Cyclooxygenase‐2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl‐2‐dependent mechanism

Cadden, Ian; Atkinson, A. B.; Johnston, Brian T.; Pogue, Kathy M.; Connolly, Roisín M.; McCance, David R.; Ardill, Joy; Russell, C. F. J.; McGinty, Ann

doi:10.1111/j.1365-2559.2007.02846.x

Cited by 12 publications

(8 citation statements)

References 22 publications

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“…Regarding COX‐2, our TMA results are in line with previous staining results on whole‐tissue sections . Strong COX‐2 expression associated with metastatic potential in pheochromocytomas and paragangliomas.…”

Section: Discussionsupporting

confidence: 90%

“…In many malignancies, COX‐2 expression is increased. In our earlier study, malignant pheochromocytomas overexpressed COX‐2 , as later confirmed by others . COX‐2 is a target of HuR, and cytoplasmic HuR expression is associated with high COX‐2 expression in mucinous‐type ovarian carcinoma , gastric cancer , oral squamous carcinoma , and colorectal adenocarcinoma .…”

supporting

confidence: 82%

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HuR in pheochromocytomas and paragangliomas – overexpression in verified malignant tumors

Leijon

Salmenkivi

Heiskanen

et al. 2016

APMIS

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Pheochromocytomas and paragangliomas are rare, neural crest-originating, neuroendocrine tumors. HuR is an mRNA-binding protein of the ELAV/Hu-protein family, which participates in posttranscriptional regulation of many cancer-associated genes. HuR expression has been connected with aggressive behavior of several malignancies. Cyclooxygenase-2 (COX-2) is also expressed in several malignant tumors, and its expression is regulated by HuR. Tissue microarray of 153 primary pheochromocytomas and paragangliomas was investigated for the expression of HuR and COX-2 proteins by immunohistochemistry using two different HuR antibodies (HuR19F12 and HuR3A). In these tumors, the expression of both intranuclear and cytoplasmic HuR was detectable. Increased cytoplasmic HuR expression was significantly associated with metastatic tumors. Increased COX-2 and MIB-1 expression also was associated with metastatic potential, and moreover, HuR and COX-2 expression correlated with each other. Our data suggest that increased expression of HuR protein is associated with metastatic potential of paragangliomas and pheochromocytomas, and COX-2 seems to be a target of HuR.

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Section: Discussionsupporting

confidence: 90%

supporting

confidence: 82%

HuR in pheochromocytomas and paragangliomas – overexpression in verified malignant tumors

Leijon

Salmenkivi

Heiskanen

et al. 2016

APMIS

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“…In some GEP-NETs with positive COX-2 staining in tumor cells, the staining was less intense for tumor-associated fibroblasts, inflammatory cells, and vascular endothelial cells than for tumor cells. Such positive staining of non-tumorous cells has been described in endocrine tumors previously [ 29 , 30 ].…”

Section: Discussionsupporting

confidence: 69%

Expression and Molecular Regulation of the Cox2 Gene in Gastroenteropancreatic Neuroendocrine Tumors and Antiproliferation of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

et al. 2018

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BackgroundGastroenteropancreatic 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/MethodsGEP-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.ResultsWe 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.ConclusionsThe 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.

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“…Malignant behaviour can be currently defined only by the appearance of metastasis. Several markers, such as COX and Bcl2, MIB-1, p53, VEGF and SNAIL among others, [25][26][27][28][29] or histological features (PASS score) 30 have been proposed as potential predictors of malignancy of pheo/pgl, but results have been inconclusive. For example, SNAIL expression had a 100% sensitivity of detecting the malignant tumours.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the insulin‐like growth factor 1 receptor (IGF‐1R) is associated with malignancy in familial pheochromocytomas and paragangliomas

Fernández

Martín

Venara

et al. 2013

Clinical Endocrinology

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between increased expression of IGF-1R and malignant behavior regardless the age at diagnosis and the genetic etiology. IGF-1R labeling was mostly weak in primary tumors from patients with non-metastatic pheo/pgl. Conversely, intense IGF-1R labeling was predominant in cases of pheo/pgl with confirmed metastatic disease. The risk of metastases was 11.7 times higher if tumor IGF-1R labeling was intense independently of age at diagnosis. The probability of remaining free of metastases was higher in patients with pheo/pgl scored weak for IGF-1R at 60 months and more than two fold higher at 120 months of follow-up than in patients with intense IGF-1R labeling in their primary tumors. Conclusions: Our results strongly suggest that IGF-1R is associated with malignancy in familial pheo/pgl and that IGF-1R expression in the primary tumor might be a useful tool to detect those patients harboring pheo/pgl that have an increased risk of metastasis.

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Cyclooxygenase‐2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl‐2‐dependent mechanism

Abstract: COX-2 and Bcl-2 may promote phaeochromocytoma malignancy, and these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

Cited by 12 publications

References 22 publications

HuR in pheochromocytomas and paragangliomas – overexpression in verified malignant tumors

HuR in pheochromocytomas and paragangliomas – overexpression in verified malignant tumors

Expression and Molecular Regulation of the Cox2 Gene in Gastroenteropancreatic Neuroendocrine Tumors and Antiproliferation of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Overexpression of the insulin‐like growth factor 1 receptor (IGF‐1R) is associated with malignancy in familial pheochromocytomas and paragangliomas

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