Research IndicatorsGraph generated 01 September 2019 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (13)
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: PTGS2 (cancer-related)
Protzel C, Hakenberg OW[Molecular tumor board penile cancer-a challenge].
Urologe A. 2019; 58(7):774-780 [PubMed
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Due to its low incidence there is only very limited data concerning molecular markers in penile cancer. Recent studies show potential prognostic markers for lymph node metastasis, survival and response to chemotherapy or targeted therapy. Nevertheless the number of patients in the studies is very limited. Therefor clear recommendations for clinical decisions remain very weak. Patients with metastatic disease should be treated in clinical trials with translational biomarker research to improve the molecular tumor board in the future.
Naji S, Issa K, Eid A, et al.Cadmium Induces Migration of Colon Cancer Cells: Roles of Reactive Oxygen Species, P38 and Cyclooxygenase-2.
Cell Physiol Biochem. 2019; 52(6):1517-1534 [PubMed
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BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure.
METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase reporter assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E
RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE
CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE
Mantso T, Vasileiadis S, Lampri E, et al.Hyperthermia Suppresses Post -
Anticancer Res. 2019; 39(5):2307-2315 [PubMed
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BACKGROUND: Several studies have highlighted hyperthermia's ability to enhance the effectiveness of radiation and chemotherapy in various in vitro and in vivo cancer models.
MATERIALS AND METHODS: In vivo murine models of malignant melanoma and colon carcinoma were utilized for demonstrating hyperthermia's therapeutic effectiveness by examining levels of caspase 3, COX-2 and phospho-H2A.X (Ser139) as endpoints of apoptosis, proliferation and DNA damage respectively.
RESULTS: Hyperthermia induced in vitro cytotoxicity in malignant melanoma (B16-F10) and colon carcinoma (CT26) cell lines. In addition, it reduced post-in vitro proliferation and suppression of tumor growth by inducing the expression of caspase-3 and phospho-H2A.X (Ser139) while reducing the expression of COX-2 in both murine cancer models.
CONCLUSION: Hyperthermia can exert therapeutic effectiveness against melanoma and colon carcinoma by inhibiting a number of critical cellular cascades including apoptosis, proliferation and DNA damage.
OBJECTIVE: Previous studies have reported an association between cyclooxygenase-2 (COX-2) polymorphism and gastric cancer (GC) susceptibility, but their results are controversial. This meta-analysis was intended to evaluate the relationship between the COX-2 rs20417 polymorphism and GC susceptibility in different ethnic groups.
METHODS: We searched PubMed, EMBASE, Web of Knowledge, and the Chinese Biomedical Database (CBM) for relevant case-control studies published up to October 6, 2018, which reported an association between the COX-2 rs20417 polymorphism and gastric cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of this association.
RESULTS: 15 papers detailing case-control studies were included in the analysis, which included a total of 2848 GC cases and 4962 healthy controls. The meta-analysis results indicated that the COX-2 rs20417 polymorphism was associated with increased GC susceptibility under allele (G vs C: OR = 1.67, 95%CI = 1.19-2.35, P = .003), heterozygous (GG vs CG: OR = 1.44, 95%CI = 1.03-2.02, P = .034), dominant (GC+CC vs GG: OR = 1.66, 95%CI = 1.18-2.34, P = .004), homozygous (GG vs CC:OR = 2.20, 95%CI = 1.07-4.54, P = .033), and recessive models (CC vs GG+CG:OR = 2.05, 95%CI = 1.09-3.85, P = .025). An analysis of ethnic subgroups revealed that the COX-2 rs20417 polymorphism was significantly associated with GC susceptibility in Asians under all 5 models (G vs C: OR = 2.22, 95%CI = 1.66-2.96, P < .001; GG vs CC: OR = 4.29, 95%CI = 1.94-9.50, P < .001; GG vs CG: OR = 1.86, 95%CI = 1.34-2.58, P < .001; CC vs GG+CG: OR = 3.73, 95%CI = 1.92-7.24, P < .001; GC+CC vs GG: OR = 2.20, 95%CI = 1.65-2.93, P < .001). Helicobacter pylori positive patients suffered a high risk of GC, compared to H pylori negative patients under the dominant model (OR = 3.09, 95%CI = 1.80-5.32, P < .001).
CONCLUSION: This meta-analysis of 15 case-control studies provides strong evidence that the COX-2 rs20417 polymorphism increases the risk of GC susceptibility in general populations, especially in Asians. Helicobacter pylori positive patients and those with the COX-2 rs20417 polymorphism had a higher risk of developing GC.
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal-e.g., TLR2 ligands-may modify their responses in the cancer milieu.
Osman J, Bellamkonda K, Liu Q, et al.The WNT5A Agonist Foxy5 Reduces the Number of Colonic Cancer Stem Cells in a Xenograft Mouse Model of Human Colonic Cancer.
Anticancer Res. 2019; 39(4):1719-1728 [PubMed
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BACKGROUND: The wingless-type mammary tumour virus integration site 5A (WNT5A) agonist Foxy5 was shown in vitro to affect intracellular signalling implicated in the regulation of colonic cancer stem cells (CSCs).
MATERIALS AND METHODS: In order to study whether Foxy5 can modulate CSCs, either HT-29 or Caco-2 human colonic cancer cells, both lacking endogenous WNT5A expression, were inoculated subcutaneously into nude mice.
RESULTS: Foxy5 reduced the expression of the stem-cell marker aldehyde dehydrogenase and, interestingly, the specific colon CSC marker double cortin-like kinase 1. Foxy5 also reduced active β-catenin and the expression of its downstream target Achaete Scute complex homolog 2, a CSC-preserving transcription factor. Foxy5 also reduced cyclo-oxygenase 2 expression, responsible for the formation of the CSC-promoting prostaglandin E
CONCLUSION: Our data suggest that Foxy5 can complement the traditional adjuvant chemotherapeutic treatment to which CSCs are resistant.
Ren J, Liu J, Sui XCorrelation of COX-2 and MMP-13 expressions with gastric cancer and their effects on prognosis.
J BUON. 2019 Jan-Feb; 24(1):187-193 [PubMed
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PURPOSE: To study the expressions of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-13 (MMP-13) genes in gastric cancer, and to investigate the correlation between them and gastric cancer and their effects on prognosis.
METHODS: 80 cases of tumor tissues and 40 cases of normal tumor-adjacent tissues were collected from patients with gastric cancer admitted to the Surgical Department of our hospital. The mRNA expression levels of COX-2 and MMP-13 in tumor tissues and normal tumor-adjacent tissues were detected via real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR). The expressions of COX-2 and MMP-13 in gastric cancer tissues and normal tumor-adjacent tissues were detected via immunohistochemical method. The clinical data of patients were recorded and the correlation between the COX-2 and MMP-13 expressions and the pathological parameters and prognosis of patients with gastric cancer were analyzed.
RESULTS: RT-PCR results showed that the mRNA expressions of COX-2 and MMP-13 in gastric cancer tissues were significantly higher than those in normal tumor-adjacent tissues. Immunohistochemical results showed that the positive expression rates of COX-2 and MMP-13 in gastric cancer tissues were 76.25% (60/80) and 71.25% (57/80), respectively and the high expression was related to the invasion, metastasis and tumor stage. The 5-year overall survival of patients was 16.6% (13/80). Single-factor survival analysis showed that both COX-2 and MMP-13 were factors influencing the overall survival of patients with gastric cancer (p<0.01).
CONCLUSION: The high expressions of COX-2 and MMP-13 are closely related to the pathological parameters of patients with gastric cancer, especially the invasion, metastasis and tumor stage. COX-2 and MMP-13 can be used as reference indexes to guide the treatment of gastric cancer and predict the disease prognosis.
Cai MJ, Cui Y, Fang M, et al.Inhibition of PSMD4 blocks the tumorigenesis of hepatocellular carcinoma.
Gene. 2019; 702:66-74 [PubMed
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Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high mortality and frequent recurrence. Although various therapies provide potential cure for HCC patients, unfortunately the five-year survival rate of advanced HCC remains dismal. It is critical to explore the pathogenesis of HCC and identify novel biomarkers for early HCC diagnosis. PSMD4 is a major receptor of the 26S proteasome involved in ubiquitindependent and proteasome-mediated protein degradation. In our study, PSMD4 was overexpressed in HCC tissues and cell lines determined by Northern blot, western blot and immunohistochemistry. The silencing of PSMD4 blocked cell proliferation and tumor growth, induced cell apoptosis and inhibited the proteasome activity. Western blot results showed that the knockdown of PSMD4 blocked the expression of cyclooxygenase 2 (COX2), phosphorylated Sarcoma tyrosine kinase (P-SRC) and Bcl-2, but improved the levels of p53 and Bax in HCC, lung cancer, colorectal cancer, breast cancer and endometrial cancer cell lines. Taken together, these findings indicated that the subunit of 26S proteasome PSMD4 exerts as an oncogene in HCC and other cancers via regulating the expression p53, Bcl-2 and Bax. These findings enriched the pathogenesis of HCC, and provided a new biomarker for cancers diagnosis and a new target for cancers therapy.
Tsagozis P, Augsten M, Zhang Y, et al.An immunosuppressive macrophage profile attenuates the prognostic impact of CD20-positive B cells in human soft tissue sarcoma.
Cancer Immunol Immunother. 2019; 68(6):927-936 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Immune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized.
METHODS: Marker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics.
RESULTS: B cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10
CONCLUSIONS: Analysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages.
Sahay S, Tiwari P, Pandey M, Gupta KPPI3K/Akt Pathway and miR-21 are Involved in N-Ethyl-N-Nitrosourea-Induced F1 Mouse Lung Tumorigenesis: Effect of Inositol Hexaphosphate.
J Environ Pathol Toxicol Oncol. 2019; 38(1):69-81 [PubMed
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The risk of cancer development in offspring due to carcinogen exposure during pregnancy is a serious issue. In this study, we explored the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and microRNA-21 (miR-21) in transplacental lung tumorigenesis and its prevention by dietary compound inositol hexaphosphate (IP6) in F1 mice. Balb/c mice were exposed to the N-ethyl-N-nitrosourea (ENU) intraperitoneally on the 17th day of gestation. After weaning, half of the litters were fed with oral 2% IP6. At the end of 30, 120, or 240 days, we did not observe any effect on fetal viability or weight between ENU-exposed and non-exposed litters and the same was true of IP6. Altered expressions of the PI3K/Akt pathway were observed in F1 mice. Further, miR-21 expressions were found to be modulated at the respective time as well, along with the activation of matrix metalloproteinase (MMP-9) and vascular endothelial growth factor expression. Akt activation also enhanced the expression of cyclin D1, cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κBp50), and mammalian target of rapamycin (mTOR). IP6-fed F1 mice showed reduced tumorigenesis along with reduced expression of the PI3K/Akt pathway miR-21 and downstream targets. The PI3K/Akt pathway and miR-21 are involved in transplacental lung tumorigenesis, whereas IP6 seemed to affect lung tumorigenesis by suppressing the expression of the PI3K/Akt pathway in F1 mice.
Wu CH, Chuang HY, Wang CL, et al.Estradiol induces cell proliferation in MCF‑7 mammospheres through HER2/COX‑2.
Mol Med Rep. 2019; 19(3):2341-2349 [PubMed
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Cluster of differentiation (CD)44+/CD24- breast cancer cells have stem cell‑like characteristics and are potent initiators of tumorigenesis. Mammosphere cells can partially initiate breast tumorigenesis by inducing estradiol (E2)‑dependent breast cancer cells. However, the mechanisms by which E2 mediates cancer formation in MCF‑7 mammosphere (MS) cells have remained elusive. In the present study, MS cells were isolated by sphere culture. It was possible to maintain these MS cells in culture for long periods of time, while retaining the CD44+/CD24- stem cell marker status. The CD44+/CD24- status was confirmed by flow cytometry. Furthermore, the stem‑cell markers Musashi‑1, cytokeratin (CK)7 and CK19 were identified by immunofluorescence microscopy. It was revealed that treatment of MS cells with E2 increased the expression of CD44, whereas decreased the expression of CD24 on MS cells. In addition, treatment with E2 increased colony formation by MS cells. E2 also induced cyclooxygenase‑2 (COX‑2) expression in MS cells, which promoted their proliferation through the estrogen receptor/human epidermal growth factor receptor 2 (HER2)/mitogen‑activated protein kinase/phosphoinositide‑3 kinase signaling pathway. The results suggested a tumorigenic mechanism by which E2 promotes tumor cell proliferation via HER2/COX‑2 signaling. The present study provided evidence for the molecular impact of E2 on breast tumorigenesis, and suggested possible strategies for preventing and treating human breast cancer.
BACKGROUND This study aimed to investigate the effects of metastasis-associated 1 (MTA1) gene expression and gene silencing in human non-small cell lung cancer (NSCLC) cells in vitro and on angiogenesis in tumor xenografts in vivo in nude mice. MATERIAL AND METHODS Human H460 and H1299 NSCLC cell lines underwent transfection with lentiviral transfer plasmids (lenti) and short-interfering RNA (si-RNA) and included a control group, a lenti-MTA1 group, a lenti-si-MTA1 group, a lenti control group, and a si-RNA control group. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect MTA1 gene expression after cell transfection. MTA1 transfection was more effective in H460 cells, which were selected for further in vivo studies. Sixty Balb/c nude mice, containing human H460 cell tumor xenografts, included a control group (N=20), a lenti-MTA1 group (N=20), and a lenti-si-MTA1 group (N=20). Tumor tissue immunohistochemistry was used to detect the expression of MTA1 protein and microvessel density (MVD) using CD31. Western blot was used to quantify the expression of cyclooxygenase-2 (COX-2), angiopoietin 1/2 (Ang1/2), hypoxia-inducible factor 1-a (HIF-1a), and vascular endothelial growth factor (VEGF). RESULTS MTA1 silencing with si-RNA significantly reduced the tumor growth rate in nude mice (p<0.01), reduced tumor MVD, and 70% of mice survived for more than 30 days. MTA1 overexpression resulted in the death of all mice at 30 days after tumor inoculation and upregulated the expression of COX-2, Ang1/2, HIF-1a and VEGF, which were down-regulated by MTA1 silencing. CONCLUSIONS MTA1 gene expression promoted angiogenesis in mouse xenografts from human NSCLC cells.
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States,
INTRODUCTION: Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in estrogen receptor α-positive (ERα
METHODS: To assess the context-dependent roles, we carried out MDM2 and MDMX knockdown in orthotopic tumors of TNBC MDA-MB-231 cells expressing mtp53 R280K and MDM2 knockdown in ERα
RESULTS: Knocking down MDMX or MDM2 in MDA-MB-231 cells reduced cell migration and CTC detection, but only MDMX knockdown reduced tumor volumes at early time points. This is the first report of MDMX overexpression in TNBC enhancing the CTC phenotype with correlated upregulation of CXCR4. Experiments were carried out to compare MDM2-knockdown outcomes in nonmetastatic ERα
CONCLUSIONS: This is the first report showing that the expression of MDM2 in ERα
BACKGROUND: We previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-γ-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-γ-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-γ-linolenic acid peroxidation in xenograft tumor mice model.
METHODS: Four-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-γ-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-γ-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis.
RESULTS: Delta-5-desaturase knockdown (shRNA) together with dihomo-γ-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors' metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-γ-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil.
CONCLUSIONS: We have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients.
Inflammatory and microenvironmental factors produced by cancer cells are thought to directly or indirectly promote cancer cell growth. Prostaglandins, including prostaglandin E2, have key roles as a microenvironment factor in influencing the development of tumors, and are produced by the rate limiting enzyme cyclooxygenase 2 (COX-2). In this study, we used canine melanoma cells treated with the proinflammatory cytokine interleukin 1β (IL-1β) and investigated the transcriptional factor nuclear factor-κB (NF-κB) signaling in IL-1β-induced COX-2 expression. IL-1β induced prostaglandin E2 release and COX-2 mRNA expression in a time- and dose-dependent manner. In the cells treated with the NF-κB inhibitors BAY11-7082 and TPC-1, IL-1β-mediated prostaglandin E2 release and COX-2 mRNA expression were inhibited. IL-1β also provoked phosphorylation of p65/RelA and p105/NF-κB1, which are members of the NF-κB families. The IL-1β-induced phosphorylation of p65 and p105 was attenuated in the presence of both NF-κB inhibitors. In melanoma cells transfected with siRNA of p65 or p105, IL-1β-mediated COX-2 mRNA expression was inhibited. These findings suggest that canonical activation of NF-κB signaling plays a crucial role for inflammatory states in melanoma cells.
Xie WY, He RH, Zhang J, et al.β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms.
Oncol Rep. 2019; 41(1):341-350 [PubMed
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The β2‑adrenergic receptor (β2‑AR, encoded by the ADRB2 gene) is a member of the G‑protein‑coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that β‑blockers (β‑AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single‑nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of β2‑AR, which may alter the β‑blocker drug response. The aim of the present study was to investigate the effect of β‑blockers on triple‑negative breast cancer cells and determine whether ADRB2 SNPs affect the response to β‑blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA‑MB‑231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular‑signal‑regulated kinase (ERK)1/2 and the expression levels of cyclo‑oxygenase 2 (COX‑2) were significantly decreased following β‑blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild‑type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX‑2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA‑MB‑231 cells by downregulating the ERK/COX‑2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.
Jin J, Guo T, Guo Y, et al.Methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer by targeting COX‑2 in areas with a high incidence of esophageal cancer.
Int J Oncol. 2019; 54(2):644-654 [PubMed
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Esophageal cancer is one of the most common cancer types in the world, with a widely varying incidence between different regions. Zinc deficiency (ZD) is very common in high‑risk areas for esophageal cancer. Dietary ZD is reported to be associated with esophageal squamous cell carcinoma (ESCC). In the current study, the effects of ZD on tumorigenesis and expression of inflammatory factors were investigated in mice. It was identified that a ZD diet advanced ESCC and increased the expression of cyclooxygenase‑2 (COX‑2) prior to the occurrence of ESCC in mice. ZD significantly enhanced DNA methyltransferase (DNMT) activity and increased the expression of DNMT1 and DNMT3B. Furthermore, the expression of miR‑128 was downregulated by methylation, and COX‑2, a direct target of miR‑128, was upregulated with the reduction in miR‑128. Upregulation of miR‑128 inhibited the cell cycle, proliferation and metastasis, and the expression of COX‑2, cyclin D1 and retinoblastoma protein (Rb). Furthermore, the relative expression level of miR‑128 was negatively associated with COX‑2 in ESCC tissues. Collectively, these findings indicate that methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer through upregulation of the expression of cyclin D1 and Rb by targeting COX‑2 in ZD regions with a high incidence of esophageal cancer.
Cacina C, Kaşarci G, Bektaş K, et al.The COX2 genetic variants in oral squamous cell carcinoma in Turkish population.
Cell Mol Biol (Noisy-le-grand). 2018; 64(14):96-100 [PubMed
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Oral squamous cell carcinoma (OSCC) is a common type of cancer that genetic and environmental factors also lifestyle habits, infections play important roles in the pathogenesis of disease. Cyclooxygenase 2 (COX2) is the inducible isoform of enzyme which convert arachidonic acid to prostaglandins. It was known that alterations in COX2 gene functions contribute to the inflammation process thus induce cancer progression, including cell proliferation, apoptosis, adhesion, invasion and metastasis. A total of 114 cases 165 healthy individuals were included in present study. We aimed to evaluate possible association between the COX2; -765, -1195 polymorphisms and the risk of OSCC. The genotypes were determined by using polymerase chain reaction restriction fragment length polymorphism techniques. In our study group the carriers of COX2 -765 C allele were statistically higher in patients compared with controls and individuals who had CC genotype had a 3,4 fold high risk for OSCC (p <0,05). We also observed the COX2 -1195 AA genotype frequency was higher in cases that of healthy group and individuals who had AA genotype showed a 1,7 fold increased risk for OSCC (p < 0,05). Haplotype analysis confirmed our result and revealed that the frequencies of COX2 -765C, -1195A haplotype frequencies were significantly higher in patients as compared with those of controls. In conclusion we suggest that COX2, -765, -1195 polymorphisms appear to be an important predictive factor and may be a prognostic biomarker for risk of OSCC. Further investigations with larger study groups are needed to fully elucidate the role of COX2 -765, -1195 variations in the development of OSCC.
Arya M, Singh P, Tripathi CB, et al.Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets.
Drug Deliv Transl Res. 2019; 9(1):53-65 [PubMed
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Phytic acid (PA) has momentous chemotherapeutic potential. Due to the chelate formation and rapid elimination, it is not popular in cancer treatment. The present work was inquested to develop a surface-modified nanoformulation of PA which prevents its speedy elimination and maximizes chemotherapeutic action. Chloroauric acid was reduced with pectin to produce pectin-gold nanoparticles (PGNPs). PGNPs were incubated with PA and jacalin for drug loading and surface modifications, respectively, to form PA-loaded jacalin-pectin-gold nanoparticles (PA-J-PGNPs). Formulation(s) were assessed for various pharmaceutical/pharmacological parameters. To validate the efficacy against colon carcinogenesis, formulation(s) were assessed in 1,2-dimethylhydrazine (DMH)-treated Wistar rats. DMH treatment distorted colonic architecture, oxidative, and hemodynamic parameters, which were favorably restored by PA-J-PGNP administration. To further confirm our deliberations, formulation(s) were also examined against DMH-altered metabolic changes and expression of markers pertaining to cellular proliferation, which was reinstated by PA-J-PGNPs. Our findings establish PA formulation(s) as a promising approach for suppression of colon carcinogenesis.
Gaballah HH, Gaber RA, Elrashidy MA, et al.Expression of long non-coding RNA CCHE1 in colorectal carcinoma: correlations with clinicopathological features and ERK/COX-2 pathway.
Mol Biol Rep. 2019; 46(1):657-667 [PubMed
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Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide. Compelling evidence suggests that long non-coding RNA (lncRNAs) can control carcinogenesis by regulating various aspects of cell biology. However, limited number of CRC-related lncRNAs has been well characterized. This study was undertaken to investigate the expression pattern of the novel lncRNA-CCHE1 in CRC patients and to examine its correlation with clinicopathological features, ERK/COX-2 pathway and some cell proliferation markers in order to gain biological insights on its role in CRC pathogenesis. Colon cancer specimens with their adjacent non-cancerous tissues were taken from 60 patients with primary CRC. LncRNA-CCHE1 relative expression was assessed using quantitative real-time RT-PCR. P-ERK ½ and cyclin D1 levels were estimated by ELISA. COX-2 and proliferating cell nuclear antigen (PCNA) expression were assessed immunohistochemically. lncRNA-CCHE1 expression was upregulated in CRC tissues compared to adjacent non-cancerous tissues, and was significantly associated with larger tumor size, less differentiated histology, advanced dukes' stage, positive lymph node involvement and vascular invasion. It also showed a significant positive correlation with the expression of p-ERK1/2, COX-2 as well as cyclin D1and PCNA (as markers for cell proliferation). These findings signify that lncRNA-CCHE1 is a key oncogene possibly involved in CRC development and progression by modulating ERK/COX-2 pathway and cell proliferation activity. Our study also provides a rationale for potential use of lncRNA-CCHE1 as a novel prognostic marker, and opens the door for the development of lncRNA-CCHE1-directed therapeutic approaches for CRC patients.
BACKGROUND: Drugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-α (IFN-α) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-α could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-α and MEK/ERK pathway will help enhance the efficacy of IFN-α or MEK inhibitors on bladder cancer.
METHODS: Immunoprecipitation and pull-down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E
RESULTS: IFN-α down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-κB pathway; IFN-α also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-α against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients.
CONCLUSIONS: Our data reveal that IFN-α can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-α in the context of bladder cancer therapy. The antitumor effects of IFN-α and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-α and MEK inhibitors in bladder cancer treatment.
Gao F, Zafar MI, Jüttner S, et al.Expression and Molecular Regulation of the Cox2 Gene in Gastroenteropancreatic Neuroendocrine Tumors and Antiproliferation of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).
Med Sci Monit. 2018; 24:8125-8140 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has had a significant increase over the past 4 decades. The pathophysiological role of the cyclooxygenase-2 (cox-2) gene and factors responsible for the expression in GEP-NETs is of clinical value. Current study determined the expression of cox-2 gene in human GEP-NET tissues and corresponding cell lines, investigated the molecular mechanisms underlying the regulation of cox-2 gene expression and assessed the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on both anchorage-dependent and independent growth of GEP-NET cells. MATERIAL AND METHODS GEP-NET tissues and QGP-1, BON, and LCC-18 GEP-NET cell lines were used. The expression of cox-2 gene was analyzed by immunohistochemistry, western blot, RT-PCR, and enzyme immunoassay. Transient transfection and luciferase assays along with electrophoretic mobility shift assays were conducted to explore the regulation of cox-2 gene expression. The effect of COX-inhibitors on GEP-NET cell growth was determined by proliferation assays and colony growth assessment. RESULTS We found 87.8% of GEP-NET tissues stained positive for COX-2. QGP-1 and LCC-18 cells expressed cox-2 gene. PGE2 (prostaglandin E2) amounts quantified in the supernatants of NET cells matched to cox-2 expression level. The CRE-E-box element (-56 to -48 bp) and binding of USF1, USF2, and CREB transcription factors to this proximal promoter element were essential for cox-2 promoter activity in GEP-NET cells. COX-2-specific inhibitor NS-398 potently and dose-dependently inhibited PGE2 release from QGP-1 cells. Interestingly, both NS-398 and acetylic salicylic acid effectively suppressed proliferation of QGP-1 and BON cells in a dose-dependent manner. CONCLUSIONS The majority of GEP-NETs over express cox-2 gene. The binding of CREB and USF-1/-2 transcription factors to a proximal, overlapping CRE-Ebox element is the underlying mechanism for cox-2 gene expression. NSAIDs potently suppressed the proliferations and may offer a novel approach for chemoprevention and therapy of GEP-NETs.
Luo MX, Long BB, Li F, et al.Roles of Cyclooxygenase-2 gene -765G > C (rs20417) and -1195G > A (rs689466) polymorphisms in gastric cancer: A systematic review and meta-analysis.
Gene. 2019; 685:125-135 [PubMed
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BACKGROUND: The roles of cyclooxygenase-2 (COX2) -765G > C (rs20417) and -1195G > A (rs689466) polymorphisms in gastric cancer were intensively analyzed, but the results of these studies were inconsistent. We conducted a meta-analysis and trial sequential analysis to elucidate the associations between these two COX2 polymorphisms and gastric cancer risk.
METHODS: Eligible studies were searched in PubMed, Embase, Cochrane library databases, China National Knowledge Infrastructure, Vip, and Wanfang databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the genetic correlation between COX2 polymorphisms and gastric cancer susceptibility in five genetic models. Trial sequential analysis (TSA) was conducted to estimate whether the evidence of the results is sufficient. Furthermore, their interactions with Helicobacter pylori (H. pylori) or smoking in gastric cancer were also assessed using a case-only method.
RESULTS: The COX2 gene -765G > C polymorphism showed no significant association with gastric cancer susceptibility under all the five genetic models (take the allelic model for example: OR = 1.41, 95% CI: 0.95-2.09) in total analysis, and the stratification analysis by ethnicity indicated a similar association in Caucasian group under four genetic models (allelic model, dominant model, homozygous model, and heterozygous model). But in the subgroup of the Asian population, the -765G > C polymorphism was significantly associated with gastric cancer risk under the same contrast. The COX2 -1195G > A polymorphism showed significant correlation with gastric cancer susceptibility in total analysis, and stratification analysis by ethnicity also revealed a similar association in both Asian and Caucasian groups under the same contrast. Moreover, TSA confirmed such associations. Both H. pylori infection and cigarette smoking interacted with -765 C allele in gastric cancer (OR = 3.79, 95% CI: 1.15-12.43 and OR = 2.48, 95% CI: 1.38-4.48, respectively), but not in -1195 A allele (OR = 1.96, 95% CI: 0.62-6.21, and OR = 1.24, 95% CI: 0.93-1.64, respectively).
CONCLUSIONS: COX2 -765G > C polymorphism may serve as a genetic biomarker of gastric cancer in Asians, but not in Caucasians. COX2 -1195G > A polymorphism may serve as a genetic biomarker of gastric cancer in both Asians and Caucasians. The -765G > C, rather than -1195G > A polymorphism interacted with H. pylori infection or cigarette smoking to increase gastric cancer risk.
Zhou M, Wang A, Yin B, et al.SND1 promotes the proliferation of osteosarcoma cells by upregulating COX‑2/PGE2 expression via activation of NF‑κB.
Oncol Rep. 2019; 41(1):579-589 [PubMed
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Osteosarcoma is the most frequent primary bone tumor. Staphylococcal nuclease domain‑containing 1 (SND1) is a multifunctional protein that plays important roles in tumor development and progression. Overexpression of SND1 has been found in several malignancies, however, its expression and function in osteosarcoma is largely unknown. In the present study, we firstly examined the expression of SND1 in 12 pairs of osteosarcoma and healthy bones by immunoblotting and real time‑PCR. The results revealed that osteosarcoma tissues expressed significantly high SND1 mRNA and protein expression compared to normal bone tissues. Next, we stably overexpressed SND1 ORF in MG‑63 cells and further defined the biological function of SND1 in osteosarcoma by flow cytometry, cell proliferation and in vivo assays. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo. Furthermore, the non‑targeted metabolic profiling, ELISA and luciferase reporter assays were performed on stable overexpressing cells and blood samples to elucidate the underlying mechanisms of SND1‑mediated oncogenic features. The results revealed that SND1 increased the production of arachidonic acid PGE2. The serum PGE2 expression level had a significant positive association with the SND1 mRNA expression level in osteosarcoma tissues. The SND1 overexpression‑stimulated cell proliferation was enhanced by exogenous addition of PGE2. Additionally, we found that SND1 upregulated PGE2 expression through the NF‑κB/cyclooxygenase‑2 (COX‑2) pathway. In summary, our findings revealed the mechanisms of SND1 involvement in osteosarcoma tumor development, and support the targeting of SND1 as a new anti‑tumor strategy for patients with osteosarcoma. In addition, SND1 may act as a potential biomarker of the therapeutic strategies utilizing COX‑2 inhibitors.
Wang Q, Lu D, Fan L, et al.COX-2 induces apoptosis-resistance in hepatocellular carcinoma cells via the HIF-1α/PKM2 pathway.
Int J Mol Med. 2019; 43(1):475-488 [PubMed
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The pyruvate kinase M2 isoform (PKM2) is a key component of aerobic glycolysis and has been reported to regulate apoptosis. However, it is unclear whether PKM2 is involved in cyclooxygenase‑2 (COX‑2) induced apoptosis‑resistance in hepatocellular carcinoma (HCC) cells. In the present study, it was observed that COX‑2 and PKM2 were significantly elevated in hepatocellular carcinoma tissues compared with adjacent liver tissues (P<0.05). Furthermore, their expression was positively associated with worse clinicopathological characteristics, which indicates poor prognosis in patients with HCC. COX‑2 knockdown significantly reduced the expression of PKM2 and hypoxia inducible factor‑1α (HIF‑1α) at the mRNA and protein levels in addition to inhibiting proliferation (P<0.05), whereas apoptosis was notably increased. Furthermore, HIF‑1α and PKM2‑knockdown increased cell apoptosis without inhibiting COX‑2 expression. PKM2 inhibition did not have a marked effect on COX‑2 and HIF‑1α expression. In conclusion, the results of the present study suggested that HIF‑1α/PKM2 pathway‑associated metabolic changes may facilitate COX‑2‑induced apoptosis resistance in HCC cells.
AbdElhamid AS, Zayed DG, Helmy MW, et al.Lactoferrin-tagged quantum dots-based theranostic nanocapsules for combined COX-2 inhibitor/herbal therapy of breast cancer.
Nanomedicine (Lond). 2018; 13(20):2637-2656 [PubMed
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AIM: Herein, tumor-targeted quantum dots (QDs)-based theranostic nanocapsules (NCs) coloaded with celecoxib and honokiol were developed. Materials & methodology: The anionic CD44-targeting chondroitin sulfate and cationic low density lipoprotein (LDL)-targeting lactoferrin (LF) were sequentially assembled onto the surface of the positively charged oily core. As an imaging probe, highly fluorescent mercaptopropionic acid-capped cadmium telluride QDs were coupled to LF.
RESULTS: In vitro, fluorescence of QDs was quenched (OFF state) due to combined electron/energy transfer-mediated processes involving LF. After intracellular uptake of NCs, fluorescence was restored (ON state), thus enabled tracing their internalization. The NCs demonstrated enhanced cytotoxicity against breast cancer cells as well as superior in vivo antitumor efficacy.
CONCLUSION: We propose these multifunctional nanotheranostics for imaging and targeted therapy of breast cancer.
In our research we used the extract from dietary supplement of elderberry (EE) and its dominant anthocyanin-cyanidin 3-
Li F, Sun Y, Jia J, et al.Silibinin attenuates TGF‑β1‑induced migration and invasion via EMT suppression and is associated with COX‑2 downregulation in bladder transitional cell carcinoma.
Oncol Rep. 2018; 40(6):3543-3550 [PubMed
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Transforming growth factor (TGF)‑β1 is highly expressed in bladder transitional cell carcinoma (TCC) and is positively associated with tumor grade. TGF‑β1 signaling promotes cell metastasis by inducing epithelial‑mesenchymal transition (EMT), however, the underlying mechanisms are not fully understood. Our previous study demonstrated the anti‑metastatic effects of silibinin, a natural flavonoid derived from milk thistle, against TCC. The present study investigated the effects of silibinin on TGF‑β1‑induced EMT in TCC, focusing on the role of prostaglandin‑endoperoxide synthase 2 (COX‑2). Cell migration was determined by a wound healing assay and Transwell migration assay, and cell invasion was investigated using a Transwell invasion assay. Cell morphology was observed using an inverted microscope. Cell viability was evaluated by an MTT and cell counting assays. EMT markers were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting. Specific small interfering RNA was used to knockdown COX‑2 gene expression. TGF‑β1 promoted cell migration and invasion, induced EMT and upregulated the expression of COX‑2. COX‑2 knockdown attenuated TGF‑β1‑induced EMT, indicating that COX‑2 upregulation was essential for TGF‑β1‑induced EMT. Silibinin attenuated TGF‑β1‑induced migration and invasion by inhibiting EMT, and was associated with COX‑2 downregulation. TGF‑β1‑induced COX‑2 upregulation, which was inhibited by silibinin. In addition, TGF‑β1‑induced EMT was further inhibited when silibinin treatment was combined with COX‑2‑knockdown. The results suggested that silibinin may be a potential future treatment for metastatic TCC.
Jeong JW, Park C, Cha HJ, et al.Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.
BMB Rep. 2018; 51(10):532-537 [PubMed
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Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells. Our data indicate that cordycepin suppressed lipopolysaccharide (LPS)-enhanced cell migration and invasion through the inactivation of matrix metalloproteinase (MMP)-9 as well as the down-regulation of COX-2 expression and PGE2 production. These events were shown to be associated with the inactivation of EP4 and activation of AMP-activated protein kinase (AMPK). Moreover, the EP4 antagonist AH23848 prevented LPS-induced MMP-9 expression and cell invasion in HCT116 cells. However, the AMPK inhibitor, compound C, as well as AMPK knockdown via siRNA, attenuated the cordycepin-induced inhibition of EP4 expression. Cordycepin treatment also reduced the activation of CREB. These findings indicate that cordycepin suppresses the migration and invasion of HCT116 cells through modulating EP4 expression and the AMPK-CREB signaling pathway. Therefore, cordycepin has the potential to serve as a potent anti-cancer agent in therapeutic strategies against colorectal cancer metastasis. [BMB Reports 2018; 51(10): 533-538].