogs on cytokine expression in human myeloid dendritic cells via epigenetic regulation,” Molecular Medicine, vol. 18, no. 1, pp. 433–444, 2012.
- S. Sakaguchi, M. Ono, R. Setoguchi et al., “Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease,” Immunological Reviews, vol. 212, pp. 8–27, 2006.
- W. Zou, “Regulatory T cells, tumour immunity and immunotherapy,” Nature Reviews Immunology, vol. 6, no. 4, pp. 295–307, 2006.
- F. Baratelli, Y. Lin, L. Zhu et al., “Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells,” The Journal of Immunology, vol. 175, no. 3, pp. 1483–1490, 2005.
- S. Yaqub, K. Henjum, M. Mahic et al., “Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner,” Cancer Immunology, Immunotherapy, vol. 57, no. 6, pp. 813–821, 2008.
- M. Huang, S. Sharma, J. T. Mao, and S. M. Dubinett, “Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production,” The Journal of Immunology, vol. 157, no. 12, pp. 5512–5520, 1996.
- M. Stolina, S. Sharma, Y. Lin et al., “Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis,” Journal of Immunology, vol. 164, no. 1, pp. 361–370, 2000.
- S. Sharma, M. Stolina, S.-C. Yang et al., “Tumor cyclooxygenase 2-dependent suppression of dendritic cell function,” Clinical Cancer Research, vol. 9, no. 3, pp. 961–968, 2003.
- S. Sharma, S.-C. Yang, L. Zhu et al., “Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer,” Cancer Research, vol. 65, no. 12, pp. 5211–5220, 2005.
- J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003.
- S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory T cell development by the transcription factor Foxp3,” Science, vol. 299, no. 5609, pp. 1057–1061, 2003.
- X.-L. Yuan, L. Chen, M.-X. Li et al., “Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner,” Clinical Immunology, vol. 134, no. 3, pp. 277–288, 2010.
- M. Tsujii and R. N. DuBois, “Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2,” Cell, vol. 83, no. 3, pp. 493–501, 1995.
- M. S. Simper, J. E. Rundhaug, C. Mikulec et al., “The tumor promoting activity of the EP4 receptor for prostaglandin E2 in murine skin,” Molecular Oncology, vol. 8, no. 8, pp. 1626–1639, 2014.
- A. M. Algra and P. M. Rothwell, “Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials,” The Lancet Oncology, vol. 13, no. 5, pp. 518–527, 2012.
- M. J. Thun, E. J. Jacobs, and C. Patrono, “The role of aspirin in cancer prevention,” Nature Reviews Clinical Oncology, vol. 9, no. 5, pp. 259–267, 2012.
- X. Liao, P. Lochhead, R. Nishihara et al., “Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival,” The New England Journal of Medicine, vol. 367, no. 17, pp. 1596–1606, 2012.
- J. Huang, C. Plass, and C. Gerhäuser, “Cancer chemoprevention by targeting the epigenome,” Current Drug Targets, vol. 12, no. 13, pp. 1925–1956, 2011.
- E. Yiannakopoulou, “Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents—implications for cancer treatment and chemoprevention,” Cellular Oncology, vol. 37, no. 3, pp. 167–178, 2014.
- E. Okuda-Ashitaka, K. Sakamoto, T. Ezashi, K. Miwa, S. Ito, and O. Hayaishi, “Suppression of prostaglandin E receptor signaling by the variant form of EP1 subtype,” The Journal of Biological Chemistry, vol. 271, no. 49, pp. 31255–31261, 1996.
- M. Toyota, L. Shen, M. Ohe-Toyota, S. R. Hamilton, F. A. Sinicrope, and J.-P. J. Issa, “Aberrant methylation of the cyclooxygenase 2 CpG island in colorectal tumors,” Cancer Research, vol. 60, no. 15, pp. 4044–4048, 2000.
- E. R. Greene, S. Huang, C. N. Serhan, and D. Panigrahy, “Regulation of inflammation in cancer by eicosanoids,” Prostaglandins and Other Lipid Mediators, vol. 96, pp. 27–36, 2011.
- D. Wang and R. N. Dubois, “Eicosanoids and cancer,” Nature Reviews Cancer, vol. 10, no. 3, pp. 181–193, 2010.
- D. G. Menter, R. L. Schilsky, and R. N. DuBois, “Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward,” Clinical Cancer Research, vol. 16, no. 5, pp. 1384–1390, 2010.
- H.-S. Jong, H. Inoue, T. Tanabe, and Y.-J. Bang, “Transcriptional silencing of cyclooxygenase-2 by hyper-methylation of the 5′ CpG island in human gastric carcinoma cells,” Cancer Research, vol. 61, no. 11, pp. 4628–4635, 2001.
- T. Kikuchi, F. Itoh, M. Toyota et al., “Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer,” International Journal of Cancer, vol. 97, no. 3, pp. 272–277, 2002.
- N. Omura, M. Griffith, A. Vincent et al., “Cyclooxygenase-deficient pancreatic cancer cells use exogenous sources of prostaglandins,” Molecular Cancer Research, vol. 8, no. 6, pp. 821–832, 2010.
- X. Ma, Q. Yang, K. T. Wilson, N. Kundu, S. J. Meltzer, and A. M. Fulton, “Promoter methylation regulates cyclooxygenase expression in breast cancer,” Breast Cancer Research, vol. 6, no. 4, pp. R316–R321, 2004.
- L. W. C. Chow, L. Zhu, W. T. Y. Loo, and E. L. H. Lui, “Aberrant methylation of cyclooxygenase-2 in breast cancer patients,” Biomedicine and Pharmacotherapy, vol. 59, no. 2, pp. S264–S267, 2005.
- H. Murata, S. Tsuji, M. Tsujii et al., “Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells,” Laboratory Investigation, vol. 84, no. 8, pp. 1050–1059, 2004.
- N. Nishida, T. Nagasaka, T. Nishimura, I. Ikai, C. R. Boland, and A. Goel, “Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma,” Hepatology, vol. 47, no. 3, pp. 908–918, 2008.
- T.-H. Um, H. Kim, B.-K. Oh et al., “Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis,” Journal of Hepatology, vol. 54, no. 5, pp. 939–947, 2011.
- R. Soo, T. Putti, Q. Tao et al., “Overexpression of cyclooxygenase-2 in nasopharyngeal carcinoma and association with epidermal growth factor receptor expression,” Archives of Otolaryngology—Head and Neck Surgery, vol. 131, no. 2, pp. 147–152, 2005.
- D. Lodygin, A. Epanchintsev, A. Menssen, J. Diebold, and H. Hermeking, “Functional epigenomics identifies genes frequently silenced in prostate cancer,” Cancer Research, vol. 65, no. 10, pp. 4218–4227, 2005.
- P. J. Bastian, J. Ellinger, L. C. Heukamp, P. Kahl, S. C. Müller, and A. von Rücker, “Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy,” European Urology, vol. 51, no. 3, pp. 665–674, 2007.
- S. P. Dawsey, M. J. Roth, L. Adams et al., “COX-2 (PTGS2) gene methylation in epithelial, subepithelial lymphocyte and stromal tissue compartments in a spectrum of esophageal squamous neoplasia,” Cancer Detection and Prevention, vol. 32, no. 2, pp. 135–139, 2008.
- X. Y. Meng, S. T. Zhu, Y. Zong, Y. J. Wang, P. Li, and S. T. Zhang, “Promoter hypermethylation of cyclooxygenase-2 gene in esophageal squamous cell carcinoma,” Diseases of the Esophagus, vol. 24, no. 6, pp. 444–449, 2011.
- S. Kulkarni, J. S. Rader, F. Zhang et al., “Cyclooxygenase-2 is overexpressed in human cervical cancer,” Clinical Cancer Research, vol. 7, no. 2, pp. 429–434, 2001.
- K. Subbaramaiah and A. J. Dannenberg, “Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence of a corepressor/coactivator exchange,” Cancer Research, vol. 67, no. 8, pp. 3976–3985, 2007.
- I. Venza, M. Visalli, C. Fortunato et al., “PGE2 induces interleukin-8 derepression in human astrocytoma through coordinated DNA demethylation and histone hyperacetylation,” Epigenetics, vol. 7, no. 11, pp. 1315–1330, 2012.
- Y. Sugimoto and S. Narumiya, “Prostaglandin E receptors,” The Journal of Biological Chemistry, vol. 282, no. 16, pp. 11613–11617, 2007.
- K. Gomi, F. G. Zhu, and J. S. Marshall, “Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1/EP3-dependent mechanism,” The Journal of Immunology, vol. 165, no. 11, pp. 6545–6552, 2000.
- Y. Shoji, M. Takahashi, T. Kitamura et al., “Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development,” Gut, vol. 53, no. 8, pp. 1151–1158, 2004.
- S. G. Gray, N. Al-Sarraf, A.-M. Baird, M.-C. Cathcart, E. McGovern, and K. J. O'Byrne, “Regulation of EP receptors in non-small cell lung cancer by epigenetic modifications,” European Journal of Cancer, vol. 45, no. 17, pp. 3087–3097, 2009.
- A. M. Fulton, X. Ma, and N. Kundu, “Targeting prostaglandin E EP receptors to inhibit metastasis,” Cancer Research, vol. 66, no. 20, pp. 9794–9797, 2006.
- D. S. Shames, L. Girard, B. Gao et al., “A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies,” PLoS Medicine, vol. 3, article e486, 2006.
- K. Krysan, K. L. Reckamp, H. Dalwadi et al., “Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner,” Cancer Research, vol. 65, no. 14, pp. 6275–6281, 2005.
- Y. Sugino, A. Misawa, J. Inoue et al., “Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas,” Oncogene, vol. 26, no. 53, pp. 7401–7413, 2007.
- J. Chen, C. Röcken, L. Klein-Hitpass et al., “Microarray analysis of gene expression in metastatic gastric cancer cells after incubation with the methylation inhibitor 5-aza-2′-deoxycytidine,” Clinical & experimental metastasis, vol. 21, no. 5, pp. 389–397, 2004.
- L. Tian, M. Suzuki, T. Nakajima et al., “Clinical significance of aberrant methylation of prostaglandin E receptor 2 (PTGER2) in nonsmall cell lung cancer association with prognosis, PTGER2 expression, and epidermal growth factor receptor mutation,” Cancer, vol. 113, no. 6, pp. 1396–1403, 2008.
- S. K. Huang, A. S. Fisher, A. M. Scruggs et al., “Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice,” The American Journal of Pathology, vol. 177, no. 5, pp. 2245–2255, 2010.
- E. Piazuelo, P. Jiménez, M. Strunk et al., “Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus,” Prostaglandins and Other Lipid Mediators, vol. 81, no. 3-4, pp. 150–161, 2006.
Copyright © 2015 Hedi Harizi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.