Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase or COX , is a rate-limiting enzyme in the conversion of arachidonic acid, a product of damaged cell membranes, into prostaglandins. PTGS exist in at least 2 isoforms, PTGS1 (COX-1), and PTGS2 (COX-2). PTGS1 is constitutively expressed in many tissues and is the predominant form in gastric mucosa and in the kidneys. PTGS2 is unexpressed under normal conditions, but elevated levels are found during inflammation which is induced by cytokines and growth factors. Among other prostaglandins, PTGS2 activation produces prostaglandin E2 (PGE2), which acts on a number of cell signaling pathways involving cell proliferation, angiogenesis, apoptosis inhibition, invasion,immune response suppression, and tumor cell invasion and metastasis which could increase cancer progression. Hypoxia led to a preferential PTGS2 induction in tumor cells and fostered ahigher metastatic take of tumor cells [1].

There is strong evidence that PTGS2 expressed in most solid tumor types. Cellular expression of PTGS2 is increased in the earliest stages of carcinogenesis and through tumor development and invasive tumor growth.A large number of studies have examined  that PTGS2 up regulation is particularly common and associated with worse survival among colon cancer patients [2].PTGS2 genotype is also be found  associated with breast cancer,biliary tract cancer and colorectal cancer [3] [4][5].PTGS2 CpG island hypermethylation portended an increased risk of recurrence in human prostate cancer [6].In PTGS2 -positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth[7].PTGS-2 overexpression is observed in breast cancer and has been associated with indicators of poor prognosis, such as lymph node metastasis, poor differentiation, and large tumor size. Furthermore, inhibition of PTGS-2 by nonsteroidal anti-inflammatory drugs has been associated with a protective effect against a variety of cancers and may be effective in the prevention and treatment of breast cancer.Evidence is emerging that the use of nonsteroidal anti-inflammatory drugs (NSAID), such as aspirin or selective PTGS2 inhibitors celecoxib, may reduce risk of colorectal cancer.And it is almost consensus that  PTGS2 has been associated with the breast cancer and patient prognosis. However, not all breast cancer patients has the abnormal in PTGS2 gene or PTGS2 expression, so it is still indeterminacy that PTGS2 can be defined as diagnostic markers or drug target.

The Cancer Genome Atlas (TCGA) Data Portal provides a platform for cancer research which also including bound of breast cancer datas contains genomic characterization data, clinical information,and so on. Tumor and germline DNA samples were obtained from 825 patients.The Cancer Genome Atlas Network [8]

In this study, we systematically evaluated the biologically interesting features of PTGS2 alteration and the relationship with breast cancer prognosis from The Cancer Genome Atlas (TCGA). Finally, we related our results to distinct patterns of EMT activation in different subtypes and characterized their prognostic effects. Therefore, the expression of the genes in this study clearly revealed the evidence that elucidates their functional significance between the molecular environments. Our findings also have important implications for glioma biology and heterogeneity and possible therapeutic intervention for patients with GBM.The aim of the study was to systematically identify all studies that analyzed the association between PTGS2 expression in colorectal tumors at diagnosis and subsequent survival and/or recurrence and to clarify the associations using meta-analyses.

Associations of PTGS2 with chemical compounds

• Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics-based prescription of celecoxib [9].
• Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue [3].
• These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals [10].
• CONCLUSION(S): Monkey OSE expresses mRNA for PTGS1, PTGS2, and all PGE synthases and produces PGE(2) both before and 36 hours after hCG [11].
• Our data indicate that F-IPF have a striking defect in their capacity to synthesize the antiinflammatory and antifibrogenic molecule PGE2, apparently because of a diminished induction of COX-2 protein [12].
• GS-HCl (5 mM) also facilitated degradation of the higher molecular species of COX-2 in IL-1beta-treated A549 cells that was retarded by MG132 [13].
• Inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBS-stimulated cells [14].

Physical interactions of PTGS2

• Here we describe two heterodimers in which a native subunit of human PGHS-2 has been coupled to a subunit having a defect within the COX active site at some distance from the dimer interface [15].
• Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein delta and CREB-binding protein [16].
• Recent evidence suggests that cyclooxygenase-2 (COX-2) modulates angiogenesis by interacting with the VEGF system [17].
• Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis [18].
• The ability of PPARgamma ligands to inhibit COX-2 appears to be mediated predominantly through inhibition of AP-1 protein binding to the CRE site in the COX-2 promoter [19].

Co-localisations of PTGS2

• Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages [20].

Regulatory relationships of PTGS2

• Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase [21].
• The side chain structures of Asn-382 and Thr-383 in PGHS-2 thus selectively influence two important aspects of cyclooxygenase catalytic regulation: activation by peroxide and self-inactivation [22].
• The adenomatous polyposis coli tumor suppressor gene regulates expression of cyclooxygenase-2 by a mechanism that involves retinoic acid [23].
• Cyclooxygenase 2 (COX-2) was also induced by OSM [24].
• In the present study, we tested the hypothesis that progesterone/PR inhibits uterine contractility by blocking nuclear factor kappaB (NF-kappaB) activation and induction of cyclooxygenase-2 (COX-2), a contractile gene that is up-regulated in labor [25].

Other interactions of PTGS2

• The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression [26].
• Also, a selective Cox-2 inhibitor, NS-398, significantly enhanced genotoxic stress-induced apoptosis in several types of p53+/+ normal human cells, through a caspase-dependent pathway [27].
• Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade [28].
• Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta-globin-Cox-2 transcripts [28].
• Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms [29].

Analytical, diagnostic and therapeutic context of PTGS2

• Islet PTGS2 production in animal models was assessed by immunofluorescence [30].
• In a Minnesota-based case-control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 -765G > C promoter polymorphism [31].
• Immediately following oocyte retrieval, the cumulus was stripped from the oocyte, and cumulus gene expression for PTGS2, HAS2 and GREM1 was assessed using a one-step real-time quantitative RT-PCR assay [32].
• A fluorescence in situ hybridization study showed that the human genes coding for prostaglandin-endoperoxide synthase 1 (PTGS1) and prostaglandin-endoperoxidase synthase 2 (PTGS2) were mapped to distinct chromosomes 9q32-q33.3 and 1q25.2-q25.3, respectively, indicating that these genes are not genetically linked [33].
• MAIN OUTCOME MEASURE(S): Ovarian surface epithelium expression of prostaglandin-endoperoxide synthase 1 (PTGS1) and PTGS2 proteins was determined by immunocytochemistry [11].

Disccusion

Tumor size, histologic grade, presence of primarylymph node metastases, or age atdiagnosis were not associated with the genotypes [4].

References