COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables

Perrone, Giuseppe; Santini, Daniele; Verzı̀, A; Vincenzi, Bruno; Borzomati, Domenico; Vecchio, Fabio Maria; Coppola, Roberto; Antinori, Armando; Magistrelli, Paolo; Tonini, Giuseppe; Rabitti, Carla

doi:10.1136/jcp.2005.030098

Cited by 17 publications

(12 citation statements)

References 34 publications

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“…COX-2 is a major driver of human breast cancer progression (1)(2)(3)(4)(5), in which EP4 receptor activity plays a significant role (17,19,20). The role of COX-2 in regulating miRNAs has never been tested.…”

Section: Discussionmentioning

confidence: 99%

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

Majumder

Landman

Liu

et al. 2015

Molecular Cancer Research

115

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MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX-2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR-526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR-526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist-mediated miR526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-kB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-kB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2-overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR-526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival.Implications: This study presents novel findings that miRNA 526b is a COX-2 upregulated, oncogenic miRNA promoting SLCs, the expression of which follows EP4 receptor-mediated signaling, and is a promising biomarker for monitoring and personalizing breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

Majumder

Landman

Liu

et al. 2015

Molecular Cancer Research

115

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“…To date, only limited studies on COX-2 expression were carried out on surgically removed cancers of the ampulla of Vater [1,16,23,28]. In the current study 45 ampullary carcinomas were analyzed for COX-2 expression.…”

Section: Discussionmentioning

confidence: 99%

COX-2 expression of ampullary carcinoma: correlation with different histotypes and clinicopathological parameters

et al. 2006

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Epidemiological studies suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced incidence of gastrointestinal cancer. Several lines of evidence indicate that the antineoplastic effect of NSAIDs is attributable to COX-2 inhibition. The aim of our study was to assess COX-2 expression in a series of primary untreated ampullary carcinomas and its possible correlation with clinicopathological parameters. In the present study, 45 surgical specimens of invasive ampullary carcinomas were histologically classified into pancreaticobiliary, intestinal, and unusual types. COX-2 expression by immunohistochemical method was analyzed. High COX-2 expression was detected in 35 (77.8%) ampullary carcinomas. Among these, 20/21 (95.2%) were classified as intestinal, 9/18 (50%) pancreaticobiliary, and 6/6 (100%) unusual type. A significant statistical difference in terms of COX-2 expression was found between pancreaticobiliary vs intestinal type (P=0.002). Furthermore, a negative significant statistical correlation was found between T factor and COX-2 expression (P=0.047). The different COX-2 expression among histopathological types supports the concept of histogenetical difference of ampullary carcinomas. Furthermore, the high rate of COX-2 expression in the intestinal subtype of ampullary carcinoma may represent the rational for a histotype-tailored therapy targeting COX-2.

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“…For that, it was used four micrometers thick paraffin-embedded tissue sections at 60°C degree glass-house, subjected to xylene, rehydrated in absolute alcohol, performing antigen retrieval by Steamer, with citric acid at a pH 6.0 for 60 minutes, incubated for primary cleaved caspase-3 antibody For COX-2, it was used a calculated immunohistochemical score as proposed by Perrone et al 16 by multiplying the quantity and staining intensity scores. The raw data were obtained from an estimate percentage of immunoreactive cells (quantity score), ranging from zero to four; and an estimate of the color intensity (staining intensity score), which was assessed on a scale from zero to three.…”

Section: Histological and Immunohistochemical Assaysmentioning

confidence: 99%

Effects of maternal ischemic preconditioning in the colon of newborn rats submitted to hypoxia-reoxygenation insult

et al. 2014

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PURPOSE:To evaluate the effects of maternal remote ischemic preconditioning (IPCr) in the colonic mucosa of newborn rats subjected to hypoxia and reoxygenation. METHODS:Newborn Wistar rats were divided into three groups. Control Group (CG), Hypoxia and Reoxygenation Group (HRG) and Remote Ischemic Preconditioning Group (IPCrG). Hypoxia and reoxygenation was performed 2x per day, with an interval of 6 hours, on the 1st, 2nd and 3rd days of life, with 10 minutes of CO 2 at 100%, followed by 10 minutes O 2 at 100%(HRG/IPCrG). The maternal IPCr was performed 24 hours before delivery by applying a rubber band tourniquet to the left hind limb (IPCrG). Segments of the colon underwent histological (HE) and immunohistochemical analysis for caspase-3 and COX -2. RESULTS:The histological findings showed no intestinal mucosal damage in the CG group and severe lesions in HRG that was attenuated in the IPCrG (p<0.05). The expression of the apoptotic cells was lower in the HRG group than in the CG and IPCrG. The COX-2 expression was intense in HRG and attenuated in the IPCrG (p<0.05). CONCLUSIONS:Maternal IPCr protected the colonic mucosa of newborn rats subjected to hypoxia and reoxygenation, reducing the morphological alterations and inflammatory response. It ameliorates the occurrence of apoptosis, keeping the physiological process of renewal and regeneration in the epithelial lining of the colonic mucosa.Key words: Enterocolitis, Necrotizing. Colon. Apoptosis. Rats. Effects of maternal ischemic preconditioning in the colon of newborn rats submitted to hypoxia-reoxygenation insultActa

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COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables

Abstract: COX-2 is highly expressed in ampullary carcinomas. This suggests an involvement of the COX-2 pathway in ampullary tumour associated angiogenesis, providing a rationale for targeting COX-2 in the treatment of ampullary cancer.

Cited by 17 publications

References 34 publications

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation

COX-2 expression of ampullary carcinoma: correlation with different histotypes and clinicopathological parameters

Effects of maternal ischemic preconditioning in the colon of newborn rats submitted to hypoxia-reoxygenation insult

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