Down-Regulation of Nitric Oxide Synthase-2 and Cyclooxygenase-2 Pathways by p53 in Squamous Cell Carcinoma

Gallo, Oreste; Schiavone, Nicola; Papucci, Laura; Sardi, Iacopo; Magnelli, Lucia; Franchi, Alessandro; Masini, Emanuela; Capaccioli, S.

doi:10.1016/s0002-9440(10)63699-1

Cited by 72 publications

(54 citation statements)

References 42 publications

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“…Another interesting observation was the higher positive immunostaining rate of eNOS in Ki-67-positive intracranial ependymomas, compared with that in Ki-67-negative group, which showed more eNOS-negative cases. This suggests that eNOS expression may be associated with the cell proliferation of intracranial ependymomas.This is consistent with findings in human hepatocellular 19 , endometrial 20 , pharyngeal 21 tumours. Thus, overexpression of Ki-67 protein and eNOS protein play an important role in the carcinogenesis of human intracranial ependymomas.…”

Section: Discussionsupporting

confidence: 93%

Clinicopathological evaluation of immunohistochemical Ki-67 and endothelial nitric oxide synthase expression in intracranial ependymoma

Yan

Cheng²,

Liu³

et al. 2008

CIM

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Clin Invest Med 2008; 31 (4): E206-E211. AbstractPurpose: To analyze the association between Ki-67 and eNOS expression with the pathological grades of patients with intracranial ependymomas, and to determine its value in distinguishing the progression of the disease. Methods: A clinicopathological study was undertaken in 82 patients with intracranial ependymomas. Tissue samples, obtained by tumour resection, were divided into three groups: low-grade, mid-grade and high-grade ependymomas. Tissue samples obtained from 15 patients with brain contusion were used as control. Immuno-histochemical staining was performed to analyze the association between Ki-67 and eNOS expression with various tumour grades. The cell proliferating marker Ki-67 was assessed by positive cell count. The levels of eNOS positive expression were evaluated as slight, moderate and intense. Results: 48 of 82 cases (58.54%) expressed Ki-67 protein.Expression of Ki-67 and eNOS was negative in all control samples. Positive cell rates were 2.65±0.83 % in the lowgrade, 9.63±0.08 % in the mid-grade, and 28.41±0.71 % in the high-grade ependymoma groups. In low-grade ependymomas there were 8 and 12 cases that expressed eNOS slightly or moderately. In the mid-grade ependymoma group eNOS was expressed moderately in 10 cases and intensely in 15. In the high-grade group 20 cases showed intense positive expression of eNOS. The Ki-67 positive cell counts for slight, moderate and intense eNOS expression were 2.20, 6.07 and 22.25, respectively. Conclusion: Ki-67 and eNOS expression in intracranial ependymoma tissue was associated with the histopathological grade and malignant degree.Ependymomas and malignant ependymomas constitute approximately 2%~9% of all intracranial carcinomas and 18.2% of nervous epithelium tumours. 1 After pilocytic astrocytoma and medulloblastoma, ependymomas are the third most common brain tumours in children. In adults, most ependymomas are intraspinal but, in children, these tumours develop preferentially in the posterior fossa where they arise from the fourth ventricle ependymal cells. 2 The prognosis remains poor, regardless of introduction of radiotherapy or chemotherapy in the treatment protocol. Age, surgical removal, tumuor location and histology have been evaluated as important factors affecting ORIGINAL RESEARCH

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Section: Discussionsupporting

confidence: 93%

Clinicopathological evaluation of immunohistochemical Ki-67 and endothelial nitric oxide synthase expression in intracranial ependymoma

Yan

Cheng²,

Liu³

et al. 2008

CIM

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“…43 Activation of p53 has been shown to decrease the expression of Cox-2, thereby reducing the inflammatory response. 4,44,45 We 4 and others 46,47 have previously demonstrated that several biologically active substances, 14 including p53 tumor suppresser gene, can induce transcriptional repression of Cox-2, as well as decrease Cox-2 protein levels. In this study we found that levels of phospho-p53 ser15 , presumably active form of p53, were increased in the skin of PL-fed mice, which inversely correlated with decreased Cox-2 levels, suggesting that orally administered PL reduces UV-induced Cox-2 levels in mouse skin through, at least in part, by activating tumor suppressor protein p53.…”

Section: Discussionmentioning

confidence: 96%

Polypodium leucotomos Extract Decreases UV-Induced Cox-2 Expression and Inflammation, Enhances DNA Repair, and Decreases Mutagenesis in Hairless Mice

Zattra

Coleman

Arad

et al. 2009

The American Journal of Pathology

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mice were fed for 10 days with PL (300 mg/kg) or vehicle then UV-irradiated, once. By 24 hours, UVinduced Cox-2 levels were increased in vehicle-fed and PL-fed mice, whereas by 48 and 72 hours, Cox-2 levels were four-to fivefold lower in PL-fed mice (P < 0.05). p53 expression/activity was increased in PL-fed versus vehicle-fed then UV-irradiated mice. UV-induced inflammation was decreased in PL-fed mice, as shown by ϳ60% decrease (P < 0.001) in neutrophil infiltration at 24 hours, and macrophages by ϳ50% (<0.02) at 24 and 48 hours. By 72 hours, 54 ؎ 5% cyclobutane pyrimidine dimers remained in vehiclefed versus 31 ؎ 5% in PL-fed skin (P < 0.003). The number of 8-hydroxy-2-deoxyguanosine-positive cells were decreased before UV irradiation by ϳ36% (P < 0.01), suggesting that PL reduces constitutive oxidative DNA damage. By 6 and 24 hours, the number of 8-hydroxy-2-deoxyguanosine-positive cells were ϳ59% (P < 0.01) and ϳ79% (P < 0.03) lower in PL-fed versus vehicle-fed mice. Finally, UV-induced mutations in PL-fed-mice were decreased by ϳ25% when assessed 2 weeks after the single UV exposure. These data demonstrate that PL extract supplementation affords the following photoprotective effects: p53 activation and reduction of acute inflammation via Cox-2 enzyme inhibition, increased cyclobutane pyrimidine dimer removal, and reduction of oxidative DNA damage.

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“…In addition to ovarian cancer, which has been found in our work and those of others (31), association of COX-2 expression and p53 immunostaining has previously been found in gastric and breast cancers (37,38). Because the COX-2 gene has been shown to be induced in p53 defective cells and down-regulated by wild-type p53 (39,40), there may exist a direct link between a defective p53 pathway and elevated levels of COX-2 expression in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Elevated Cyclooxygenase-2 Expression Is Associated with Altered Expression of p53 and SMAD4, Amplification of HER-2/neu, and Poor Outcome in Serous Ovarian Carcinoma

Erkinheimo

Lassus²,

Finne

et al. 2004

Clinical Cancer Research

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Purpose and Experimental Design: Cyclooxygenase-2 (COX-2) is frequently expressed in human adenocarcinomas and inhibition of COX-2 suppresses tumor formation in various animal models of carcinogenesis. We analyzed expression of COX-2 protein in human serous ovarian carcinomas by immunohistochemistry (n ‫؍‬ 442) and by Western blotting (n ‫؍‬ 12) and COX-2 mRNA by reverse transcriptase PCR (n ‫؍‬ 12). COX-2 immunoreactivity was correlated to clinicopathological variables and to expression of p53 and SMAD4 as detected by immunohistochemistry and to amplification of HER-2/neu as detected by in situ hybridization.Results: COX-2 mRNA expression was detected in 75% (9 of 12) and COX-2 protein in 42% (5 of 12) of the serous ovarian adenocarcinoma specimens as detected by reverse transcriptase-PCR and Western blot analysis, respectively. Moderate to strong (elevated) immunoreactivity for COX-2 was detected in 70% (310 of 442) of the tumors. Elevated COX-2 expression associated with reduced disease-specific survival (P ‫؍‬ 0.0011), high histological grade (P < 0.0001), residual tumor size > 1 cm (P ‫؍‬ 0.0111), and age > 57 years (P ‫؍‬ 0.0099). Tumors with altered immunostaining pattern for p53 or SMAD4 expressed more frequently elevated levels of COX-2 when compared with the tumors with normal staining pattern of these tumor suppressor genes (P < 0.0001 and P ‫؍‬ 0.0004, respectively). In addition, elevated COX-2 expression associated with amplification of HER-2/ neu oncogene (P ‫؍‬ 0.0479).Conclusions: Our results suggest that elevated expression of COX-2 associates with reduced survival in serous ovarian carcinomas and that expression of COX-2 may be induced in these tumors by loss of tumor suppressor genes such as p53 and SMAD4 and by amplification of HER-2/neu oncogene.

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Down-Regulation of Nitric Oxide Synthase-2 and Cyclooxygenase-2 Pathways by p53 in Squamous Cell Carcinoma

Cited by 72 publications

References 42 publications

Clinicopathological evaluation of immunohistochemical Ki-67 and endothelial nitric oxide synthase expression in intracranial ependymoma

Clinicopathological evaluation of immunohistochemical Ki-67 and endothelial nitric oxide synthase expression in intracranial ependymoma

Polypodium leucotomos Extract Decreases UV-Induced Cox-2 Expression and Inflammation, Enhances DNA Repair, and Decreases Mutagenesis in Hairless Mice

Elevated Cyclooxygenase-2 Expression Is Associated with Altered Expression of p53 and SMAD4, Amplification of HER-2/neu, and Poor Outcome in Serous Ovarian Carcinoma

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