NF-κB and COX-2 Expression in Nonmalignant Endometrial Lesions and Cancer

Faloppa, Carlos Chaves; Baiocchi, Glauco; Cunha, Isabela Werneck da; Fregnani, José Humberto Tavares Guerreiro; Osório, Cynthia A. B. T.; Fukazawa, Elza Mieko; Kumagai, Lillian Yuri; Badiglian-Filho, Levon; Pinto, Gabriel Lowndes Souza; Soares, Fernando Augusto

doi:10.1309/ajcpv7u7pghoweqg

Cited by 14 publications

(9 citation statements)

References 46 publications

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“…Consistent with these findings, upregulation of NFKB activity was observed in human EC cells expressing phospho-Akt and was responsible for the increase of COX2 gene expression closely associated with parameters of tumor aggressiveness (St-Germain et al 2004). In a multistep model of EEC carcinogenesis, the activation of COX2 and NFKB signaling was hypothesized to mediate the progression of hyperplasia to cancer (Faloppa et al 2014). Blockade of NFKB activity by RTK inhibitor sunitinib reduced cell viability, proliferation, clonogenicity, and induced apoptotic cell death in EC cell lines (Sorolla et al 2012).…”

Section: Cell Signaling Pathwaysmentioning

confidence: 58%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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Section: Cell Signaling Pathwaysmentioning

confidence: 58%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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“…Cyclooxygenase-2 (COX-2), also known as Prostaglandin-Endoperoxide Synthase 2 (PTGS2), is an isoform of the cyclooxygenase (COX) enzyme. It is involved in the conversion of arachidonic acid to prostaglandin H2, leading subsequently to the production of prostaglandin E2 (PGE2) ( Erkanli et al ., 2007 ; Faloppa et al ., 2014 ). PGE2 has an established role in cell growth and development ( Faloppa et al ., 2014 ).…”

Section: Immunohistochemical Biomarkers For Diagnosis Of Endometrial mentioning

confidence: 99%

“…It is involved in the conversion of arachidonic acid to prostaglandin H2, leading subsequently to the production of prostaglandin E2 (PGE2) ( Erkanli et al ., 2007 ; Faloppa et al ., 2014 ). PGE2 has an established role in cell growth and development ( Faloppa et al ., 2014 ). In normal endometrial physiology, the expression of COX-2 and the metabolizing enzyme 15-Hydroxyprostaglandin Dehydrogenase (PGDH) are both regulated by progesterone ( Baird et al ., 1996 ; Hapangama et al ., 2002 ).…”

Section: Immunohistochemical Biomarkers For Diagnosis Of Endometrial mentioning

confidence: 99%

“… Faloppa et al . (2014) investigated COX-2 and nuclear factor-κB (NF-κB) expression in hyperplastic and malignant samples utilizing EIN diagnostic criteria, finding no significant difference in COX-2 expression between benign hyperplasia and EIN following post hoc analysis ( Faloppa et al ., 2014 ). Cao et al .…”

Section: Immunohistochemical Biomarkers For Diagnosis Of Endometrial mentioning

confidence: 99%

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New concepts for an old problem: the diagnosis of endometrial hyperplasia

Sanderson

Critchley

Williams

et al. 2016

Hum. Reprod. Update

216

244

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BACKGROUNDEndometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterized by an increase in the endometrial gland-to-stroma ratio when compared to normal proliferative endometrium. The clinical significance of EH lies in the associated risk of progression to endometrioid endometrial cancer (EC) and ‘atypical’ forms of EH are regarded as premalignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and, as a consequence, standardized patient management can be challenging.OBJECTIVE AND RATIONALEEC is the most common gynaecological malignancy in developed countries. The incidence of EC is rising, with alarming increases described in the 40–44-year-old age group. This review appraises the current EH classification systems used to stratify women at risk of malignant progression to EC. In addition, we summarize the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis.SEARCH METHODSPubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. The following search terms were used: ‘endometrial hyperplasia’, ‘endometrial intraepithelial neoplasia’, ‘atypical hyperplasia’, ‘complex atypical hyperplasia’, ‘biomarker’, ‘immunohistochemistry’, ‘progression’, ‘genomic’, ‘classification’ and ‘stratification’.OUTCOMESRecent changes to EH classification reflect our current understanding of the genesis of endometrioid ECs. The concept of endometrial intraepithelial neoplasia (EIN) as a mutationally activated, monoclonal pre-malignancy represents a fundamental shift from the previously held notion that unopposed oestrogenic stimulation causes ever-increasing hyperplastic proliferation, with accumulating cytological atypia that imperceptibly leads to the development of endometrioid EC. Our review highlights several key biomarker candidates that have been described as both diagnostic tools for EH and markers of progression to EC. We propose that, moving forwards, a ‘panel’ approach of combinations of the immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role.WIDER IMPLICATIONSEC has historically been considered a predominantly postmenopausal disease. Owing in part to the current unprecedented rates of obesity, we are starting to see signs of a shift towards a rising incidence of EC amongst pre- and peri-menopausal woman. This creates unique challenges both diagnostically and therapeutically. Furthering our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions.

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“…The most extensively studied eicosanoid metabolic pathway in cancer is the COX‐2/PGE 2 axis, where upregulation of the inducible COX isoform (COX‐2; PTGS2) and concomitant increased PGE 2 production are associated with malignant transformation . High tumour PTGS2 expression is associated with adverse prognosis in various cancers, although inconsistent findings emanate from the relatively small studies conducted in EC . COX enzymes (PTGS1, PTGS2) oxygenate arachidonic acid (AA) to PGH 2 , which is converted to PGE 2 via PGE synthases.…”

Section: Introductionmentioning

confidence: 99%

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

Cummings

Massey

Mappa

et al. 2018

The Journal of Pathology

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Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography-tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE /PGF inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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NF-κB and COX-2 Expression in Nonmalignant Endometrial Lesions and Cancer

Abstract: We conclude that COX-2 and NF-κB expression are lower in EC compared with nonmalignant endometrial lesions. COX-2 and NF-κB expression have no prognostic value in EC.

Cited by 14 publications

References 46 publications

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

New concepts for an old problem: the diagnosis of endometrial hyperplasia

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

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