Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HPGD (cancer-related)
PGE2, the major product of cyclooxygenases implicated in carcinogenesis, is significantly upregulated in cervical cancer. PGE2 via prostanoid receptor EP4 stimulates proliferation and motility while inhibiting apoptosis and immune surveillance. It promotes angiogenesis by stimulating the production of pro-angiogenic factors. The present study demonstrates GW627368X, a highly selective competitive EP4 antagonist, which hinders cervical cancer progression by inhibiting EP4/epithelial growth factor receptor (EGFR) interactive signaling. GW627368X reduced protein kinase A (PKA) phosphorylation which in turn leads to decreased cAMP response element-binding protein (CREB) activation. Decreased PKA phosphorylation also directly enhanced Bax activity and in part reduced glycogen synthase kinase 3 (GSK3)β phosphorylation. Owing to the interactive signaling between EP4 and EGFR, GW627368X lowered EGFR phosphorylation in turn reducing Akt, mitogen-activated protein kinase (MAPK) and GSK3β activity significantly. Sublethal dose of GW627368X was found to reduce the nuclear translocation of β-catenin in a time dependent manner along with time-dependent decrease in cytoplasmic as well as whole-cell β-catenin. Decreased CREB and β-catenin transcriptional activity restricts the aberrant transcription of key genes like EP4, cyclooxygenase (COX)-2, vascular endothelial growth factor and c-myc, which ultimately control cell survival, proliferation and angiogenesis. Reduced activity of EGFR resulted in enhanced expression of 15-hydroxyprostaglandin dehydrogenase increasing PGE2 degradation thereby blocking a positive feedback loop. In xenograft model, dose-dependent decrease in cancer proliferation was observed characterized by reduction in tumor mass and volume and a marked decrease in Ki67 expression. A diminished CD31 specific staining signified decreased tumor angiogenesis. Reduced expression of pAkt, pMAPK, pEGFR and COX-2 validated in vitro results. GW627368X therefore effectively inhibits tumor survival, motility, proliferation and angiogenesis by blocking EP4/EGFR interactive signaling. EP4 is a potent therapeutic target in cervical cancer and can be explored in combination with conventional therapies to attain superior outcomes and to overcome complications associated with organ toxicities, therapeutic resistance and disease relapse.
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.
Kangwan N, Kim YJ, Han YM, et al.Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15-hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer.
Int J Cancer. 2016; 138(6):1482-93 [PubMed
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The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-κB as well as significant ameliorations of β-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-α, regulated with repressed NF-κb and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15-PGDH preservation and apoptosis induction.
Takeda S, Tanigawa T, Watanabe T, et al.Reduction of prostaglandin transporter predicts poor prognosis associated with angiogenesis in gastric adenocarcinoma.
J Gastroenterol Hepatol. 2016; 31(2):376-83 [PubMed
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BACKGROUND AND AIM: Prostaglandin (PG) E2 promotes gastrointestinal carcinogenesis and tumor progression. The total amount of biologically active PGE2 in tissues is determined by a balance of PG biosynthesis and degradation pathways, which involve the PG transporter (PGT). We investigated PGT in gastric adenocarcinoma by determining its expression pattern and examining associations of PGT with prognosis and tumor angiogenesis.
METHODS: PGT expression was determined by immunohistochemistry in advanced gastric adenocarcinoma specimens obtained from 96 patients who underwent surgical resection. Correlations between PGT expression level and clinicopathological factors were statistically analyzed. Angiogenesis in the tumor tissue was evaluated by counting the number of microvessels. The role of PGT in mRNA and protein expression of vascular endothelial growth factor (VEGF) was examined in gastric cancer cells stimulated by PGE2 .
RESULTS: Based on multivariate and Kaplan-Meier analyses, negativity for PGT expression was an independent poor prognostic factor. There were more microvessels in PGT-negative tumors than in PGT-positive tumors. Transfection of AGS and MKN7 gastric cancer cells with PGT-specific siRNA led to increased VEGF mRNA and protein expression accompanied by increased PGE2 in the culture media.
CONCLUSIONS: PGT expression is an independent predictor of poor survival and is associated with tumor angiogenesis in gastric adenocarcinoma.
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.
Famularo G, Stasolla A, Gasbarrone LPachydermoperiostosis and bladder cancer.
Dermatol Online J. 2015; 21(6) [PubMed
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Pachydermoperiostosis or the Touraine-Soulente-Golé syndrome is a rare monogenetic disorder characterized by pachydermia, periostosis and digital clubbing accounts for approximately 3∼5% of all patients with hypertrophic osteoarthropathy. Missense mutations in SLCO2A1 and HPGD genes could plausibly underlie the pathogenesis of pachydermoperiostosis. Patients have usually a favorable outcome with very few cases associated with cancer. Herein, we report the first case of a patient with pachydermoperiostosis associated with bladder cancer.
MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance.
Kim HR, Lee HN, Lim K, et al.15-Deoxy-Δ12,14-prostaglandin J2 induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells.
Mutat Res. 2014; 768:6-15 [PubMed
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Overproduction of prostaglandin E2 (PGE2) has been reported to be implicated in carcinogenesis. The intracellular level of PGE2 is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE2 to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ(12,14)-prostaglandin J2 (15 d-PGJ2), one of the terminal products of cyclooxygenase-2, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15 d-PGJ2 induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15 d-PGJ2 to upregulate 15-PGDH expression. Furthermore, 15 d-PGJ2-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) 1/2. Treatment of U0126, a pharmacological inhibitor of MEK1/2-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15 d-PGJ2-treated MDA-MB-231 cells. Moreover, 15 d-PGJ2 generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15 d-PGJ2 inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15 d-PGJ2 induces the expression of 15-PGDH through ROS-mediated activation of ERK1/2 and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin.
Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its inactivation. Therefore, 15-PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here, we report that omega-3 polyunsaturated fatty acids (ω-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to ω-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH enzymes levels, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miR-26a and miR-26b, which target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ω-3 PUFA suppressed miR-26a and miR-26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of ω-3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for ω-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ω-3 PUFA in treatment of this malignancy.
Apocrine carcinoma of the breast is a distinctive malignancy with unique morphological and molecular features, generally characterized by being negative for estrogen and progesterone receptors, and thus not electable for endocrine therapy. Despite the fact that they are morphologically distinct from other breast lesions, no standard molecular criteria are currently available for their diagnosis. Using gel-based proteomics in combination with mass spectrometry and immunohistochemistry we have identified two novel markers, HMGCS2 and FABP7 that categorize the entire breast apocrine differentiation spectrum from benign metaplasia and cysts to invasive stages. Expression of HMGCS2 and FABP7 is strongly associated with apocrine differentiation; their expression is retained by most invasive apocrine carcinomas (IAC) showing positive immunoreactivity in 100% and 78% of apocrine carcinomas, respectively, as compared to non-apocrine tumors (16.7% and 6.8%). The nuclear localization of FABP7 in tumor cells was shown to be associated with more aggressive stages of apocrine carcinomas. In addition, when added to the panel of apocrine biomarkers previously reported by our group: 15-PGDH, HMGCR and ACSM1, together they provide a signature that may represent a golden molecular standard for defining the apocrine phenotype in the breast. Moreover, we show that combining HMGCS2 to the steroidal profile (HMGCS2+/Androgen Receptor (AR)+/Estrogen Receptor(ER)-/Progesteron Receptor (PR)- identifies IACs with a greater sensitivity (79%) as compared with the steroidal profile (AR+/ER-/PR-) alone (54%). We have also presented a detailed immunohistochemical analysis of breast apocrine lesions with a panel of antibodies against proteins which correspond to 10 genes selected from published transcriptomic signatures that currently characterize molecular apocrine subtype and shown that except for melanophilin that is overexpressed in benign apocrine lesions, these proteins were not specific for morphological apocrine differentiation in breast.
BACKGROUND: Single nucleotide polymorphisms (SNPs) that reside in microRNA target sites may play an important role in breast cancer development and progression. To reveal the association between microRNA target site SNPs and breast cancer risk, we performed a large case-control study in China.
METHODS: We performed a two-stage case-control study including 2744 breast cancer cases and 3125 controls. In Stage I, we genotyped 192 SNPs within microRNA binding sites identified from the "Patrocles" database using custom Illumina GoldenGate VeraCode assays on the Illumina BeadXpress platform. In Stage II, genotyping was performed on SNPs potentially associated with breast cancer risk using the TaqMan platform in an independent replication set.
RESULTS: In stage I, 15 SNPs were identified to be significantly associated with breast cancer risk (P<0.05). In stage II, one SNP rs8752 was replicated at P<0.05. This SNP is located in the 3' untranslated region (UTR) of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene at 4q34-35, a miR-485-5p binding site. Compared with the GG genotype, the combined GA+AA genotypes has a significantly higher risk of breast cancer (OR = 1.18; 95% CI: 1.06-1.31, P = 0.002). Specifically, this SNP was associated with estrogen receptor (ER) positive breast cancer (P = 0.0007), but not with ER negative breast cancer (P = 0.23), though p for heterogeneity not significant.
CONCLUSION: Through a systematic case-control study of microRNA binding site SNPs, we identified a new breast cancer risk variant rs8752 in HPGD in Chinese women. Further studies are warranted to investigate the underling mechanism for this association.
Guda K, Fink SP, Milne GL, et al.Inactivating mutation in the prostaglandin transporter gene, SLCO2A1, associated with familial digital clubbing, colon neoplasia, and NSAID resistance.
Cancer Prev Res (Phila). 2014; 7(8):805-12 [PubMed
] Free Access to Full Article Related Publications
HPGDand SLCO2A1 genes encode components of the prostaglandin catabolic pathway, with HPGD encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD-null mice show increased prostaglandin E2 (PGE2), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We, here, characterize a family with digital clubbing and early-onset colon neoplasia. Whole-exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in 3 males with digital clubbing. Two of these males further demonstrated notably early-onset colon neoplasia, 1 with an early-onset colon cancer and another with an early-onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M, whereas, female mutation carriers were in the normal range. Furthermore, in the male proband, urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD-null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early-onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man.
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.
UNLABELLED: miRNAs are a group of small, noncoding RNAs that modulate the translation of genes by binding to specific target sites in the target mRNA. This study investigated the biologic function and molecular mechanism of miR-21 in human cholangiocarcinoma. In situ hybridization analysis of human cholangiocarcinoma specimens showed increased miR-21 in cholangiocarcinoma tissue compared with the noncancerous biliary epithelium. Lentiviral transduction of miR-21 enhanced human cholangiocarcinoma cell growth and clonogenic efficiency in vitro, whereas inhibition of miR-21 decreased these parameters. Overexpression of miR-21 also promoted cholangiocarcinoma growth using an in vivo xenograft model system. The NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH/HPGD), a key enzyme that converts the protumorigenic prostaglandin E2 (PGE2) to its biologically inactive metabolite, was identified as a direct target of miR-21 in cholangiocarcinoma cells. In parallel, cyclooxygenase-2 (COX2) overexpression and PGE2 treatment increased miR-21 levels and enhanced miR-21 promoter activity in human cholangiocarcinoma cells.
IMPLICATIONS: Cholangiocarcinogenesis and tumor progression are regulated by a novel interplay between COX-2/PGE2 and miR-21 signaling, which converges at 15-PGDH.
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
] Free Access to Full Article 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.
Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) are proinflammatory cytokines that play a critical role in inflammatory bowel disease, as well as in colorectal tumorigenesis. We hypothesize that these cytokines modulate the expression and thus activity of the vitamin D system in colonic epithelial cells. We treated the colon cancer cell line COGA-1A for 6, 12, and 24h with 1,25-dihydroxyvitamin D3 (1,25-D3), IL-6, TNFα, and with combinations of these compounds. Using quantitative RT-PCR, we analyzed mRNA expression of genes activating and catabolizing 1,25-D3 (1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1)), expression of several vitamin D target genes, as well as expression of cyclooxygenase 2 (COX-2) and 15-hydroxyprostaglandin dehydrogenase. As expected, treatment with 1,25-D3 resulted in an upregulation of CYP24A1, whereas expression of CYP27B1 was not affected. Treatment with TNFα and IL-6 led to decreased expression of the vitamin D activating enzyme CYP27B1. The strong inflammatory property of TNFα was mirrored by its activation of COX-2 and inhibition of prostaglandin E2 (PGE2) catabolism. Interestingly, expression of the calcium ion channel TRPV6 was markedly decreased by TNFα. We conclude from these results that the presence of proinflammatory cytokines might impair activation of 1,25-D3, limiting its anti-inflammatory action. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
Castro-Sánchez L, Agra N, Llorente Izquierdo C, et al.Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma.
Int J Biochem Cell Biol. 2013; 45(11):2501-11 [PubMed
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Cyclooxygenase-2 (COX-2), a rate limiting step in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E2 (PGE2) upon inflammatory stimuli, growth factors, hormones and other cellular stresses. Overproduction of PGE2 stimulates proliferation of various cancer cells, confers resistance to apoptosis and favors metastasis and angiogenesis. The steady-state level of PGE2 is maintained by interplay between the biosynthetic pathway including COX and PGE2 synthases and the catabolic pathways involving nicotinamide adenine dinucleotide (NAD(+))-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-PGDH is a crucial enzyme responsible for the biological inactivation of PGE2. Adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used. COX-2 is induced in hepatocytes after partial hepatectomy (PH), in animal models of cirrhosis, in human hepatoma cell lines, in human HCC and after HBV and HCV infection. However, no data are available regarding 15-PGDH expression in HCC. Our results show that 15-PGDH is downregulated in human hepatoma cells with a high COX-2 expression, in chemical and genetic murine models of HCC and in human HCC biopsies. Moreover, 15-PGDH expression is suppressed by EGF (epidermal growth factor) and HGF (hepatocyte growth factor) mainly involving PI3K (phosphatidylinositol-3-kinase), ERK (extracellular signal-regulated kinase) and p38MAPK (mitogen-activated protein kinase) activation. Conversely, ectopic expression of 15-PGDH induces apoptosis in hepatoma cells and decreases the growth of hepatoma cells in nude mice whereas the silencing of 15-PGDH increases the tumor formation. These data suggest a potential therapeutic application of 15-PGDH in HCC.
BACKGROUND: Analysis of genome-wide data is often carried out using standard methods such as differential expression analysis, clustering analysis and heatmaps. Beyond that, differential correlation analysis was suggested to identify changes in the correlation patterns between disease states. The detection of differential correlation is a demanding task, as the number of entries in the gene-by-gene correlation matrix is large. Currently, there is no gold standard for the detection of differential correlation and statistical validation.
RESULTS: We developed two untargeted algorithms (DCloc and DCglob) that identify differential correlation patterns by comparing the local or global topology of correlation networks. Construction of networks from correlation structures requires fixing of a correlation threshold. Instead of a single cutoff, the algorithms systematically investigate a series of correlation thresholds and permit to detect different kinds of correlation changes at the same level of significance: strong changes of a few genes and moderate changes of many genes. Comparing the correlation structure of 208 ER- breast carcinomas and 208 ER+ breast carcinomas, DCloc detected 770 differentially correlated genes with a FDR of 12.8%, while DCglob detected 630 differentially correlated genes with a FDR of 12.1%. In two-fold cross-validation, the reproducibility of the list of the top 5% differentially correlated genes in 140 ER- tumors and in 140 ER+ tumors was 49% for DCloc and 33% for DCglob.
CONCLUSIONS: We developed two correlation network topology based algorithms for the detection of differential correlations in different disease states. Clusters of differentially correlated genes could be interpreted biologically and included the marker genes hydroxyprostaglandin dehydrogenase (PGDH) and acyl-CoA synthetase medium chain 1 (ACSM1) of invasive apocrine carcinomas that were differentially correlated, but not differentially expressed. Using random subsampling and cross-validation, DCloc and DCglob were shown to identify specific and reproducible lists of differentially correlated genes.
Dorjgochoo T, Zheng Y, Gao YT, et al.No association between genetic variants in angiogenesis and inflammation pathway genes and breast cancer survival among Chinese women.
Cancer Epidemiol. 2013; 37(5):619-24 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown.
METHODS: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS).
RESULTS: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study.
CONCLUSIONS: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer.
IMPACT: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.
BACKGROUND: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2) and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor.
METHODS: We evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs) in the 15-PGDH gene, spanning ∼50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3).
RESULTS: In the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897) were statistically significant (p<0.05) in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted = 0.063). In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC) of 1.50 (95% CI = 1.05-2.15, p = 0.026).
CONCLUSIONS: Our data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin (PG) metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-prostaglandin E2 (15-keto-PGE2)/peroxisome proliferator-activated receptor-γ (PPARγ)/p21(WAF1/Cip1) signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in severe combined immunodeficiency mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, whereas knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The antitumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21(WAF1/Cip1) promoter and increased p21 expression and association with cyclin-dependent kinase 2 (CDK2), CDK4 and proliferating cell nuclear antigen. Depletion of p21 by short hairpin RNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results show a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21(WAF1/Cip1) signaling cascade that regulates hepatocarcinogenesis and tumor progression.
Wang J, Scholtens D, Holko M, et al.Lipid metabolism genes in contralateral unaffected breast and estrogen receptor status of breast cancer.
Cancer Prev Res (Phila). 2013; 6(4):321-30 [PubMed
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Risk biomarkers that are specific to estrogen receptor (ER) subtypes of breast cancer would aid the development and implementation of distinct prevention strategies. The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk because women with ER-negative (ER-) index primaries are at high risk for subsequent ER-negative primary cancers. We conducted random fine needle aspiration of the unaffected breasts of cases. Samples from 30 subjects [15 ER-positive (ER+) and 15 ER- cases matched for age, race and menopausal status] were used for Illumina expression array analysis. Findings were confirmed using quantitative real-time PCR (qRT-PCR) in the same samples. A validation set consisting of 36 subjects (12 ER+, 12 ER- and 12 standard-risk healthy controls) was used to compare gene expression across groups. ER- case samples displayed significantly higher expression of 18 genes/transcripts, 8 of which were associated with lipid metabolism on gene ontology analysis (GO: 0006629). This pattern was confirmed by qRT-PCR in the same samples, and in the 24 cases of the validation set. When compared to the healthy controls in the validation set, significant overexpression of 4 genes (DHRS2, HMGCS2, HPGD and ACSL3) was observed in ER- cases, with significantly lower expression of UGT2B11 and APOD in ER+ cases, and decreased expression of UGT2B7 in both subtypes. These data suggest that differential expression of lipid metabolism genes may be involved in the risk for subtypes of breast cancer, and are potential biomarkers of ER-specific breast cancer risk.
Helicobacter pylori (H. pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H. pylori. 15-PGDH expression in gastric biopsies from H. pylori-infected (n = 25) and noninfected (n = 15) subjects was analyzed by quantitative real-time PCR, Western blot analysis, and immunohistochemistry. 15-PGDH DNA methylation was evaluated by methylation-specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, extracellular signal-regulated kinase (ERK)1/2, TLR4, and MyD88 in response to H. pylori infection was assessed by immunoblot analysis. Compared with negative specimens, H. pylori-positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H. pylori-infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H. pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H. pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of EGF receptor (EGFR)-Snail. Inhibition of Snail and MyD88 reversed suppression of 15-PGDH expression, and siMyD88 reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 and EGFR inhibitor also restored 15-PGDH expression. H. pylori appeared to promote gastric carcinogenesis by suppressing 15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 or EGFR-Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H. pylori-induced gastric carcinogenesis.
Zhang B, Ma X, Li Z, et al.Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.
J Cancer Res Clin Oncol. 2013; 139(5):797-807 [PubMed
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PURPOSE: The overexpression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been proved to inhibit tumor growth and metastasis through degradation of prostaglandin E2 (PGE2), which is often overexpressed in various cancers and accelerates tumor progression. Cyclooxygenase-2 (COX-2), a synthase of PGE2, actively produces much PGE2 to counteract the 15-PGDH-induced antitumor efficacy. Here, we investigated the combinational effect by using pcDNA3.1(+) encoding mouse 15-PGDH gene therapy and celecoxib, a COX-2 inhibitor, in mouse breast cancers.
METHODS: Mice bearing 4T1 were treated with short-term administration of the COX-2 inhibitor celecoxib (40 mg/kg/day) plus liposome-encapsulated mouse 15-PGDH in order to determine their synergistic antitumor activity in vivo. And the possible mechanisms were investigated.
RESULTS: We observed that the combination treatment of 15-PGDH and celecoxib significantly inhibited tumor growth and lung metastases than monotherapy or controls. Moreover, the effect of combination treatment was associated with significant reduction of PGE2 in serum, which resulted from increased 15-PDGH and decreased COX-2 in tumor tissues. The tumor tissues in combination treatment presented more apoptotic cells and less microvessel density. Notably, the number of myeloid-derived suppressor cells in the spleen was also significantly decreased in the combination treatment than others.
CONCLUSIONS: Our findings suggested that celecoxib increased the antitumor activity of 15-PGDH by synergistically blocking PGE2 pathway, which might be a new feasible way for cancer therapy.
Jiang Y, Turgeon DK, Wright BD, et al.Effect of ginger root on cyclooxygenase-1 and 15-hydroxyprostaglandin dehydrogenase expression in colonic mucosa of humans at normal and increased risk for colorectal cancer.
Eur J Cancer Prev. 2013; 22(5):455-60 [PubMed
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Elevated tissue levels of prostaglandin E2, produced by cyclooxygenase (COX), are an early event in colorectal cancer (CRC). Data suggest the efficacy of nonsteroidal anti-inflammatory drugs, such as cancer preventives, in the inhibition of COX activity; however, side effects of nonsteroidal anti-inflammatory pose unacceptable limitations. Ginger has been reported to have anti-inflammatory activities with significant CRC preventive potential. We investigated whether consumption of 2.0 g ginger daily regulated the level of two key enzymes that control prostaglandin E2 production, COX-1 and NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Thirty participants at normal and 20 participants at increased risk for CRC were randomized and given 2.0 g/day ginger or placebo for 28 days. Flexible sigmoidoscopy was used to obtain colon biopsies at baseline and the end of the study. Tissue levels of COX-1 and 15-PGDH were assessed using western blotting. After ginger consumption, participants at increased risk for CRC had a significantly reduced colonic COX-1 protein level (23.8±41%) compared with the placebo group (18.9±52%; P=0.03). Protein levels of 15-PGDH in the colon were unchanged. In participants who were at normal risk for CRC, neither protein levels of COX-1 nor 15-PGDH in the colon were altered by ginger consumption. Ginger significantly lowered COX-1 protein expression in participants at increased risk for CRC but not in those at normal risk for CRC. Ginger did not alter 15-PGDH protein expression in either increased or normal-risk participants. Further investigation, in larger studies with a longer ginger intervention, is needed to examine the ability of ginger to impact tissue levels of prostaglandin.
Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E(2) (PGE(2)) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues improve our understanding of the molecular mechanisms by which PPARγ inhibits aromatase expression. They found that pioglitazone, a PPARγ agonist, inhibited aromatase expression by inhibition of PGE(2) signaling and upregulation of BRCA1. Their findings provide potential targets for preventing or treating obesity-related breast cancer.
Smartt HJ, Greenhough A, Ordóñez-Morán P, et al.β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: a role in the chemopreventive efficacy of aspirin?
Br J Cancer. 2012; 107(9):1514-7 [PubMed
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BACKGROUND: Levels of the pro-tumorigenic prostaglandin PGE(2) are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression.
METHODS: The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin(-/lox)-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting.
RESULTS: This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma- and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.
CONCLUSIONS: These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirin's chemopreventive efficacy.
Subbaramaiah K, Howe LR, Zhou XK, et al.Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.
Cancer Prev Res (Phila). 2012; 5(10):1183-94 [PubMed
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Estrogen synthesis is catalyzed by cytochrome P450 aromatase, which is encoded by the CYP19 gene. In obese postmenopausal women, increased aromatase activity in white adipose tissue is believed to contribute to hormone-dependent breast cancer. Prostaglandin E(2) (PGE(2)) stimulates the cAMP→protein kinase A (PKA) pathway leading to increased CYP19 transcription and elevated aromatase activity in inflamed white adipose tissue. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE(2). Here, we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor PPARγ suppressed aromatase expression. Treatment of human preadipocytes with pioglitazone suppressed Snail, a repressive transcription factor, resulting in elevated levels of 15-PGDH and reduced levels of PGE(2) in the culture medium. Pioglitazone also inhibited cAMP→PKA signaling leading to reduced interaction between phosphorylated cAMP responsive element-binding protein, p300, and CYP19 I.3/II promoter. BRCA1, a repressor of CYP19 transcription, was induced by pioglitazone. Consistent with these in vitro findings, treatment of mice with pioglitazone activated PPARγ, induced 15-PGDH and BRCA1 while suppressing aromatase levels in the mammary gland. Collectively, these results indicate that the activation of PPARγ induces BRCA1 and suppresses the PGE(2)→cAMP→PKA axis leading to reduced levels of aromatase. PPARγ agonists may have a role in reducing the risk of hormone-dependent breast cancer in obese postmenopausal women.
Bai JW, Wang Z, Gui SB, Zhang YZLoss of 15-hydroxyprostaglandin dehydrogenase indicates a tumor suppressor role in pituitary adenomas.
Oncol Rep. 2012; 28(2):714-20 [PubMed
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15-hydroxyprostaglandin dehydrogenase (15-PGDH) may function as a tumor suppressor that antagonizes the action of the cyclooxygenase-2 (COX-2) oncogene in several types of tumors. However, it is unknown if it has a role in the pituitary. Recently, our group found that 15-PGDH expression was low in prolactin (PRL) secreting adenomas (prolactinomas) and growth hormone (GH) secreting adenomas (GHomas) using fiber-optic BeadArray technology. In this study, we examined the relative expression of 15-PGDH and COX-2 mRNA in clinical specimens and examined the effects of 15-PGDH on GH3 rat pituitary tumor cell proliferation, apoptosis and hormone secretion. 15-PGDH expression was lower and COX-2 expression was higher in prolactinomas and GHomas compared with normal controls. Overexpressed 15-PGDH inhibited tumor cell proliferation and induced apoptosis. It had a significant suppressive effect on mRNA levels and on the secretion of PRL and GH in GH3 cells. The inhibition of cell proliferation was accompanied by the decreased expression of cox-2, matrix metalloproteinase-9 (MMP-9) and B cell leukemia/lymphoma-2 (Bcl-2). These data are suggestive of a previously unrecognized pathway in pituitary tumorigenesis, and this novel observation may shed light on therapeutic strategies for pituitary tumors.
Edwards TL, Shrubsole MJ, Cai Q, et al.A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.
Cancer Prev Res (Phila). 2012; 5(6):855-63 [PubMed
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Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.