High Cyclooxygenase-2 Expression Research Articles

Erratum: Inhibition of cyclooxygenase-2 sensitizes lung cancer cells to radiation-induced apoptosis.

[This corrects the article DOI: 10.3892/ol.2017.6940.].

Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2.

Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro.Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro.Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion.Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.

Abstract P5-18-04: HER2 overexpression in ductal carcinoma in situ: A biomarker for risk stratification and therapeutic implication

Abstract Background: After initial treatment for ductal carcinoma in situ (DCIS), a subsequent clinically significant event (SCSE) such as another diagnosis of DCIS, atypia or invasive breast cancer (IBC), will likely lead to further surgical/medical therapy. Pathologically, DCIS is treated on the basis of estrogen (ER) and progesterone receptor (PR) status with hormonal therapy (HT), ie, tamoxifen (TMX) or aromatase inhibitor, regardless of human epidermal growth factor receptor (HER2) overexpression. Although HER2 is a well-established prognostic marker for IBC, the role of HER2 in DCIS is less appreciated. Recent studies have documented the prognostic value of p16, COX-2 and Ki67 as prognostic biomarkers for locoregional invasive recurrences due to abrogated response to cellular stress (ARCS). Notably, a high-risk population of DCIS patients lacking ER expression but over-expressing HER2, p16 and COX-2 has been recently identified. In the present study, we compared expression levels of HER2 and the 3 ARCS markers in a large cohort of DCIS patients treated with contemporary standard of care and with >5-year follow-up to assess their association with cancer progression and predictive value for developing a SCSE. Methods: Formalin-fixed paraffin-embedded tissue sections from 99 patients diagnosed with primary DCIS(1999-2013) were stained forER, PR and HER2 expression by immunohistochemistry (IHC).If equivocal, HER2 amplification was assessed by Silver In Situ Hybridization. An additional slide was stained forp16, Ki67 and COX-2 using a novel multiplex IHC strategy. Quantification of the 3 ARCS markers' expression in both epithelial and stromal compartments was carried out using a software (InformTM)-guided approach. For expression level comparison of the three markers between HER2+ and HER2- DCIS, Wilcoxon-Mann-Whitney test was used. Fisher's exact or Chi-square test was used for other data analysis. Results: Simultaneous increase in epithelial p16, COX-2 and Ki67 expression in DCIS lesions was associated with subsequent IBC progression. HER2+ DCIS was significantly associated with high grade (p=0.0014), comedo-necrosis subtype (p=0.0022) compared to HER2- lesions. Upregulation of stromal COX-2 and p16 was significantly (p=0.008) associated with progression to SCSE in HER2- DCIS. The majority (5/6, 83%) of HER2+ DCIS patients treated with HT developed a SCSE, while only 22% (6/27) of HER2- DCIS patients treated with HT developed a SCSE. COX-2 upregulation was significantly associated with resistance to HT in HER2+ DCIS patients. Conclusion: High expression of p16, COX-2 and Ki67 in DCIS lesions can serve as powerful predictive biomarkers for DCIS progression to IBC. Our preliminary data suggest that overexpression of stromal p16 and COX-2 may help predict SCSEs in HER2- DCIS. Additionally, assessment of HER2 expression in DCIS may allow identification of patients who would not benefit from traditional HT as HER2 overexpression may predict TMX resistance. Since our data suggest that TMX resistance in HER2+ DCIS may be linked to upregulation of COX-2, one may propose that COX-2 inhibitors in conjunction with TMX may minimize TMX resistance in HER2+ DCIS. These preliminary data will need to be reproduced in a larger cohort to solidify their significance. Citation Format: Yin J, Gascard P, Last B, Singh M, Tlsty T, Tjoe JA. HER2 overexpression in ductal carcinoma in situ: A biomarker for risk stratification and therapeutic implication [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-04.

Danzhi Jiangtang Capsule ameliorates kidney injury via inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats.

Danzhi Jiangtang Capsule (DJC), a traditional Chinese medicinal formula, has been used clinically in treating diabetes and diabetic nephropathy (DN). We previously demonstrated that DJC is capable of improving renal function in patients and rats with DN, but the mechanisms underlying these therapeutic benefits of DJC are not quite clear yet. In this study, STZ-induced diabetic rats were orally administered DJC for 8 weeks. Fasting blood glucose, renal function indicators in the serum, renal index, and the expression of proteins related to JAK-STAT signaling pathway were evaluated at the end of the experiment. The kidneys were sliced for pathological histology. Antioxidant status was assessed by measuring SOD, LPO and MDA in serum. The expression levels of COX2, iNOS, SOCS and the phosphorylation status of JAK2, STAT1, and STAT3 in renal tissues were evaluated by Western blot analyses. IL-6, TNF-α, and MCP-1 expression levels in renal tissues were determined using double-antibody sandwich ELISA. Diabetic renal dysfunction and its associated pathologies were ameliorated by DJC treatment. DJC significantly reversed the high expression of COX2 and iNOS in renal tissues. Furthermore, DJC inhibited the JAK2-STAT1/STAT3-SOCS3 signaling pathway, resulting in decreased concentrations of IL-6, TNF-α, and MCP-1. Moreover, the oxidant status in the kidney was substantially ameliorated by DJC treatment. In conclusion, the ability of DJC to ameliorate diabetic renal dysfunction and the associated pathologies of this disease might be due to its antioxidant capacity and suppression of the JAK2-STAT1/STAT3 cascade.

Molecular profiling analysis for colorectal cancer patients with Pi-Xu or Shi-Re syndrome

BackgroundTraditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) constitute the basis of understanding the disorders of patients and guiding the use of the Chinese herbs. Colorectal cancer is divided into various subtypes mainly according to the ZHENG identification. ObjectiveWe aimed to determine the molecular basis underlying Pi-Xu (spleen deficiency) and Shi-Re (dampness-heat) ZHENG that are commonly found in colorectal cancer patients. MethodsAbout 80 colorectal cancer patients, including 47 Pi-Xu ZHENG and 33 Shi-Re ZHENG were enrolled. Blood and tissue samples of these patients were available for protein and mRNA expression. The protein expression was determined by Immunohistochemistry (IHC) staining and mRNA profiling was detected by expression microarray. Furthermore, mRNA fold change was evaluated by qRT-PCR. ResultsThe colorectal cancer patients with Shi-Re ZHENG had a poor prognosis, compared with Pi-Xu ZHENG (95% CI: 0.05–0.33; p<0.0001). Moreover, there was a significant difference in protein expression levels (especially for mutant TP53, PCNA, PD-L1 and Ki-67) among Pi-Xu and Shi-Re ZHENG (p<0.01). Meanwhile, mRNA expression (especially for wild type TP53, KDM6A, PCNA, PD-L1, Ki-67, CCL-2, IL-1a and COX-2) was also remarkably different between Pi-Xu and Shi-Re groups (p<0.01). ConclusionOur results suggest that Shi-Re ZHENG conditions may contribute to poor overall survival in patients with colorectal cancer. Compared with Pi-Xu ZHENG, high expression of mutant TP53, PCNA, PD-L1, Ki-67, CCL-2, IL-1a and COX-2 may serve as potential biomarkers for diagnosis and prognosis of colorectal cancer patients displayed Shi-Re ZHENG.

Transcriptomic analysis of differential gene expression reveals an increase in COX2 levels during in vitro canine herpesvirus infection

ABSTRACT: Canine herpesvirus (CaHV-1) affects canids worldwide, causing death in neonates and immunosuppressed hosts. Acute infection by CaHV-1 can cause reproductive, respiratory, and neurological problems in adult animals. Viral pathogenesis and host genes expressions during of CaHV-1infection are not clearly understood. In the present study, the transcriptome of canine kidney cell Mardin-Darby (MDCK) infected in vitro with canine herpesvirus was explored. For this, RNA sequencing (RNA-seq) of the samples in different moments during infection was carried out. Subsequently, the transcriptomic analysis genes related to cell activities and process involved to viral cycle infection were evaluated until 32h post-inoculation (pi). Among evaluated genes, was verified a significant and gradative increase of the prostaglandin-endoperoxide synthase 2 (PTGS2) or cyclooxygenase 2 (COX2) gene expression, throughout of infection, though differential gene expression analysis and validated by quantitative reverse transcription PCR (RT-qPCR). High COX2 expression is usually induced in response to inflammation, pathogens or activation of the immune system but can be a viral mechanism to favor viral replication. Thus, COX2 level increase can be a favorable factor for viral infection with Cahv-1 virus and the use of selective COX2 inhibitors may be beneficial for limiting the infection or clinical signs by causing interruption of the viral replication cycle during active infection. Additionally, the regulation genes expression differential verified in this study can contribute to determining important targets for inhibiting canine herpesvirus infection either by cellular or viral mechanisms.

Molecular carcinogenesis in equine penile cancer: A potential animal model for human penile cancer

ObjectivesTo evaluate the expression of COX-2, E-cadherin, vimentin, 14-3-3σ, and Phosphatase and tensin homolog (PTEN) tumor-related proteins in equine penile papillomas (ePP) and squamous cell carcinomas (ePSCC), the occurrence of epithelial-mesenchymal transition (EMT) at the invasion front (IF) and compare our findings with current knowledge on human penile squamous cell carcinoma (hPSCC). Material and methodsWe analyzed, by immunohistochemistry in 45 equine penile proliferative epithelial lesions, the expression of COX-2, E-cadherin, vimentin, 14-3-3σ, and PTEN using monoclonal antibodies. Tumors were histopathologically classified as well-differentiated or poorly differentiated using the IF grading scheme. Semiquantitative analysis was performed to determine down or up-regulation of the proteins and association with histopathological characteristics were statistically investigated using Mann–Whitney U test and/or Spearman's tests. ResultsCOX-2 was neo-expressed in 86.6% of the cases and expression progressively increased from ePP to ePSCC (P = 0.0003) and from well to poorly differentiated (P = 0.033). High COX-2 expression was associated with a high mitotic index (MI) (P = 0.026). In contrast to normal epidermis, ePSCC had very low E-cadherin expression in 64% of the cases (P = 0.0005). Vimentin was neo-expressed in 65% of poorly differentiated ePSCC at the IF indicating EMT. Cytoplasmic 14-3-3σ protein expression was reduced in 42% of the ePSCC and additionally, nuclear expression of 14-3-3σ in neoplastic keratinocytes and in the cytoplasm of stromal fibroblasts at the IF was features only found in ePSCC. PTEN protein showed a tendency to be decreased or lost in ePSCC. ConclusionsOur study provides evidence of molecular abnormalities in ePSCC similar to those reported for human PSCC. The occurrence of EMT at the IF is a common event in ePSCC. Naturally occurring ePSCC could serve as a valuable preclinical animal model to explore upcoming therapeutic options for hPSCC.

PS02.043: OVEREXPRESSION OF HSP27 AND HSP70 ARE ASSOCIATED WITH DECREASED SURVIVAL AMONG PATIENTS WITH ESOPHAGEAL ADENOCARCINOMA

Abstract Background Heat shock protein (HSP) 27 and 70 overexpression is associated with several malignancies but reports of their incidence and association with survival among patients with esophageal carcinoma (EC) are scarce. COX-2 expression is induced by inflammation, and it has been linked to a Barrett's esophagus and a wide variety of cancers. High COX-2 expression has been linked to poor survival in EC but results regarding association to clinicopathological factors are conflicting. Methods Immunohistochemical analysis for HSP27, HSP70 and COX-2 was performed on 97 cancer cases, 19 Barrett cases and 5 controls treated between 1990 - 2007. Data was gathered from patient records and survival data was acquired in December 2015. Results Higher tumor stage was significantly associated with poorer survival (P &lt; 0001), which was independent of HSP27, HSP70 and COX-2 immunostaining. HSP27 was moderately or strongly positive in 61,8% of the cancer cases, which was significantly associated to poorer survival (25,6 and 19 months versus 65,1 in weakly positive samples) (P = 0,01). Similar results were seen for HSP70, for which 30,4% of the cases were stained moderately or strong positive, and survival was 15 and 17,3 months compared to 41,7 months in weakly stained cases. COX-2 was negative in 83,3% of the cancer cases, and none of the samples had strong COX-2 immunostaining. COX-2 did not correlate with survival. Conclusion Moderate or high HSP27 and HSP70 staining intensities were associated with poor survival among patients with esophageal adenocarcinoma, which is now reported for the first time. According to previous studies opposite conclusions for esophageal squamous cell carcinoma was found. COX-2 did not impact survival in our study even though it's been found to be a negative prognostic factor in several previous studies. Disclosure All authors have declared no conflicts of interest.

COX-2/EP2-EP4/β-catenin signaling regulates patulin-induced intestinal cell proliferation and inflammation

Patulin (PAT), a mycotoxin, is a natural contaminant that is produced by certain species of Penicillium, Aspergillus and Byssochlamys. The major contamination of PAT is in apple and apple based products. PAT is known to cause glutathione depletion, oxidative DNA damage and cell proliferation. Recently, in vitro studies have indicated that PAT can also increase the intestinal epithelial permeability, modulate tight junctions and decrease transepithelial electrical resistance. Nonetheless, no previous study has evaluated the mechanisms responsible for PAT-induced intestinal toxicity or its relevance to the in vivo situation. Here, Wistar rats were orally treated with 100 μg/kg body weight (b.wt.) of PAT, either alone or along with 100 mg/kg b. wt. of celecoxib for 3 days. We found that PAT exposure led to significantly higher levels of PGE2 in serum and intestinal tissue and high expression of COX-2 and Ki-67 compared to controls. Interestingly, our results showed that celecoxib treatment could decrease the PAT-induced PGE2 and reduce the PAT-induced intestinal damage. To study the mechanistic aspect, normal rat intestinal epithelial cells (IEC-6) were treated with non-toxic concentrations (100 nM, 250 nM and 500 nM) of PAT for 6 h. It was observed that PAT exposure caused enhanced proliferation, higher expression of COX-2, and EP2 and EP4 receptors, along with increased PGE2 secretion. Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3β and stabilizes β-catenin. Overall, our study suggests that the COX-2/EP2-EP4/β-catenin signaling cascades are involved in the regulation of PAT-induced intestinal cell proliferation and inflammation.

Relationship between the sensitivity of neoadjuvant chemoradiotherapy and the expression of cyclooxygenase-2 in locally advanced rectal cancer

Objective To investigate the relationship between the sensitivity of neoadjuvant chemoradiotherapy and the expression of cyclooxygenase-2 (COX-2) in locally advanced rectal cancer. Methods Clinicopathologic data of 42 patients with local mid-low advanced rectal cancer receiving preoperational concomitant chemoradiotherapy were retrospectively analyzed. Immunohistochemical assay was performed in pre-chemoradiotherapy specimens to determine the expression of COX-2 protein. Postoperative pathological tissue sections were reassessed for evaluation of tumor regression grade [0-4, complete pathological response (pCR)=4] after radiochemotherapy. The relationship of expression COX-2 with pCR was analyzed by chisquare test. Results Patients with low expression of COX-2 had significantly higher incidence of pCR than those with high expression of COX-2 (63.6% vs. 36.3%). The expression of COX-2 was negatively correlated with pCR (r=-0.762, P=0.019). Patients with high expression of COX-2 had significantly higher expression of VEGF than those with low expression of COX-2 (64.0% vs. 36.0%). The expression of COX-2 was positively correlated with VEGF (r=0.531, P=0.028). The univariate analysis showed that age, gender, distance between tumor and the anal verge, circumferential extent of the tumor, clinical stage and T-staging were not clearly associated with the expression of COX-2 in rectal cancer. Conclusion The expression of COX-2 is associated with efficiency of neoadjuvant chemoradiation of rectal cancer. Key words: Rectal neoplasm; Cyclooxygenase-2; Neoadjuvant chemoradiotherapy; Complete pathological response

Impact of cyclooxygenase-2 over-expression on the prognosis of colorectal cancer patients. An experience from Western Saudi Arabia.

Objectives:To evaluate cyclooxygenase-2 (COX-2) over-expression in colorectal cancer (CRC) and its role in carcinogenesis and prognosis.Methods:It was a retrospective study. Archival samples were obtained from Pathology Department at King Fahad Hospital, Madinah, Saudi Arabia, over 11 years’ period (January 2006 to December 2017). Samples were analyzed using immunohistochemistry for COX-2 and Ki67 over-expression in 324 CRC patients, 40 cases of colorectal adenomas and 20 cases of normal colonic mucosa.Results:Cyclooxygenase-2 over-expression was observed in 40% of normal colonic mucosa, 65% of colorectal adenoma and 84.6% of CRC cases. There were no significant correlations between COX-2 over-expression and age, gender, tumor site, or tumor size. However, COX-2 over-expression revealed highly significant correlations with tumor differentiation, lymph node metastasis, lympho-vascular invasion, distant metastasis, advanced stages, and high Ki67 expression. Univariate Kaplan-Meir survival analysis showed that patients with high COX-2 expression had significantly shorter periods of survival. Multivariate analysis by means of the COX-2 regression model revealed that high COX-2 over-expression, AJCC, and Ki67 expression were the only significant independent prognostic indicators.Conclusion:Cyclooxygenase-2 over-expression increases during normal-adenoma-carcinoma sequence, moreover COX-2 over-expression is associated with advanced tumor stage and Ki67 over-expression. These findings suggest a significant role of COX-2 in the carcinogenesis and prognosis of CRC in our study population.

Abstract 2641: The presence of Cyclooxygenase 2, tumor-associated macrophages, and collagen features as prognostic markers for invasive breast carcinoma patients

Abstract Inflammation and the organization of collagen in the breast tumor microenvironment is an important mediator of tumor progression. The objective of this study was to assess whether the tissue localization of COX-2 and tumor-associated macrophages were associated with clinicopathological features of invasive carcinoma, including collagen deposition and patient survival outcome. A tumor microarray (TMA) of 371 biopsy specimens from patients with invasive breast carcinoma was analyzed for expression levels of COX-2, the macrophage marker CD68 and activated macrophage marker CD163 in either the tumor nest (TN) or the tumor-associated stroma (TS). The TMA cohort included females; age 18 to 80, with a median follow up of 8.4 years. Biomarkers were correlated against clinicopathological and collagen features. Additionally, survival curves were calculated according to the Kaplan-Meier method. We found that high expression of COX-2 was associated with tumor size (P = 0.006), grade (P &amp;lt; 0.0001), proliferation (P &amp;lt; 0.0001), ER+ (P = 0.001), collagen deposition (P &amp;lt; 0.0001) and density (P = 0.001). One possible mechanism for this, is COX-2 dependent recruitment of macrophages to the tumor microenvironment. This is supported by our finding of high infiltration of both macrophage markers that were associated with tumor size and proliferation; however, only high levels of stromal CD163 were associated with collagen deposition. In order to better analyze patient survival data, samples were divided into quartiles based on their levels of COX-2 expression and/or macrophage infiltration. COX-2 localization in the TN (P = 0.016, HR = 1.71), perpendicular alignment of collagen to the tumor boundary (TACS-3) (P = 0.049, HR = 1.65) and macrophage recruitment were predictors of poor overall survival (OS). Furthermore, patient survival was worsened if patients had a high CD163 macrophage infiltration (TN: P &amp;lt; 0.0001, HR = 2.86; TS: P = 0.002, HR = 2.54). This notion is further established by the finding of our multivariate analysis that high numbers of CD163+ macrophages in the TS as an independent prognostic factor (P = 0.001, HR = 2.90). These results suggest that in invasive carcinoma the localization of inflammatory markers within the tumor are biomarkers for patient survival outcome. Therefore, we propose that these patients may benefit from a selective COX-2 inhibitor and/or immune modulation therapies. Citation Format: Karla Esbona, Yanyao Yi, Menggang Yu, Rachel Van Doorn, Matthew Conklin, Douglas Graham, Kari Wisinski, Suzanne Ponik, Kevin Eliceiri, Lee Wilke, Patricia Keely. The presence of Cyclooxygenase 2, tumor-associated macrophages, and collagen features as prognostic markers for invasive breast carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2641.

High COX-2 expression contributes to a poor prognosis through the inhibition of chemotherapy-induced senescence in nasopharyngeal carcinoma.

Resistance to radiotherapy and chemotherapy currently represents one of the major reasons for therapeutic failure in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying resistance to chemotherapy in NPC remain unclear. In this study, cell counting assay, cell cycle assay and senescence associated β-galactosidase activity were performed to evaluate cell growth, proliferation and senescence, respectively. We found that the aberrant expression of cyclooxygenase-2 (COX-2) was associated with a poor outcome and recurrance in patients with NPC. In NPC cells, COX-2 overexpression increased cell proliferation, inhibited cellular senescence and resulted in chemoresistance, while the knockdown of COX-2 reduced cell proliferation, promoted cellular senescence and overcame chemoresistance. Furthermore, fibroblasts from COX-2 knockout mice exhibited cellular senescence, particularly when treated with chemotherapeutic agents. Mechanistically, COX-2 interacted with p53 protein and inhibited cellular senescence, which resulted in chemotherapeutic resistance. On the whole, these findings indicate that COX-2 may play a critical role in chemotherapeutic resistance in NPC via the inhibition of chemotherapy-induced senescence via the inactivation of p53. This study provides experimental evidence for the preclinical value of increasing chemotherapy-induced senescence by targeting COX-2 as an effective antitumor treatment in patients with recurrent NPC.

LIN28A is overexpressed in osteoarthritis and is essential for the stability and high level expression of IL-6 and COX-2 in human chondrocytes

LIN28A is overexpressed in osteoarthritis and is essential for the stability and high level expression of IL-6 and COX-2 in human chondrocytes

The Presence of Cyclooxygenase 2, Tumor-Associated Macrophages, and Collagen Alignment as Prognostic Markers for Invasive Breast Carcinoma Patients

Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclooxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163+ macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stromal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers.

Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors

BackgroundHigh cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.MethodsWe developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.ResultsType I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84–22.01) and OS (HR: 2.26, 95% CI: 1.04–4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06–3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06–3.53).ConclusionsThese findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.

Vitamin D receptor and cyclooxygenase-2 expression in uterine leiomyoma tissues and their correlation

Background: To explore vitamin D receptor (VDR) and cyclooxygenase-2 (COX-2) expression in uterine leiomyomas and normal myometrium tissues, and further analyze their correlation in the etiopathogenesis of uterine leiomyomas. Methods: We collected uterine leiomyoma tissues and their paired adjacent normal myometrium tissues from 20 cases of uterine leiomyomas and examined the expression of VDR and COX-2 in the tissues by real-time polymerase chain reaction and Western blotting, respectively. We further analyzed the correlation between VDR and COX-2 as well as their expressions with correlation to the size of uterine leiomyomas. Results: The expression of VDR mRNA in 15 of 20 uterine leiomyoma tissues decreased compared with the healthy uterine smooth muscle tissues (P 0.05 for transcriptional level; r=−0.165, P>0.05 for protein level). There was not significant correlation between VDR expression and uterine leiomyoma size, as well as between COX-2 expression and uterine leiomyoma size (r=−0.008, P>0.05; r=0.150, P>0.05, respectively). Conclusions: VDR expression decreased and COX-2 expression increased in uterine leiomyomas compared with the healthy uterine smooth muscles. Decreased VDR expression and high COX-2 expression may play a role in the etiopathogenesis of uterine leiomyomas. There may be a negative relevance between VDR and COX-2 in leiomyomas.

Correlation of Inflammatory Markers, Survival, and COX2 Expression in Oral Cancer and Implications for Prognosis.

Objective Peripheral blood-derived inflammation-based scores, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and the combination of platelet count and NLR, have recently been proposed as prognostic markers in solid tumors. The purpose of this study was to investigate the validity of inflammatory markers as predictive prognostic factors for locally advanced oral squamous cell carcinoma (OSCC). In addition, we evaluated the potential correlation between systemic inflammation and local expression of COX2. Study Design Retrospective chart review and histologic analysis. Setting Tertiary referral academic center. Subjects and Methods We conducted a retrospective analysis of 94 patients with advanced OSCC treated with surgery at our hospital between 2007 and 2015. The relationship among patient survival, systemic inflammatory markers, and local COX2 expression was evaluated. Local COX2 expression in surgical specimens was measured by immunohistochemistry. Results High NLR and high PLR were associated with significantly shorter overall survival and cancer-specific survival. Multivariate analysis revealed that cN stage, NLR, and postoperative radiation/chemoradiation were significantly associated with overall survival and cancer-specific survival. PLR and combination of platelet count and NLR were significantly correlated with tumor expression of COX2. Finally, patients with cN2 stage disease and high local COX2 expression had a significantly worse prognosis than other patient groups. Conclusion Pretreatment inflammatory markers are useful as prognostic factors in advanced OSCC. Our study suggests that local COX2 may be affected by systemic inflammation and that the prognostic impact of COX2 expression depends on host factors and tumor characteristics.

High Inflammatory Infiltrate Correlates With Poor Symptomatic Improvement After Surgical Treatment for Superior Limbic Keratoconjunctivitis.

Superior limbic keratoconjunctivitis (SLK) is a chronic and recurrent condition of unknown etiology. It is often managed conservatively, but there is a high rate of success with surgical management for severe or recalcitrant cases. The purpose of this article is to describe and analyze clinicopathological features of patients with SLK who underwent surgical treatment and their association with the clinical outcome. A total of 22 eyes from 18 patients who underwent surgical SLK management were retrospectively analyzed. Clinicopathological data were collected including details of follow-up and patient satisfaction (n = 15). Moreover, 12 cases had specimens available for review of histopathologic findings and COX-2 expression analysis by immunohistochemistry. From a clinical perspective, 66.7% of the SLK eyes had nonmechanical factors contributing to SLK, and 66.7% of eyes demonstrated significant symptomatic improvement after surgery. Histopathological analysis of all the lesions showed acanthosis and goblet cell loss. Unexpectedly, in 93% of the eyes, dilated lymphatic vessels were found. Furthermore, a high inflammatory infiltrate correlated with minimal symptomatic improvements (P = 0.013). Moreover, COX-2 expression was higher in patients with SLK than in a normal conjunctiva (P = 0.001). In this study, the most common systemic association with SLK was the patient's autoimmune status. Histopathological evaluation revealed that high inflammatory infiltration in the biopsy might be predictive of minimal symptomatic improvement with surgical management. Finally, the higher COX-2 expression in patients with SLK compared with that in individuals with a normal conjunctiva supports the use of anti-COX-2 drugs as a possible therapeutic target.

Graphene oxide regulates cox2 in human embryonic kidney 293T cells via epigenetic mechanisms: dynamic chromosomal interactions

To extend the applications of engineered nanomaterials, such as graphene oxide (GO), it is necessary to minimize cytotoxicity. However, the mechanisms underlying this cytotoxicity are unclear. Dynamic chromosomal interactions have been used to illustrate the molecular bases of gene expression, which offers a more sensitive and cutting-edge technology to elucidate complex biological processes associated with epigenetic regulations. In this study, the role of GO-triggered chromatin interactions in the activation of cox2, a hallmark of inflammation, was investigated in normal human cells. Using chromosome conformation capture technology, we showed that GO triggers physical interactions between the downstream enhancer and the cox2 promoter in human embryonic kidney 293T (293T) via p65 and p300 complex-mediated dynamic chromatin looping, which was required for high cox2 expression. Moreover, tumor necrosis factor-α (TNF-α), located upstream of the p65 signaling pathway, contributed to the regulation of cox2 activation through dynamic chromatin architecture. Compared with pristine GO and aminated GO (GO-NH2), poly (acrylic acid)-functionalized GO (GO-PAA) induced a weaker inflammatory response and a weaker effect on chromatin architecture. Our results mechanistically link GO-mediated chromatin interactions with the regulation of cox2 and suggest that GO derivatives may minimize toxicity in practical applications.