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PTGS2; prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (1q25.2-q25.3)

Gene Summary

Gene:PTGS2; prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
Aliases: COX2, COX-2, PHS-2, PGG/HS, PGHS-2, hCox-2, GRIPGHS
Location:1q25.2-q25.3
Summary:Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase, is the key enzyme in prostaglandin biosynthesis, and acts both as a dioxygenase and as a peroxidase. There are two isozymes of PTGS: a constitutive PTGS1 and an inducible PTGS2, which differ in their regulation of expression and tissue distribution. This gene encodes the inducible isozyme. It is regulated by specific stimulatory events, suggesting that it is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis. [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:prostaglandin G/H synthase 2
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (62)

Pathways:

What pathways are this gene/protein implicaed in?
- Eicosanoid Metabolism BIOCARTA
- Mechanism of Acetaminophen Activity and Toxicity BIOCARTA
- Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) BIOCARTA
- Arachidonic acid metabolism KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (13)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Colorectal CancerCOX2 Inhibitors for Colorectal Cancer Therapy View Publications358
Colorectal CancerPTGS2 (COX2) and Colorectal Cancer View Publications335
Head and Neck CancersPTSG2 (COX2) and Head and Neck Squamous Carcinoma View Publications161
Breast CancerPTGS2 (COX2) and Breast Cancer View Publications150
Lung CancerPTGS2 (COX2) and Lung Cancer View Publications124
Stomach CancerPTGS2 (COX2) and Stomach Cancer View Publications119
Breast CancerCOX2 Inhibitors for Breast Cancer Therapy View Publications84
Prostate CancerPTGS2 (COX2) and Prostate Cancer View Publications80
Esophageal CancerPTGS2 (COX2) Overexpression in Esophageal Cancer View Publications71
Colorectal CancerCOX2 Polymorphisms and Colorectal Cancer View Publications49
Cervical CancerPTGS2 (COX2) and Cervical Cancer View Publications28
Skin CancerPTGS2 (COX2) Overexpression in Skin Cancer View Publications23
Esophageal CancerCOX2 Polymorphisms and Esophageal Cancer View Publications10

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: PTGS2 (cancer-related)

Koumarianou A, Tzeveleki I, Mekras D, et al.
Prognostic markers in early-stage colorectal cancer: significance of TYMS mRNA expression.
Anticancer Res. 2014; 34(9):4949-62 [PubMed] Related Publications
BACKGROUND: Several studies have recently indicated the prognostic or predictive role of several biomarkers in colorectal cancer. We sought to investigate the prognostic value of prostaglandin synthase 2 (PTGS2), cyclooxygenase 2 (COX2), thymidylate synthetase (TYMS), thymidine phosphorylase (TYMP), dihydropyrimidine dehydrogenase (DPYD) and topoisomerase I (TOPO1) in colorectal cancer patients treated with 5-FU-based regimens, such as De Gramont and FOLFOX in the adjuvant setting.
MATERIALS AND METHODS: In total, 96 formalin-fixed paraffin-embedded and 30 fresh-frozen tumor tissue samples were evaluated using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and microarray gene expression profiling, respectively.
RESULTS: The majority of tumors exhibited protein overexpression of COX2 (69%), TYMS (75%) and TOPO1 (75%). There was a significant association of TYMP protein expression with T classification, gender and stage (p=0.040, p=0.041 and p=0.011, respectively). TOPO1 protein expression was correlated with TOPO1 mRNA expression and was positively associated with stage (p=0.002) and lymph node infiltration (p=0.004). In univariate analysis, patients with high TYMS mRNA expression were shown to have a significantly lower risk for progression and death (Wald's p=0.030 and p=0.015, respectively). However, in multivariate analysis, only a trend for decreased risk for death was shown in patients with high TYMS mRNA expression (Wald's p=0.083), while patients with high PTGS2 mRNA expression had a trend for lower risk for progression (p=0.064). Using supervised hierarchical clustering, based on the expression in fresh-frozen tumor tissue of PTGS2, TYMS, TYMP and DPYD, our 30 patients were separated into two clusters. One of the clusters was enriched with patients with infiltrated lymph nodes (p<0.05), suggesting that these genes might have an impact on the tumor's ability to metastasize.
CONCLUSION: These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.

Related: Colorectal (Bowel) Cancer


Cheng Y, Li Y, Liu D, et al.
miR-137 effects on gastric carcinogenesis are mediated by targeting Cox-2-activated PI3K/AKT signaling pathway.
FEBS Lett. 2014; 588(17):3274-81 [PubMed] Related Publications
The discovery of microRNAs (miRNAs) provided a new avenue for early diagnosis and treatment of GC. MiR-137 has been reported to be under-expressed and involved in various cell processes. However, the role of miR-137 in GC is less known. In this study, we show that miR-137 is under-expressed in GC and functions as a tumor suppressor through targeting Cyclooxygenase-2 (Cox-2), which subsequently suppresses the activation of PI3K/AKT signaling pathway both in vitro and in vivo. Moreover, restored Cox-2 expression partially abolished the tumor suppressive effects of miR-137 in GC cells, suggesting miR-137 may suppress GC carcinogenesis by targeting Cox-2.

Related: AKT1 Signal Transduction Stomach Cancer Gastric Cancer


Cornett AL, Lutz CS
Regulation of COX-2 expression by miR-146a in lung cancer cells.
RNA. 2014; 20(9):1419-30 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition.

Related: Non-Small Cell Lung Cancer Lung Cancer


An J, Li XN, Zhao BC, et al.
[Chemo-preventive effect of Angelica sinensis' supercritical extracts on AOM/DSS-induced mouse colorectal carcinoma associated with inflammation].
Zhongguo Zhong Yao Za Zhi. 2014; 39(7):1265-9 [PubMed] Related Publications
To study the chemo-preventive effect of the supercritical extracts from Angelica sinensis (SFE-AS) on induced colorectal carcinoma in mice by using the AOM/DSS-induced male mice colorectal carcinoma model, and discuss its possible action mechanism. Male Balb/c mice were subcutaneously injected with single dose of azoxymethane (AOM, 10 mg x kg(-1) body weight). One week later, they were given 2% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colorectal carcinoma. Each drug group was orally administered with supercritical extracts from Angelica sinensis at 15, 30, 60 mg x kg(-1) until the 17th week. The tumor incidence rate of the SFE-AS group, mice tumor-bearing quantity and tumor-bearing volume of the SFE-AS group were lower than that of the AOM/DSS model control group, which may be related with the significant reduction of PCNA, COX-2, iNOS in the AOM/DSS-induced mouse colorectal carcinoma model associated with inflammation by SFE-AS. According to the results of this study, SFE-AS showed an intervention effect in the incidence and development of AOM/DSS-induced mouse colorectal carcinoma associated with inflammation, and could be further used in chemo-preventive studies on human colorectal carcinoma.

Related: Colorectal (Bowel) Cancer PCNA: Proliferating cell nuclear antigen


Magnowska M, Zaborowski M, Surowiak P, et al.
COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis.
Ginekol Pol. 2014; 85(5):335-41 [PubMed] Related Publications
OBJECTIVE: Numerous studies suggest that cyclooxygenase-2 (COX-2) is overexpressed in cancer. Our objective was to investigate the relationship between COX-2 expression in ovarian carcinoma and clinicopathological factors. An emphasis was put on the association with the new pattern of tumorigenesis that divides tumors into type I--less aggressive, and type II--more aggressive one. The prognostic significance of COX-2 expression was evaluated.
METHODS: Ovarian cancer tissues were obtained from 65 patients in FIGO III stage (23 with type I and 42 with type II ovarian cancer). COX-2 expression was evaluated by immunohistochemistry. The statistical analysis was performed in order to assess the connection between COX-2 expression and characteristic factors of ovarian cancer patients as well as the new division for type I and type II ovarian cancer
RESULTS: COX-2 expression was detected in 91% of tissue samples. It was markedly elevated in well differentiated tumors (p = 0.0041). The platinum-resistant tumors had significantly higher expression of COX-2 (p = 0.0337). There was no difference between COX-2 expression in type I and type II ovarian cancer (p = 0.6720). The COX-2 staining was not associated to age, CA125 level, the presence of ascites or any special histological type. An increased expression of COX-2 was an unfavorable prognostic factor for overall survival (p = 0.0369) and progression-free survival (p = 0.0218). Multivariate analysis confirmed that COX-2 overexpression is an independent unfavorable prognostic factor of shorter progression-free survival (p = 0.048).
CONCLUSIONS: COX-2 expression is an unfavorable prognostic factor for progression-free survival and overall survival in ovarian cancer There is no relationship between COX-2 expression in ovarian cancer tissue and the examined model of ovarian cancer pathogenesis.

Related: Ovarian Cancer


Gakis G
The role of inflammation in bladder cancer.
Adv Exp Med Biol. 2014; 816:183-96 [PubMed] Related Publications
The aim of this book chapter is to present the latest basic research developments on the role of inflammation in bladder cancer and provide insights into their future clinical significance in preventing bladder carcinogenesis and progression. Bladder cancer is a highly immunogenic malignancy. Urothelial cancer cells aim to manipulate the immune system by inhibiting its cytotoxic function while stimulating the secretion of growth promoting factors. Cytokine-induced imbalances in the distribution and differentiation of tumor-infiltrating cytotoxic cells can boost bladder cancer cell proliferation. Tumor-induced release of excessive amount of cytokines causes an "inflammatory storm" which drives metastasis formation via degradation of extracellular matrix proteins. Tumor-related selective cyclooxygenase-2 (COX-2) upregulation suppresses the cell-mediated immune response via aberrant prostaglandin metabolism resulting in failure of differentiation of myeloid cell progenitors into mature antigen-presenting cells. T cells are capable of increasing the oxidative stress on bladder cancer cells via induction of COX-2 and STEAP expression. Some evidence also suggests that COX-2 activation may be also involved in inflammation-mediated cancer stem cell proliferation. Antibodies against the VEGF-co-receptor neuropilin decrease the angiogenetic potential of bladder cancer cells. Inflammation-based predictive bladder cancer models have demonstrated to accurately predict response to treatment both in the curative and palliative setting. While randomized trials do not support a clinical benefit for the use of anti-inflammatory drugs (i.e., celecoxib, atorvastatin) in preventing recurrence of low-grade bladder cancer, further investigations are warranted in the setting of high-grade tumors since the immune response to cancer stimuli is most probably more pronounced in advanced stages.

Related: Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Altamemi I, Murphy EA, Catroppo JF, et al.
Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in Apc(Min/+) mice.
J Pharmacol Exp Ther. 2014; 350(1):99-109 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-α protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA-455, were validated to be upregulated with resveratrol treatment by reverse-transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation.

Related: TNF


Yan F, Fu Q
PLCε1: a potential target of RNA interference therapy for gastric cancer.
Biochem Biophys Res Commun. 2014; 448(4):409-13 [PubMed] Related Publications
Phospholipase C epsilon 1 (PLCε1) has been recently identified as a novel potential biomarker for gastric cancer because of its critical role in inflammation and tumorigenesis. Until now, there are no further reports to investigate the feasibility of gene therapy by suppressing PLCε1 expression for gastric cancer. In this study, a small interfering RNA (shRNA) targeting PLCε1 was firstly transfected into gastric cancer cells in order to silence PLCε1 expression. Both mRNA and protein expression of PLCε1 in gastric cancer cells significantly reduced by RT-PCR and Western blotting analysis. Moreover, subsequent results revealed that PLCε1 shRNA depressed the in vitro and in vivo growth of gastric cancer cells by using MTT assay and tumor xenograft experiment. Furthermore, after PLCε1 shRNA transfection, the expression of proinflammatory molecules including tumor necrosis factor-α (TNF-α), cyclooxygenase 2 (COX-2), interleukin (IL)-6 and chemokine (C-X-C motif) ligand (CXCL)-1 were unaffected, but only chemokine (C-C motif) ligand (CCL)-2 expression decreased in the gastric cancer cells. It is implied that PLCε1 may inhibit the growth of gastric cancer cells via CCL-2 protein mediated pathway. These results suggest that PLCε1 might be an alternative molecular target for gastric cancer gene therapy.

Related: Signal Transduction Stomach Cancer Gastric Cancer


Gharib AF, Karam RA, Abd El Rahman TM, Elsawy WH
COX-2 polymorphisms -765G→C and -1195A→G and hepatocellular carcinoma risk.
Gene. 2014; 543(2):234-6 [PubMed] Related Publications
Cyclooxygenase-2 (COX-2) is overexpressed in hepatocellular carcinoma (HCC) and considered to play a role in hepatic carcinogenesis. Our aim was to examine the associations between polymorphisms in COX-2 -765G→C and -1195A→G and risk of HCC. We conducted a case-control study including 120 patients with HCC and 130 age- and gender-matched controls. Genotypes of the COX-2 polymorphisms -765G→C and -1195A→G were determined by polymerase chain reaction-based restriction fragment length polymorphism. No significant difference was observed in the genotype distribution of the -765G→C polymorphism between patients and controls. The -1195AA genotype was associated with an increased risk of developing HCC (OR, 2.5; 95%CI, 1.18-5.37). The A allele was present significantly more often in HCC patients (OR 1.5; 95%CI, 1.05-2.14). In conclusion, our results demonstrated that the -1195AA genotype and A allele have an important role in HCC risk in Egyptian patients.

Related: Liver Cancer


Cha W, Park SW, Kwon TK, et al.
Endoplasmic reticulum stress response as a possible mechanism of cyclooxygenase-2-independent anticancer effect of celecoxib.
Anticancer Res. 2014; 34(4):1731-5 [PubMed] Related Publications
BACKGROUND: We investigated whether the endoplasmic reticulum (ER) stress response could be a cyclooxygenase-2 (COX2)-independent mechanism of growth inhibition by celecoxib in a head and neck squamous cell carcinoma (HNSCC) cell line.
MATERIALS AND METHODS: We performed western blotting and reverse transcription polymerase chain reaction to analyze the expression of ER stress response-associated proteins C/EBP homologous protein (CHOP), glucose-regulated protein (GRP)-78 and X-box binding protein-1 (XBP1), after treatment of celecoxib in the SNU-1041 cell line. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the change in growth inhibition by celecoxib after inhibition of the ER stress pathway by CHOP small-interfering RNA (siRNA).
RESULTS: Celecoxib triggered an ER stress response in this HNSCC cell line as shown by activation of CHOP, GRP78 and XBP1. The inhibition of cell proliferation by celecoxib was effectively hindered with CHOP siRNA.
CONCLUSION: ER stress response could be a COX2-independent anticancer mechanism of celecoxib.

Related: Cancer Prevention and Risk Reduction Signal Transduction DDIT3 gene


Yamamura T, Matsumoto N, Matsue Y, et al.
Sodium butyrate, a histone deacetylase inhibitor, regulates Lymphangiogenic factors in oral cancer cell line HSC-3.
Anticancer Res. 2014; 34(4):1701-8 [PubMed] Related Publications
AIM: Tumor angiogenesis is a focus of molecularly-targeted therapies. This study investigated the effect of sodium butyrate (SB), a histone deacetylase inhibitor, on the synthesis of antiangiogenic and lymphangiogenic factors in oral squamous cell carcinoma.
DESIGN: Gene alterations in HSC-3 cells were assessed using cDNA microarrays before and after treatment with SB. The mRNA and protein expression of lymphangiogenic factors were also assessed by quantitative PCR, western blotting and immunocytochemistry.
RESULTS: Microarray analysis revealed that treatment with SB led to altered expression of angiogenesis-related gene expression. The quantitative polymerase chain reaction showed that platelet-derived growth factor-B, angiopoietin-2, vascular endothelial growth factor (VEGF)-C, and VEGFD were down-regulated. Western blotting and immunocytochemistry confirmed reduced protein synthesis of VEGFC.
CONCLUSION: SB inhibits expression of lymphangiogenic factors in HSC-3 cells. Within the limitations of the present study, SB may have potential as an anti-metastatic pro-drug for oral cancer.

Related: Oral Cancer Angiogenesis and Cancer


Reimers MS, Bastiaannet E, Langley RE, et al.
Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer.
JAMA Intern Med. 2014; 174(5):732-9 [PubMed] Related Publications
IMPORTANCE: Use of aspirin (which inhibits platelet function) after a colon cancer diagnosis is associated with improved overall survival. Identifying predictive biomarkers of this effect could individualize therapy and decrease toxic effects.
OBJECTIVE: To demonstrate that survival benefit associated with low-dose aspirin use after a diagnosis of colorectal cancer might depend on HLA class I antigen expression.
DESIGN, SETTING, AND PARTICIPANTS: A cohort study with tumor blocks from 999 patients with colon cancer (surgically resected between 2002 and 2008), analyzed for HLA class I antigen and prostaglandin endoperoxide synthase 2 (PTGS2) expression using a tissue microarray. Mutation analysis of PIK3CA was also performed. Data on aspirin use after diagnosis were obtained from a prescription database. Parametric survival models with exponential (Poisson) distribution were used to model the survival.
MAIN OUTCOMES AND MEASURES: Overall survival.
RESULTS: The overall survival benefit associated with aspirin use after a diagnosis of colon cancer had an adjusted rate ratio (RR) of 0.53 (95% CI, 0.38-0.74; P < .001) when tumors expressed HLA class I antigen compared with an RR of 1.03 (0.66-1.61; P = .91) when HLA antigen expression was lost. The benefit of aspirin was similar for tumors with strong PTGS2 expression (0.68; 0.48-0.97; P = .03), weak PTGS2 expression (0.59; 0.38-0.97; P = .02), and wild-type PIK3CA tumors (0.55; 0.40-0.75; P < .001). No association was observed with mutated PIK3CA tumors (0.73; 0.33-1.63; P = .44).
CONCLUSIONS AND RELEVANCE: Contrary to the original hypothesis, aspirin use after colon cancer diagnosis was associated with improved survival if tumors expressed HLA class I antigen. Increased PTGS2 expression or the presence of mutated PIK3CA did not predict benefit from aspirin. HLA class I antigen might serve as a predictive biomarker for adjuvant aspirin therapy in colon cancer.


Wang R, Wang Y, Gao Z, Qu X
The comparative study of acetyl-11-keto-beta-boswellic acid (AKBA) and aspirin in the prevention of intestinal adenomatous polyposis in APC(Min/+) mice.
Drug Discov Ther. 2014; 8(1):25-32 [PubMed] Related Publications
Acetyl-11-keto-beta-BA (AKBA), a component of the gum resin of Boswellia serrata, has been recognized as a promising agent for the prevention of intestinal tumorigenesis. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has also been considered to have the activity against intestinal tumorigenesis. However, the prevention of colonic cancer is insufficient and no definitive recommendation has been made for clinic use. Herein, we compared the efficacy of AKBA with that of aspirin in an adenomatous polyposis coli intestinal neoplasia consecutive weeks. Mice were sacrificed by anesthetizing. The whole intestine was removed from each mouse. The number, size and histopathology of intestinal adenomatous polyps were examined under microscopy. The adenomatous polyps were removed for further analysis by the assays of western blotting and immunohistochemical staining. AKBA significantly prevented the formation of intestinal adenomatous polyps without toxicity to mice. Statistical analysis indicated that AKBA's activity both in the prevention of small intestinal and colonic polyps was more potently than aspirin. Histopathologic examination revealed that AKBA's effect, that is the reduction of polyp size and degree of dysplasia, was more prominent in larger sized polyps, especially those originating in colon. These effects of AKBA were associated with its role in the induction of apoptosis in carcinomas. The assays of western blotting and immunohistochemistry staining indicated that the efficacy of AKBA might arise from its activity in the modulation of the Wnt/β-catenin pathway and NF-κB/COX-2 pathway in adenomatous polyps. Conclusion, AKBA by oral application prevented intestinal tumorigenesis more potential than aspirin.

Related: Apoptosis APC CTNNB1 gene


Liu F, Wei WQ, Cormier RT, et al.
Association of single nucleotide polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) and phospholipase A₂ group IIA (PLA2G2A) genes with susceptibility to esophageal squamous cell carcinoma.
Asian Pac J Cancer Prev. 2014; 15(4):1797-802 [PubMed] Related Publications
BACKGROUND: The prostaglandin-endoperoxide synthase 2 (PTGS2) and phospholipase A2 group IIA (PLA2G2A) genes encode enzymes that are involved in arachidonic acid and prostaglandin biosynthesis. Dysregulation of both genes is associated with inflammation and carcinogenesis, including esophageal squamous cell carcinoma (ESCC). We therefore hypothesized that there is an association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to ESCC.
METHODS: We performed a gene-wide tag SNP-based association study to examine the association of SNPs in PTGS2 and PLA2G2A with ESCC in 269 patients and 269 healthy controls from Taihangshan Mountain, Henan and Hebei Provinces, the rural area of China which has the highest incidence of esophageal cancer in the world. Thirteen tag SNPs in PLA2G2A and 4 functional SNPs in PTGS2 were selected and genotyped using a high-throughput Mass Array genotyping platform.
RESULTS: We found a modest increased risk of ESCC in subjects with the PTGS2 rs12042763 AA genotype (OR=1.23; 95% CI, 1.00- 3.04) compared with genotype GG. For PLA2G2A, a decreased risk of ESCC was observed in subjects with the rs11677 CT (OR=0.51, 95%CI, 0.29-0.85) or TT genotype (OR=0.51, 95%CI, 0.17-0.96) or the T carriers (CT+TT) (OR=0.52, 95%CI, 0.31-0.85) when compared with the CC genotype. Also for PLA2G2A, rs2236771 C allele carriers were more frequent in the control group (P=0.02). Subjects with the GC (OR=0.55, 95%CI, 0.33-0.93) or CC genotype (OR=0.38, 95% CI, 0.16-0.94) or the C carriers (GC+CC) (OR=0.52, 95%CI, 0.32- 0.85) showed a negative association with ESCC susceptibility.
CONCLUSIONS: Our results suggest that PTGS2 and PLA2G2A gene polymorphisms may modify the risk of ESCC development.

Related: Cancer of the Esophagus Esophageal Cancer


Wang X, Guo X, Yu W, et al.
Expression of methionine adenosyltransferase 2A in renal cell carcinomas and potential mechanism for kidney carcinogenesis.
BMC Cancer. 2014; 14:196 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the formation of S-adenosylmethionine (SAMe) by joining methionine and ATP. SAMe is a methyl donor for transmethylation and has an important role for DNA and/or protein methylation. MAT2A is expressed widely in many tissues especially in kidney. Several studies have demonstrated that there are abnormal expressions of MAT2A in several kinds of cancers such as liver and colon cancers. But the relationship of MAT2A between renal cell carcinomas (RCC) is less understood.
METHODS: The mRNA expression level of the MAT2A gene was determined in 24 RCC patients and 4 RCC cell lines, using real-time quantitative-polymerase chain reaction (RT-PCR). The MAT2A protein content was measured by western blotting and immunohistochemical analysis in 55 RCC patients. The mRNA levels of heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were also analysized in patients using RT-PCR. The correlations between the MAT2A and HO-1 as well as COX-2 were analyzed with nonparametric Spearman method.
RESULTS: MAT2A transcript was significantly downregulated in cancer tissues compared to normal tissues (P < 0.05). Immunohistochemical analysis and western blotting indicated that level of MAT2A protein was decreased in cancer tissues. The statistical analysis reveals a negative correlation between MAT2A and HO-1 expression in RCC patients and cell lines (P < 0.01).
CONCLUSIONS: This study demonstrated that MAT2A was lower expression in cancer tissues, suggesting that it may be involved in the development of RCC. MAT2A is a transcriptional corepressor for HO-1 expression by supplying SAM for methyltransferases, which may be one of potential mechanism of MAT2A as tumor suppressor in kidney carcinogenesis.

Related: Kidney Cancer


Wu XL, Cheng B, Li PY, et al.
MicroRNA-143 suppresses gastric cancer cell growth and induces apoptosis by targeting COX-2.
World J Gastroenterol. 2013; 19(43):7758-65 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
AIM: To investigate the function of microRNA-143 (miR-143) in gastric cancer and explore the target genes of miR-143.
METHODS: A quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed to evaluate miR-143 expression in gastric cancer cell lines. After transfecting gastric cancer cells with miR-143-5p and miR-143-3p precursors, Alamar blue and apoptosis assays were used to measure the respective proliferation and apoptosis rates. Cyclooxygenase-2 (COX-2) expression was determined by real-time RT-PCR and Western blot assays after miR-143 transfection. Reporter plasmids were constructed, and a luciferase reporter assay was used to identify the miR-143 binding site on COX-2.
RESULTS: Both miR-143-5p and miR-143-3p were significantly downregulated in multiple gastric cancer cell lines. Forced miR-143-5p and miR-143-3p expression in gastric cancer cells produced a profound cytotoxic effect. MiR-145-5p transfection into gastric cancer cells resulted in a greater growth inhibitory effect (61.23% ± 3.16% vs. 46.58% ± 4.28%, P < 0.05 in the MKN-1 cell line) and a higher apoptosis rate (28.74% ± 1.93% vs. 22.13% ± 3.31%, P < 0.05 in the MKN-1 cell line) than miR-143-3p transfection. Further analysis indicated that COX-2 expression was potently suppressed by miR-143-5p but not by miR-143-3p. The activity of a luciferase reporter construct that contained the 3'-untranslated region (UTR) of COX-2 was downregulated by miR-143-5p (43.6% ± 4.86%, P < 0.01) but not by miR-143-3p. A mutation in the miR-145-5p binding site completely ablated the regulatory effect on luciferase activity, which suggests that there is a direct miR-145-5p binding site in the 3'-UTR of COX-2.
CONCLUSION: Both miR-143-5p and miR-143-3p function as anti-oncomirs in gastric cancer. However, miR-143-5p alone directly targets COX-2, and it exhibits a stronger tumor suppressive effect than miR-143-3p.

Related: Apoptosis Signal Transduction Stomach Cancer Gastric Cancer


Markkula A, Simonsson M, Rosendahl AH, et al.
Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients.
Int J Cancer. 2014; 135(8):1898-910 [PubMed] Related Publications
The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment.

Related: Breast Cancer


Wu KK, Cheng HH, Chang TC
5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis.
J Biomed Sci. 2014; 21:17 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Cyclooxygenase-2(COX-2) overexpression promotes inflammation and tumorigenesis. COX-2 expression in response to diverse stimuli is tightly controlled to avoid persistent overexpression. 5-methoxyindole metabolites of L-tryptophan represent a new class of compounds that control COX-2 expression at the transcriptional level. Two of the metabolites, the newly discovered 5-methoxytryptophan (5-MTP, also known as cytoguardin) and N-acetyl 5-methoxytryptamine (melatonin) are the focus of this review. 5-MTP is produced by mesenchymal cells such as fibroblasts via 5-hydroxytryptophan (5-HTP). It inhibits COX-2 transcriptional activation induced by diverse proinflammatory and mitogenic factors. Cancer cells are deficient in cytoguardin production which contributes to COX-2 overexpression. Fibroblast-generated 5-MTP is capable of restoring the control of COX-2 overexpression in cancer cells. 5-MTP blocks cancer cell migration and invasion in vitro and inhibits tumor growth and cancer metastasis in a xenograft model. Melatonin possesses similar COX-2 suppressing and anti-cancer properties albeit at supra-pharmacological concentrations. By contrast, 5-hydroxyindole metabolites of L-tryptophan such as 5-hydroxytryptamine (serotonin), 5-hydroxytryptophol and other serotonin catabolites do not control COX-2 expression. 5-hydroxytryptophan inhibits COX-2 expression through conversion to 5-MTP. The physiological relevance of 5-MTP as an endogenous regulator of inflammation and cancer metastasis remains to be investigated. On the other hand, 5-methoxyindole metabolites of tryptophan are valuable lead compounds for development of new anti-inflammatory drugs and cancer chemoprevention.

Related: Cancer Prevention and Risk Reduction


Yang YI, Ahn JH, Lee KT, et al.
RSF1 is a positive regulator of NF-κB-induced gene expression required for ovarian cancer chemoresistance.
Cancer Res. 2014; 74(8):2258-69 [PubMed] Related Publications
Overexpression or amplification of the RSF1 gene has been associated with poor prognosis in various human cancers, including ovarian cancer. In previous work, RSF1 was identified as an amplified gene that facilitated the development of paclitaxel-resistant ovarian cancer. In the present study, we further demonstrated that RSF1 expression inversely correlated with paclitaxel response in patients with ovarian cancer and the mouse xenograft model. In addition, RSF1-overexpressing paclitaxel-resistant ovarian cancer cell lines were found to express elevated levels of genes regulated by NF-κB, including some involved with the evasion of apoptosis (CFLAR, XIAP, BCL2, and BCL2L1) and inflammation (PTGS2). In addition, ectopic expression of RSF1 using Tet-off inducible SKOV3 cells significantly enhanced NF-κB-dependent gene expression and transcriptional activation of NF-κB. An RSF1 knockdown using short hairpin RNAs suppressed these same pathways. Moreover, pretreatment with NF-κB inhibitors or downregulation of NF-κB-regulated gene expression considerably enhanced paclitaxel sensitivity in RSF1-overexpressing OVCAR3 and/or RSF1-induced SKOV3 cells. A coimmunoprecipitation assay revealed that RSF1 interacts with NF-κB and CREB-binding protein, a ubiquitous coactivator for NF-κB. Recruitment of RSF1 to the NF-κB binding element in the PTGS2 and XIAP promoters was demonstrated by the chromatin immunoprecipitation assay. Furthermore, hSNF2H, a well-known binding partner of RSF1, was partially involved in the interaction between RSF1 and NF-κB. Taken together, these data suggest that RSF1 may function as a coactivator for NF-κB, consequently augmenting expression of genes necessary for the development of chemoresistance in ovarian cancer cells.

Related: Carboplatin Ovarian Cancer Paclitaxel Signal Transduction


Han YM, Hahm KB, Park JM, et al.
Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and GastrininAPCMin/+ intestinal polyposis model.
Neoplasia. 2014; 16(1):73-83 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Though long-term administration of proton pump inhibitor (PPI) imposed the risk of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt increases of colon cancer risk were witnessed after a long-term cohort study. Our recent investigation revealed that PPI prevented colitis-associated carcinogenesis through anti-inflammatory, anti-oxidative, and anti-mutagenic mechanisms in spite of hypergastrinemia. Therefore, we hypothesized that PPI might either antagonize the trophic action of gastrin on gastrointestinal tumorigenesis or synergize to exert augmented anti-tumorigenic actions. We challenged APCMin/+ mice with gastrin, PPI, PPI and gastrin together for 10 weeks and counted intestinal polyposis accompanied with molecular changes. Gastrin significantly increased intestinal polyposis, but combination of PPI and gastrin markedly attenuated intestinal polyposis compared to gastrin-promoted APCMin/+ mice (P<.001), in which significant β-catenin phosphorylation and inhibition of β-catenin nuclear translocation were observed with PPI alone or combination of PPI and gastrin, whereas gastrin treatment significantly increased β-catenin nuclear translocation. Significant footprints of apoptosis, G0/G1 accumulation, inactivation of p38 and extracellular signal-regulated kinase, decreased expressions of CD31, and inhibition of tumor necrosis factor-α and cyclooxygenase-2 were noted in the combination group. In vitro investigations were similar to in vivo findings as shown that PPI treatment inhibited the binding of gastrin to its receptor, inactivated β-catenin-associated signaling including Tcf/Lef and glycogen synthase kinase β, and paradoxically inhibited β-catenin-associated proliferative activities. Our investigations explain why colon cancer risk has not increased despite long-term use of PPIs and provide a rationale for using PPI to achieve anti-tumorigenesis beyond acid suppression.

Related: Apoptosis Signal Transduction TNF CTNNB1 gene


Lin C, Huang F, Zhang YJ, et al.
Roles of MiR-101 and its target gene Cox-2 in early diagnosis of cervical cancer in Uygur women.
Asian Pac J Cancer Prev. 2014; 15(1):45-8 [PubMed] Related Publications
AIMS: Early diagnosis is important for cervical cancer treatment. This study aimed to characteriz the microRNA profile and target gene protein levels of cervical cancers in Uygur women for application in early diagnosis.
METHODS: The profiles of miRNA in cervical cancer and chronic cervicitis were analyzed with miRNAmicroarray V4.0. The expression of miR-101 was detected by real-time PCR and locked nucleotide acid in situ hybridization (LNA-ISH). Cox-2 protein levels were assessed by immunohistochemistry.
RESULTS: The microarray identified a set of 12 miRNAs significantly decreased in cervical cancer in comparison to the control group. Quantitative RT-PCR analysis showed miR-101 to be significantly downregulated in cancer tissues (p<0.05) while LNA-ISH showed miR-101 positive rates of 80% (20/25) and 8% (5/25) (p<0.05) in the control and cervical cancer groups. Cox-2 positive rates of cervical cancer and control groups were 84% (21/25) and 8% (2/25) (p<0.05).
CONCLUSIONS: Use of down-regulation of miR-101 and up-regulation of Cox-2 as markers may play a role in early diagnosis of cervical cancer in Uygur women.

Related: Cancer Screening and Early Detection Cervical Cancer


Gong J, Xie J, Bedolla R, et al.
Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer.
Clin Cancer Res. 2014; 20(5):1259-73 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PURPOSE: Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-κB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-κB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.
EXPERIMENTAL DESIGN: HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-κB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdown was used to decipher STAT3/NF-κB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5-COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray.
RESULTS: Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator of NF-κB activation. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors.
CONCLUSIONS: Dual inhibition of STAT3-NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer Signal Transduction


Vasiljević N, Scibior-Bentkowska D, Brentnall AR, et al.
Credentialing of DNA methylation assays for human genes as diagnostic biomarkers of cervical intraepithelial neoplasia in high-risk HPV positive women.
Gynecol Oncol. 2014; 132(3):709-14 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
OBJECTIVE: Testing for high risk human papillomavirus (HR-HPV) is increasing; however due to limitations in specificity there remains a need for better triage tests. Research efforts have focused recently on methylation of human genes which show promise as diagnostic classifiers.
METHODS: Methylation of 26 genes: APC, CADM1, CCND2, CDH13, CDKN2A, CTNNB1, DAPK1, DPYS, EDNRB, EPB41L3, ESR1, GSTP1, HIN1, JAM3, LMX1, MAL, MDR1, PAX1, PTGS2, RARB, RASSF1, SLIT2, SOX1, SPARC, TERT and TWIST1 was measured by pyrosequencing in cytology specimens from a pilot set of women with normal or cervical intraepithelial neoplasia grade 3 (CIN3) histology. Six genes were selected for testing in Predictors 1, a colposcopy referral study comprising 799 women. The three genes EPB41L3, DPYS and MAL were further tested in a second colposcopy referral study, Predictors 2, comprising 884 women.
RESULTS: The six genes selected from the pilot: EPB41L3, EDNRB, LMX1, DPYS, MAL and CADM1 showed significantly elevated methylation in CIN2 and CIN3 (CIN2/3) versus ≤CIN1 in Predictors 1 (p<0.01). Highest methylation was observed in cancer tissues. EPB41L3 methylation was the best single classifier of CIN2/3 in both HR-HPV positive (p<0.0001) and negative samples (p=0.02). Logistic regression modeling showed that other genes did not add significantly to EPB41L3 and in Predictors 2, its classifier value was validated with AUC 0.69 (95% CI 0.65-0.73).
CONCLUSION: Several methylated genes show promise for detecting CIN2/3 of which EPB41L3 seems the best. Methylated human gene biomarkers used in combination may be clinically useful for triage of women with HR-HPV infections.

Related: Cervical Cancer


Naumov I, Zilberberg A, Shapira S, et al.
CD24 knockout prevents colorectal cancer in chemically induced colon carcinogenesis and in APC(Min)/CD24 double knockout transgenic mice.
Int J Cancer. 2014; 135(5):1048-59 [PubMed] Related Publications
Increased expression of CD24 is seen in a large variety of solid tumors, including up to 90% of gastrointestinal (GI) tumors. Stable derivatives of SW480 colorectal cancer (CRC) cells that overexpress CD24 proliferate faster, and increase cell motility, saturation density, plating efficiency, and growth in soft agar. They also produce larger tumors in nude mice as compared to the parental SW480 cells. Most significantly, even depletion of one copy of the CD24 allele in the APC(Min/+) mice of a transgenic mouse model led to a dramatic reduction in tumor burden in all sections of the small intestine. Homozygous deletion of both CD24 alleles resulted in complete abolishment of tumor formation. Moreover, CD24 knockout mice exhibited resistance to chemically induced inflammation-associated CRC. Finally, a new signal transduction pathway is suggested: namely, CD24 expression downstream to COX2 and PGE2 synthesis, which is directly regulated by β-catenin. CD24 is shown in vitro and in vivo as being an important oncogene in the gut, and one that plays a critical role in the initiation and progression of carcinogenesis.

Related: Colorectal (Bowel) Cancer Signal Transduction CTNNB1 gene


Wei G, Chang Y, Zheng J, et al.
Notch1 silencing inhibits proliferation and invasion in SGC‑7901 gastric cancer cells.
Mol Med Rep. 2014; 9(4):1153-8 [PubMed] Related Publications
Downregulation of Notch1 has been shown to exert antineoplastic effects in vivo and in vitro. However, the role of the Notch1 gene in the proliferative and invasive ability of gastric cancer cells is not clear. In this study, we investigated the effect of Notch1 gene silencing on the proliferation and invasion of gastric cancer SGC‑7901 cells. Small interfering RNA (siRNA) targeting Notch1 was transfected into SGC‑7901 cells using Lipofectamine 2000. Proliferation of SGC‑7901 cells was then determined by the MTT assay. Notch1 mRNA expression was determined by reverse transcription‑polymerase chain reaction (RT‑PCR). Invasion of the SGC‑7901 cells was detected by the Transwell assay. The protein levels of cyclin D1, cyclin A1 and cyclin-dependent kinase 2 (CDK2) were determined by western blotting. The mRNA levels of matrix metalloproteinase‑2 (MMP‑2) and cyclooxygenase‑2 (COX‑2) were determined by RT‑PCR. Compared to the control group, the Notch1 mRNA level was significantly decreased following transfection. The growth and invasion rates of SGC‑7901 cells were significantly reduced after Notch1 silencing. Additionally, the expression of cyclin D1 and cyclin A1 proteins and of the MMP‑2 and COX‑2 mRNAs was markedly attenuated. From these results, it was concluded that Notch1 gene silencing inhibits the proliferation of gastric SGC‑7901 cells by decreasing the expression of cyclins D1 and A1, and reduces the invasive ability of SGC‑7901 cells through the downregulation of MMP‑2 and COX‑2 genes. Thus, silencing of the Notch1 pathway may be a novel approach in the treatment of gastrointestinal cancer.

Related: MMP2 Stomach Cancer Gastric Cancer NOTCH1 gene


Reiter M, Baumeister P, Hartmann M, et al.
Chemoprevention by celecoxib and mutagen sensitivity of cyclin d1 in patients with oropharyngeal carcinoma.
In Vivo. 2014 Jan-Feb; 28(1):49-53 [PubMed] Related Publications
UNLABELLED: The head and neck region is one of the most important locations predisposed for tobacco-associated cancer. Chemoprevention might offer a chance to decrease the risk for this type of disease.
MATERIALS AND METHODS: Mini-organ cultures (MOC) of macroscopically-healthy pharyngeal tissues from 20 patients with oropharyngeal squamous cell carcinoma (SCC) and from 20 controls were employed in the study. MOC were firstly incubated with Celecoxib, and DNA damage was induced by incubation with Benz[a]pyren-7,8-diol-9,10-epoxid (BPDE), a major representative of tobacco-associated carcinogens. DNA damage was evaluated with the alkaline single-cell microgel electrophoresis (Comet assay). Furthermore, fragmentation of the cyclin D1 gene, a gene of special importance in head and neck carcinogenesis was examined by the Comet-FISH assay. Finally, the chemoprotective potential of Celecoxib was analyzed after incubation with MOC.
RESULTS: As expected, BPDE caused significant DNA fragmentation in tumor compared to negative control tissues. No enhanced damage was observed in the cyclin D1 gene. DNA fragmentation was significantly reduced when MOC were incubated with Celecoxib in the tumor group. Surprisingly, these effects were also observed in the group without cancer of the oropharynx, although COX-2 is not expressed in macroscopically-healthy mucosa.
CONCLUSION: Celecoxib showed considerable chemoprotective effeciency against BPDE in both groups and this effect seems to be independent of COX-2 expression. No evidence for higher mutagen sensitivity in the Cyclin D1 gene was observed.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Oropharyngeal Cancer


Dallaglio K, Bruno A, Cantelmo AR, et al.
Paradoxic effects of metformin on endothelial cells and angiogenesis.
Carcinogenesis. 2014; 35(5):1055-66 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
The biguanide metformin is used in type 2 diabetes management and has gained significant attention as a potential cancer preventive agent. Angioprevention represents a mechanism of chemoprevention, yet conflicting data concerning the antiangiogenic action of metformin have emerged. Here, we clarify some of the contradictory effects of metformin on endothelial cells and angiogenesis, using in vitro and in vivo assays combined with transcriptomic and protein array approaches. Metformin inhibits formation of capillary-like networks by endothelial cells; this effect is partially dependent on the energy sensor adenosine-monophosphate-activated protein kinase (AMPK) as shown by small interfering RNA knockdown. Gene expression profiling of human umbilical vein endothelial cells revealed a paradoxical modulation of several angiogenesis-associated genes and proteins by metformin, with short-term induction of vascular endothelial growth factor (VEGF), cyclooxygenase 2 and CXC chemokine receptor 4 at the messenger RNA level and downregulation of ADAMTS1. Antibody array analysis shows an essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells including interleukin-8, angiogenin and TIMP-1, as well as selective regulation of angiopioetin-1, -2, endoglin and others. Endothelial cell production of the cytochrome P450 member CYP1B1 is upregulated by tumor cell supernatants in an AMPK-dependent manner, metformin blocks this effect. Metformin inhibits VEGF-dependent activation of extracellular signal-regulated kinase 1/2, and the inhibition of AMPK activity abrogates this event. Metformin hinders angiogenesis in matrigel pellets in vivo, prevents the microvessel density increase observed in obese mice on a high-fat diet, downregulating the number of white adipose tissue endothelial precursor cells. Our data show that metformin has an antiangiogenic activity in vitro and in vivo associated with a contradictory short-term enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and breast cancer cells.

Related: Angiogenesis Inhibitors Cancer Prevention and Risk Reduction Angiogenesis and Cancer VEGFA CYP1B1


Zhao C, Bu X, Wang W, et al.
GEC-derived SFRP5 inhibits Wnt5a-induced macrophage chemotaxis and activation.
PLoS One. 2014; 9(1):e85058 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Aberrant macrophage infiltration and activation has been implicated in gastric inflammation and carcinogenesis. Overexpression of Wnt5a and downregulation of SFRP5, a Wnt5a antagonist, were both observed in gastric cancers recently. This study attempted to explore whether Wnt5a/SFRP5 axis was involved in macrophage chemotaxis and activation. It was found that both Wnt5a transfection and recombinant Wnt5a (rWnt5a) treatment upregulated CCL2 expression in macrophages, involving JNK and NFκB signals. Conditioned medium from Wnt5a-treated macrophages promoted macrophage chemotaxis mainly dependent on CCL2. SFRP5 from gastric epithelial cells (GECs) inhibited Wnt5a-induced CCL2 expression and macrophage chemotaxis. In addition, Wnt5a treatment stimulated macrophages to produce inflammatory cytokines and COX-2/PGE2, which was also suppressed by SFRP5 from GECs. These results demonstrate that Wnt5a induces macrophage chemotaxis and activation, which can be blocked by GEC-derived SFRP5, suggesting that Wnt5a overproduction and SFRP5 deficiency in gastric mucosa may together play an important role in gastric inflammation and carcinogenesis.

Related: MAP2K4 gene Signal Transduction


Pang LY, Gatenby EL, Kamida A, et al.
Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation.
PLoS One. 2014; 9(1):e83144 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.

Related: Bone Cancers Doxorubicin Osteosarcoma


He J, Wang M, Jiang Y, et al.
Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 pathway.
Environ Health Perspect. 2014; 122(3):255-61 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.
OBJECTIVES: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.
METHODS: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.
RESULTS: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.
CONCLUSION: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.
CITATION: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255-261; http://dx.doi.org/10.1289/ehp.1307545.

Related: HIF1A


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Cite this page: Cotterill SJ. COX2 (PTGS2), Cancer Genetics Web: http://www.cancerindex.org/geneweb/PTGS2.htm Accessed: date

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