Immunohistochemical analysis of the role and relationship between Notch‐1 and Oct‐4 expression in urinary bladder carcinoma

Abdou, Asmaa Gaber; El-Wahed, Moshira M Abd; Kandil, Mohamed; Samaka, Rehab Monir; Elkady, Noha

doi:10.1111/apm.12086

Cited by 5 publications

(4 citation statements)

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“…NOTCH1 and DLL1 were most consistently diminished in both cell lines and tissues. Downregulation of these factors is in accord with a previous report [19], whereas another paper reported decreased NOTCH1 expression in high-grade invasive UC tissues only, with more pervasive cytoplasmic localization [28]. The mechanisms underlying these changes remain to be determined.…”

Section: Discussionsupporting

confidence: 87%

Canonical Notch signalling is inactive in urothelial carcinoma

et al. 2014

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BackgroundNotch signalling regulates cell fate in most tissues, promoting precursor cell proliferation in some, but differentiation in others. Accordingly, downregulation or overactivity variously contributes to cancer development. So far, little is known about Notch pathway activity and function in the normal urothelium and in urothelial carcinoma (UC). We have therefore investigated expression of Notch pathway components in UC tissues and cell lines and studied the function of one receptor, NOTCH1, in detail.MethodsExpression of canonical Notch pathway components were studied in UC and normal bladder tissues by immunohistochemistry and quantitative RT-PCR and in UC cell lines and normal cultured urothelial cells by qRT-PCR, immunocytochemistry and Western blotting. Pathway activity was measured by reporter gene assays. Its influence on cell proliferation was investigated by γ-secretase inhibition. Effects of NOTCH1 restoration were followed by measuring cell cycle distribution, proliferation, clonogenicity and nuclear morphology.ResultsNOTCH1 and its ligand, DLL1, were expressed at plasma membranes and in the cytoplasm of cells in the upper normal urothelium layer, but became downregulated in UC tissues, especially in high-stage tumours. In addition, the proteins were often delocalized intracellularly. According differences were observed in UC cell lines compared to normal urothelial cells. Canonical Notch pathway activity in reporter assays was repressed in UC cell lines compared to normal cells and a mammary carcinoma cell line, but was induced by transfected NOTCH1. Inhibitors of Notch signalling acting at the γ-secretase step did not affect UC cell proliferation at concentrations efficacious against a cell line with known Notch activity. Surprisingly, overexpression of NOTCH1 into UC cell lines did not significantly affect short-term cell proliferation, but induced nuclear abnormalities and diminished clonogenicity.ConclusionOur data indicate that canonical Notch signalling is suppressed in urothelial carcinoma mainly through downregulation of NOTCH1. These findings can be explained by proposing that canonical Notch signalling may promote differentiation in the urothelium, like in many squamous epithelia, and its suppression may therefore be advantageous for tumour progression. As an important corollary, inhibition of canonical Notch signalling is unlikely to be efficacious and might be counter-productive in the treatment of urothelial carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-628) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Canonical Notch signalling is inactive in urothelial carcinoma

et al. 2014

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“…The Notch signaling pathway performs crucial roles in maintaining cell fate/proliferation, regulating the stem cell maintenance and differentiation and epithelial–mesenchymal transition (EMT) [ 94 , 95 , 96 ]. GGI network analysis revealed some exciting functions of Notch factors in BCa, including stem cell development and cell fate determination, indicating peculiar roles for DTX1, DLL3, DLL1, JAG1, and JAG2 in terms of Notch binding, while others are not involved.…”

Section: Discussionmentioning

confidence: 99%

“…Abdou et al described the fact that NOTCH1 over-expression in stromal cell potentially activates Oct-4 (one of the crucial regulators of cell self-renewal) and is associated with poor prognosis and liability for recurrence in BCa [ 96 , 97 , 98 ]. Furthermore, loss-of-function mutations in NOTCH1 and NOTCH2 promote an epithelial–mesenchymal transition (EMT) in BCa, stabilizing the mesenchymal phenotype [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer

Zhang

Berndt‐Paetz

Neuhaus

2021

Cancers

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Background: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear. Methods: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers. Results: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial–mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system. Conclusions: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.

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“…For this, we performed Matrigel invasion chamber assays, and we observed increased invasion in shHES1-and siHES1-treated T24 cells compared with cells treated with a nontargeting control ( Figure 5D). have suggested that the NOTCH pathway could be oncogenic in bladder cancer (37,38), there is substantial evidence indicating a tumor-suppressive role. In particular, a high fraction of bladder carcinomas present deletion of the long arm of chromosome 9q, where NOTCH1 is located (39), and low levels of NOTCH1 and JAGGED1 are associated with short survival in bladder cancer patients (40).…”

Section: Discussionmentioning

confidence: 99%