PTGS2

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:NCBIAccessed: 28 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 28 February, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: PTGS2 (cancer-related)

Ming M, Han W, Zhao B, et al.
SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer.
Cancer Res. 2014; 74(20):5925-33 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis.

Liu H, Yan ZQ, Li B, et al.
Reduced expression of SOX7 in ovarian cancer: a novel tumor suppressor through the Wnt/β-catenin signaling pathway.
J Ovarian Res. 2014; 7:87 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
BACKGROUND: Products of the SOX gene family play important roles in the life process. One of the members, SOX7, is associated with the development of a variety of cancers as a tumor suppression factor, but its relevance with ovarian cancer was unclear. In this study, we investigated the involvement of SOX7 in the progression and prognosis of epithelial ovarian cancer (EOC) and the involved mechanisms.
METHODS: Expression profiles in two independent microarray data sets were analyzed for SOX7 between malignant and normal tissues. The expression levels of SOX7 in EOC, borderline ovarian tumors and normal ovarian tissues were measured by immunohistochemistry. We also measured levels of COX2 and cyclin-D1 to examine their possible involvement in the same signal transduction pathway as SOX7.
RESULTS: The expression of SOX7 was significantly reduced in ovarian cancer tissues compared with normal controls, strongly indicating that SOX7 might be a negative regulator in the Wnt/β-catenin pathway in ovarian cancer. By immunohistochemistry staining, the protein expression of SOX7 showed a consistent trend with that of the gene expression microarray analysis. By contrast, the protein expression level of COX2 and cyclin-D1 increased as the tumor malignancy progressed, suggesting that SOX7 may function through the Wnt/β-catenin signaling pathway as a tumor suppressor. In comparison between the protein expression levels of SOX7 with pathological features of the cancer, we found that SOX7 was down-regulated mainly in serous cystadenocarcinoma and advanced stages of the cancers.
CONCLUSIONS: The expression of SOX7 correlates with tumor progression as a tumor suppressor, possibly through the Wnt/β-catenin signaling pathway in ovarian cancers, suggesting that SOX7 may be a promising prognostic marker.

Chang WS, Liao CH, Miao CE, et al.
The role of functional polymorphisms of cyclooxygenase 2 in renal cell carcinoma.
Anticancer Res. 2014; 34(10):5481-6 [PubMed] Related Publications
Renal cell carcinoma (RCC) accounts for about 3% of all cancer-related mortalities worldwide and the risk factors for the development of RCC have not yet been fully elucidated. Mounting evidence shows that overexpression of cyclo-oxygenase 2 (COX2) is commonly found in malignant tumors, including RCC. However, the contribution of genotypic variations of COX2 to RCC has not been studied. We hypothesized that variants of the COX2 gene are associated with risk of susceptibility to RCC in Taiwan. In this hospital-based case-control study, 92 patients with RCC and 580 age- and gender-matched cancer-free controls were recruited and the associations of COX2 A-1195G, G-765C, T+8473C, intron 1, intron 5, and intron 6 polymorphisms with RCC risk were examined in this Taiwanese population. The results showed that compared to the wild-type GG genotype, the CG genotype for COX2 G-765C was significantly associated with a lower risk of RCC (odds ratio=0.34, 95% confidence interval=0.15-0.80, p=0.0082). For other polymorphic sites, no obvious associations were found. There was also an obvious association of COX2 G765C genotype with reduced RCC risk among those without family cancer history (p=0.0331). These evidence indicated that COX2 G-765C genotype involved in the etiology of RCC and may serve as a novel genetic marker for susceptibility of RCC.

Park HS, Jung CK, Lee SH, et al.
Clinicopathologic characteristics and surgical outcomes of elderly patients with thyroid cancer.
Jpn J Clin Oncol. 2014; 44(11):1045-51 [PubMed] Related Publications
OBJECTIVE: Age is one of the important prognostic factors in thyroid cancer, and old age is generally related to higher rate of post-operative morbidity and mortality. The study analyzed the characteristics of thyroid cancer in elderly patients compared with those in younger patients.
METHODS: Patients who underwent surgery between 1992 and 2011 were enrolled. The patients were divided into those ≥70 years of age (older group) and <70 years of age (younger group). Data including clinicopathological features and post-operative complications was analyzed. Molecular markers including Galectin-3, Cyclooxygenase-2, bcl-2, Cyclin D1, Epidermal growth factor receptor and BRAF mutation were reviewed. Survival analyses including recurrence-free survival and overall survival were examined.
RESULTS: Of 1867 patients, 98 were age-classified in older group and the remaining 1769 were in younger group. Older group displayed larger tumor size, and increased extrathyroidal extension, vascular invasion and neural invasion than younger group, and all were statistically significant. Molecular marker analyses revealed no significant differences between the groups. Post-operative complication rates were not significantly different between the older and younger groups in both univariate and multivariate analyses. Elderly patients showed poor recurrence-free survival and overall survival than younger patients in univariate analyses. However, age ≥70 years was not associated with poor recurrence-free survival after adjustment of confounding factors.
CONCLUSION: Molecular features of elderly patients may be similar with younger patients. Even though aggravated clinicopathological features of thyroid carcinoma are more prevalent in elderly patients, thyroid surgery in elderly patients can be performed with favorable surgical and oncological outcomes.

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.

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.

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.

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.

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.

Campanholo VM, Felipe AV, de Lima JM, et al.
-765 g>c polymorphism of the cox-2 gene and gastric cancer risk in Brazilian population.
Arq Gastroenterol. 2014 Apr-Jun; 51(2):79-83 [PubMed] Related Publications
CONTEXT: Genomic alterations play important roles in gastric cancer carcinogenesis. Cyclooxygenases (COX) are important enzymes in the maintenance of mucosal integrity and in pathological processes, mainly in inflammation and cancer. The -765G>C COX-2 polymorphism has been implicated in gastric cancer risk.
OBJECTIVES: To evaluate the COX-2 gene polymorphism as a predictor of gastric cancer risk.
METHODS: One hundred gastric cancer patients and 150 controls were enrolled from a Brazilian centre. Personal data regarding related risk factors, including alcohol consumption and smoking behavior, were collected via questionnaire. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism.
RESULTS: G/G, G/C and C/C genotypes frequencies was 42.7%, 50% and 7.3%, respectively in controls and 59.0%, 34.0% and 7.0% in gastric cancer. The frequency of the genotypes differed between the groups (P = 0.033). A higher risk of gastric cancer was associated with COX-2 -765G/G genotype (P = 0.048; OR:1.98, 95% CI = 1.01-3.90). Alcohol consumption and smoking in patients with -765G/G genotype also increased the risk of gastric cancer.
CONCLUSIONS: The -765G/G genotype and the -765G allele had been associated with an increased risk for gastric cancer. The presence of smoking and alcohol consumption increased the risk for gastric cancer in subjects with -765G/G genotype compared with the control group. Polymorphism of COX-2 gene and gastric cancer risk.

Kansal S, Vaiphei K, Agnihotri N
Alterations in lipid mediated signaling and Wnt/ β -catenin signaling in DMH induced colon cancer on supplementation of fish oil.
Biomed Res Int. 2014; 2014:832025 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Ceramide mediates inhibition of cyclooxygenase-2 (COX-2) which catalyzes formation of prostaglandin further activating peroxisome proliferator-activated receptor γ (PPAR γ ) and Wnt/ β -catenin pathway; and hence plays a critical role in cancer. Therefore, in current study, ceramide, COX-2, 15-deoxy prostaglandin J2(15-deoxy PGJ2), PPAR γ , and β -catenin were estimated to evaluate the effect of fish oil on lipid mediated and Wnt/ β -catenin signaling in colon carcinoma. Male Wistar rats in Group I received purified diet while Groups II and III received modified diet supplemented with FO : CO(1 : 1) and FO : CO(2.5 : 1), respectively. These were further subdivided into controls receiving ethylenediaminetetraacetic acid and treated groups receiving dimethylhydrazine dihydrochloride (DMH)/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and those sacrificed after 16 weeks constituted postinitiation phase. Decreased ceramide and increased PPAR γ were observed in postinitiation phase only. On receiving FO+CO(1 : 1)+DMH and FO+CO(2.5 : 1)+DMH in both phases, ceramide was augmented whereas COX-2, 15-deoxy PGJ2, and nuclear translocation of β -catenin were reduced with respect to cancerous animals. Decrease was more significant in postinitiation phase with FO+CO(2.5 : 1)+DMH. Treatment with oils increased PPAR γ in initiation phase but decreased it in postinitiation phase. Hence, fish oil altered lipid mediated signalling in a dose and time dependent manner so as to inhibit progression of colon cancer.

Veits L, Schupfner R, Hufnagel P, et al.
KRAS, EGFR, PDGFR-α, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE).
Diagn Pathol. 2014; 9:116 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.
METHODS: We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-α and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets.
RESULTS: Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-α gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene.
CONCLUSIONS: All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-α gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016.

Khorshidi F, Haghighi MM, Nazemalhosseini Mojarad E, et al.
The prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/ COX2) rs5277 polymorphism does not influence risk of colorectal cancer in an Iranian population.
Asian Pac J Cancer Prev. 2014; 15(8):3507-11 [PubMed] Related Publications
BACKGROUND: The prostaglandin-endoperoxide synthase 2 [PTGS2, commonly known as cyclooxygenase-2 (COX-2)] is an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue and involved in the synthesis of prostaglandins and thromboxanes, regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether a functional genetic polymorphism, rs5277, in COX-2 may have a risk-modifying effect on sporadic colorectal cancer in an Iranian population.
MATERIALS AND METHODS: We conducted a case-control study on 167 patients with colorectal cancer and 197 cancer-free controls in Taleghani Hospital in Tehran, Iran, between 2007 and 2011. Peripheral blood samples of both groups were processed for DNA extraction and genotyping of the COX-2 gene polymorphism (rs5277) using PCR-RFLP. RFLP results were confirmed by direct sequencing. Logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI).
RESULTS: There was no significant difference in the distribution of COX-2 gene rs5277 polymorphism genotype and the allelic form, among CRC patients compared with the healthy control group (p: 0.867).
CONCLUSIONS: Our results suggest that rs5277 polymorphism in COX2 could not be a good prognostic indicator for patients with CRC.

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.

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.

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.

Zhao F, Zhu H, Huang M, et al.
The 765G>C polymorphism in the cyclooxygenase-2 gene and gastric cancer risk: an update by meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(6):2863-8 [PubMed] Related Publications
BACKGROUND: The 765G>C polymorphism in cyclooxygenase-2 (COX-2) gene has been extensively investigated for association with gastric cancer (GC). However, the results of different studies have been inconsistent. The aim of this study is to comprehensively evaluate the genetic risk of -765G>C polymorphism in the COX-2 gene for GC.
MATERIALS AND METHODS: We searched Pubmed, Embase, Medline, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on Jan 10, 2014). Statistical analyses were performed using Revman 5.2 and STATA 10.0 software.
RESULTS: A total of 1,874 cases and 3,005 controls in 10 case-control studies were included in this meta-analysis. The results indicated that the variant C allele carriers (GC+CC) had a 69% increased risk of GC when compared with the homozygote GG (odds ratio (OR)=1.69, 95% confidence interval (CI), 1.10-2.61 for GC+CC vs GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with C allele carriers in Asians (OR=1.75, 95%CI=1.40-2.18, and p<0.00001) and in Indians (OR=8.38, 95%CI=4.34-16.16, and p<0.00001) but not in Caucasians (OR=1.07, 95%CI=0.81-1.42, and p=0.62) or in Dutch (OR=0.53, 95%CI= 0.33-0.87, and p= 0.01).In the subgroup analysis by Helicobacter pylori (H. pylori) status, a significantly increased risk was identified among H. pylori (+) (OR=3.58, 95%CI=2.33-3.50, and p<0.00001) and H. pylori (-) (OR=2.32, 95%CI=1.46-3.69, and p=0.0004).
CONCLUSIONS: This meta-analysis suggested that the -765G>C polymorphism in the COX-2 gene could be a risk factor for GC in Asians and Indians.

Fink SP, Yamauchi M, Nishihara R, et al.
Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).
Sci Transl Med. 2014; 6(233):233re2 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)-related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses' Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.

Zeng W, van den Berg A, Huitema S, et al.
Correlation of microRNA-16, microRNA-21 and microRNA-101 expression with cyclooxygenase-2 expression and angiogenic factors in cirrhotic and noncirrhotic human hepatocellular carcinoma.
PLoS One. 2014; 9(4):e95826 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a classical example of inflammation-linked cancer and is characterized by hypervascularity suggesting rich angiogenesis. Cycloxygenase-2 (COX-2) is a potent mediator of inflammation and is considered to upregulate angiogenesis. The aims of the study are (1) to analyze expression of Cox-2 mRNA, Cox-2 protein, miR-16, miR-21 and miR-101 in HCC and adjacent liver parenchyma in cirrhotic and noncirrhotic liver, (2) to investigate the relation between COX-2 expression, miR-21 expression and angiogenic factors in these tissues and (3) to investigate the association between miR-16 and miR-101 and COX-2 expression.
METHODS: Tissue samples of HCC and adjacent liver parenchyma of 21 noncirrhotic livers and 20 cirrhotic livers were analyzed for COX-2 expression at the mRNA level (qRT-PCR) and at the protein level by Western blot and immunohistochemistry. Gene expression of VEGFA, VEGFR1, VEGFR2, Ang-1, Ang-2 and Tie-2 were correlated with COX-2 levels. miR-16, miR-21 and miR-101 gene expression levels were quantified in HCC tumor tissue.
RESULTS: COX-2 mRNA and protein levels were lower in HCC as compared to adjacent liver parenchyma both in cirrhotic and noncirrhotic liver. COX-2 protein localized mainly in vascular and sinusoidal endothelial cells and in Kupffer cells. At the mRNA level but not at the protein level, COX-2 correlated with mRNA levels of angiogenic factors VEGFR1, Ang-1, and Tie2. miR-21 expression was higher in cirrhotic tissues versus noncirrhotic tissues. MiR-101 expression was lower in cirrhotic versus noncirrhotic adjacent liver parenchyma. None of the miRNAs correlelated with COX-2 expression. miR-21 correlated negatively with Tie-2 receptor in adjacent liver parenchyma.
CONCLUSIONS: In human HCC, COX-2 mRNA but not COX-2 protein levels are associated with expression levels of angiogenic factors. MiR-21 levels are not associated with angiogenic molecules. MiR-16 and miR-101 levels do not correlate with COX-2 mRNA and protein levels.

Shen Z, Zhan G, Deng H, et al.
[Growth inhibitory effect of microRNA-519b-3p on larynx squamous Hep-2 cells].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014; 49(2):151-6 [PubMed] Related Publications
OBJECTIVE: To investigate the effects of microRNA-519b-3p (miR-519b-3p) on laryngeal carcinoma Hep-2 cell growth, and to analyze the underlying molecular mechanisms.
METHODS: The effects of miR-519b-3p on the growth and cell cycle of Hep-2 cells transfected with miR-519b-3p mimic were tested by MTT assay and flow cytometry, respectively. The mRNA and protein expressions of the related genes were tested by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. The expressions of miR-519b-3p were tested by real-time RT-PCR in 48 pairs of laryngeal carcinoma and adjacent tissue samples.
RESULTS: The expression of miR-519b-3p in laryngeal carcinoma tissues was significant lower than that in adjacent non-cancerous tissues (S(ΔCt) = 2.989, t = 2.693, P < 0.01) . Increasing the level of miR-519b-3p inhibited significantly Hep-2 cell proliferation, arrested the cell cycle in the G2/M phase (10.29% ± 4.63%, t = 4.395, P < 0.05) , and decreased significantly the percentage of cells in the S phase (7.56% ± 2.05%, t = 3.555, P < 0.05) , with the increase in the expression of cyclin dependent kinase (CDK) 1 and the decrease in the expressions of CDK 2 and Cyclin A. RT-PCR and Western blot showed that miR-519b-3p down-regulated the protein but not mRNA expressions of HuR and cyclooxygenase-2(COX-2) genes.
CONCLUSIONS: The expression of MiR-519b-3p as carcinoma suppressor gene is low in laryngeal carcinoma. The cell cycle of Hep-2 cells was arrested in the G2/M phase by MiR-519b-3p.

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.

Lin Y, Cui M, Xu T, et al.
Silencing of cyclooxygenase-2 inhibits the growth, invasion and migration of ovarian cancer cells.
Mol Med Rep. 2014; 9(6):2499-504 [PubMed] Related Publications
The present study aimed to investigate the effect of downregulating cyclooxygenase‑2 (COX‑2) expression on the growth of human ovarian cancer cells. The COX‑2‑specific small interfering RNA (siRNA) plasmid vector was constructed and then transfected into ovarian cancer cells. The expression of COX‑2 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation, apoptosis, cell cycle distribution and cell migration were assessed following knockdown of COX‑2 by RNA interference (RNAi). Western blot analysis was used to identify differentially expressed angiogenesis- and cell cycle‑associated proteins in cells with silenced COX‑2. The expression levels of COX‑2 in ovarian cancer cells transfected with siRNA were decreased, leading to a significant inhibition of ovarian cancer cell proliferation, migration and invasion. Western blot analysis revealed that silencing of COX‑2 may inhibit vascular endothelial growth factor, matrix metalloproteinase (MMP)‑2 and MMP‑9 protein expression. In conclusion, the present study demonstrated that RNAi can effectively silence COX‑2 gene expression and inhibit the growth of ovarian cancer cells, which indicates that there is a potential of targeting COX‑2 as a novel gene therapy approach for the treatment of ovarian cancer.

Chen X, Dong W, Wang J, et al.
[Cyclooxygenase-2 -765G>C polymorphism and susceptibility to colorectal cancer: a meta-analysis].
Zhonghua Yu Fang Yi Xue Za Zhi. 2014; 48(1):62-6 [PubMed] Related Publications
OBJECTIVE: To explore the correlation between polymorphism of cyclooxygenase-2 (COX-2) -765G>C and susceptibility to colorectal cancer.
METHODS: All eligible case-control studies published up to March 2013 were searched out from PubMed, EMABSE, CJFD, CBM, CNKI, VIP and WanFang databases, while 99 articles were concluded. Two reviewers independently identified the literature according to inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.1 and Stata 12.0 software.
RESULTS: A total of eleven studies comprising 3432 cases and 5286 controls were finally included. The included studies showed good homogeneity in the three genetic models, except the model of GC/GG genotype (I(2) = 52%, P = 0.03). Overall, there were no significant association between polymorphism of COX-2-765G>C and the susceptibility to colorectal cancer (dominant model: (GC+CC)/GG: OR = 1.08, 95%CI:0.96-1.21; recessive model:CC/(GC+GG): OR = 1.09, 95%CI:0.76-1.56; GC/GG: OR = 1.05, 95%CI:0.87-1.28; CC/GG: OR = 1.11, 95%CI:0.77-1.60). In stratification analysis by ethnicity, we observed that the polymorphism of COX-2 -765G>C could increase the susceptibility to colorectal cancer among yellow populations ((GC+CC)/GG: OR = 1.41, 95%CI:1.15-1.75; GC/ GG: OR = 1.48, 95%CI:1.15-1.90), but there was no significant association found among Caucasian populations.
CONCLUSION: This meta-analysis suggested that the polymorphism of COX-2 -765G>C may increase the susceptibility to colorectal cancer in the yellow population.

Pereira C, Queirós S, Galaghar A, et al.
Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
PLoS One. 2014; 9(4):e92000 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49-22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89-7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC etiology through the identification of biomarkers of colorectal carcinogenesis might allow a better definition of risk models that are more likely to benefit from targeted preventive strategies to reduce CRC burden.

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.

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.

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.

Zhang Q, Hu H, Shi X, Tang W
Knockdown of S100P by lentiviral-mediated RNAi promotes apoptosis and suppresses the colony-formation ability of gastric cancer cells.
Oncol Rep. 2014; 31(5):2344-50 [PubMed] Related Publications
S100P is a putative candidate oncogene in several types of human tumors. However, expression of S100P, its potential role and its clinical significance in gastric cancer remain unclear. In the present study, S100P expression was examined by immunohistochemistry using a tissue microarray. Positive staining for S100P was noted in 77.1% of the cases while 22.9% were negative. In two gastric cancer cell lines, MGC-803 and SGC-7901, S100P expression was knocked down by a lentiviral short hairpin delivery system. The RNA interference-mediated downregulation of S100P expression markedly promoted cell apoptosis and inhibited cell colony-formation ability of the gastric cancer cells. In addition, knockdown of S100P significantly regulated the expression of 12 apoptosis-associated genes with a >1.5-fold change compared with the negative control. Among them, FOS, DDIT3 and FN1 were significantly upregulated, while FASLG, DAPK1, CTNNB1 and CASP2 were notably downregulated following S100P silencing. These results suggest that S100P acts as an oncogenic factor in gastric cancer and is a potential molecular target for gastric cancer gene therapy.

Samore WR, Gondi CS
Brief overview of selected approaches in targeting pancreatic adenocarcinoma.
Expert Opin Investig Drugs. 2014; 23(6):793-807 [PubMed] Related Publications
INTRODUCTION: Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, with 5-year survival painfully inadequate at under 5%. Investigators have struggled to target and exploit PDAC unique biology, failing to bring meaningful results from bench to bedside. Nonetheless, in recent years, several promising targets have emerged.
AREAS COVERED: This review will discuss novel drug approaches in development for use in PDAC. The authors examine the continued efforts to target Kirsten rat sarcoma viral oncogene homolog (KRas), which have recently been successfully abated using novel small interfering RNA (siRNA) eluting devices. The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase.
EXPERT OPINION: Although studies into novel biomarkers and advanced imaging have highlighted the potential new avenues toward discovering localized tumors earlier, the current therapeutic options highlight the fact that PDAC is a highly metastatic and chemoresistant cancer that often must be fought with virulent, systemic therapies. Several newer approaches, including siRNA targeting of mutated KRas and enzymatic depletion of hyaluronan with PEGylated hyaluronidase are particularly exciting given their early stage results. Further research should help in elucidating their potential impact as therapeutic options.

Xu K, Wang L, Shu HK
COX-2 overexpression increases malignant potential of human glioma cells through Id1.
Oncotarget. 2014; 5(5):1241-52 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1.

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