Prognostic role of N-cadherin expression in patients with non–muscle-invasive bladder cancer

Abufaraj, Mohammad; Shariat, Shahrokh F.; Haitel, Andrea; Moschini, Marco; Foerster, Beat; Chłosta, Piotr; Gust, Kilian M.; Babjuk, Marek; Briganti, Alberto; Karakiewicz, Pierre I.; Albrecht, Walter

doi:10.1016/j.urolonc.2017.01.012

Cited by 22 publications

(15 citation statements)

References 22 publications

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“…The percentage of NMIBC patients with positive β-catenin staining in published studies was lower than that obtained in the presented study -75% in the study by Elsherif et al, 60% in the study by Koletsas et al and 40% in the study by Senol et al [18][19][20]. The obtained results of Ecadherin assays are confirmed by reports by Singh et al, whereas studies performed by Muramaki et al and Abufaraj et al showed the expression of E-cadherin in 50-60% of analyzed tissues [21][22][23]. The expression of N-cadherin, which indicates that the cell acquires migratory abilities, was only visible in 3.73% of participants of this study.…”

Section: Discussionsupporting

confidence: 75%

Intensity of Nuclear Staining for Ki-67, p53 and Survivin as a New Prognostic Factor in Non-muscle Invasive Bladder Cancer

Stec

Cierniak

Lubas

et al. 2019

Pathol. Oncol. Res.

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The aim of the study was to determine the prognostic value of expression levels of biomarkers selected on the basis of the literature: p53, Ki-67, survivin, β-catenin, E-cadherin and N-cadherin in patients with non-muscle invasive bladder cancer. Immunohistochemistry was performed on sections of primary papillary carcinoma of the bladder removed during transurethral resection of the tumor in 134 patients. The expression of β-catenin and E-cadherin was found in all analyzed cases and Ncadherin expression was demonstrated in 3.73% of the tissues examined. The expression of the p53 protein was confirmed in 96.27% of tissues examined. The expression of the Ki-67 protein was demonstrated in all analyzed cases. Survivin expression was found in 95.52% of the study group. Multivariate analysis confirmed the relationship between the recurrence-free survival (RFS) and the intensity of the nuclear reaction for p53 (HR 1417, 95% CI 1.001-2.007, p = 0.049) and survivin (HR 1.451; 95% CI 1.078-1.955; p = 0.014), the expression level of the Ki-67 protein expressed by the TS index (HR 1.146, 95% CI 1.116-1.823, p = 0.005) and the use of adjuvant BCG therapy (HR 0.218, 95% CI 0.097-0.489, p = 0.0002). The evaluation of Ki-67 expression and the intensity of nuclear staining for survivin and p53 may provide additional information that will allow more accurate stratification of the risk of NMIBC recurrence after TURBT.

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Section: Discussionsupporting

confidence: 75%

Intensity of Nuclear Staining for Ki-67, p53 and Survivin as a New Prognostic Factor in Non-muscle Invasive Bladder Cancer

Stec

Cierniak

Lubas

et al. 2019

Pathol. Oncol. Res.

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“…However, when TGFβ1treatment was applied, we detected a significant reduction in both KO clones, although the change was less dramatic than for N-Cadherin in the untreated condition. There have been numerous reports in the past stating the significance of cadherin switching in progression and malignancy of BCa pointing to the importance of elucidating the mechanism for targeted therapy (32)(33)(34)(35)(36)(37). Moreover, it was already shown that NRP2 and E-Cadherin expression are connected in multiple cancer types (23,(38)(39)(40)(41).…”

Section: Nrp2 Positively Regulates Osteopontin Expressionmentioning

confidence: 99%

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

et al. 2020

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Neuropilin-2 (NRP2) is a prognostic indicator for reduced survival in bladder cancer (BCa) patients. Together with its major ligand, vascular endothelial growth factor (VEGF)-C, NRP2 expression is a predictive factor for treatment outcome in response to radiochemotherapy in BCa patients who underwent transurethral resection. Therefore, we investigated the benefit of combining cisplatin-based chemotherapy with irradiation treatment in the BCa cell line RT112 exhibiting or lacking endogenous NRP2 expression in order to evaluate NRP2 as potential therapeutic target. We have identified a high correlation of NRP2 and the glioma-associated oncogene family zinc finger 2 (GLI2) transcripts in the cancer genome atlas (TCGA) cohort of BCa patients and a panel of 15 human BCa cell lines. Furthermore, we used in vitro BCa models to show the transforming growth factor-beta 1 (TGFβ1)-dependent regulation of NRP2 and GLI2 expression levels. Since NRP2 was shown to bind TGFβ1, associate with TGFβ receptors, and enhance TGFβ1 signaling, we evaluated downstream signaling pathways using an epithelial-to-mesenchymal transition (EMT)-assay in combination with a PCR profiling array containing 84 genes related to EMT. Subsequent target validation in NRP2 knockout and knockdown models revealed secreted phosphoprotein 1 (SPP1/OPN/Osteopontin) as a downstream target positively regulated by NRP2.

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“…In line with these findings, fluorescence immunocytochemistry revealed a lower signal for N-cadherin in MB49-I compared to MB49 cells ( Figure 2G). Previous studies have reported ∼40% of bladder tumors depicting a positive signal for this protein (37)(38)(39). This percentage was found in either NMIBC (37) or MIBC (40) tumor cohorts, showing that not all invasive tumors show increased expression of N-cadherin.…”

Section: Expression Of E-cadherin and Emt-related Markers In Mb49 Andmentioning

confidence: 84%

“…Previous studies have reported ∼40% of bladder tumors depicting a positive signal for this protein (37)(38)(39). This percentage was found in either NMIBC (37) or MIBC (40) tumor cohorts, showing that not all invasive tumors show increased expression of N-cadherin. While some of these studies showed an association between increased Ncadherin expression and recurrence-free survival (37,38), others failed to find a relationship between N-cadherin expression with clinicopathological parameters (39,41).…”

Section: Expression Of E-cadherin and Emt-related Markers In Mb49 Andmentioning

confidence: 84%

“…This percentage was found in either NMIBC (37) or MIBC (40) tumor cohorts, showing that not all invasive tumors show increased expression of N-cadherin. While some of these studies showed an association between increased Ncadherin expression and recurrence-free survival (37,38), others failed to find a relationship between N-cadherin expression with clinicopathological parameters (39,41). In line with the results of the present report, a study by Jäger et al (42) found a positive N-cadherin expression in superficial (Ta/T1) cases to be a risk factor, and a lack of expression in MIBC cases correlated with reduced patient survival.…”

Section: Expression Of E-cadherin and Emt-related Markers In Mb49 Andmentioning

confidence: 95%

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Ephrin-B1 Is a Novel Biomarker of Bladder Cancer Aggressiveness. Studies in Murine Models and in Human Samples

et al. 2020

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Bladder cancer (BC) is the ninth most common cancer worldwide, but molecular changes are still under study. During tumor progression, Epithelial cadherin (E-cadherin) expression is altered and β-catenin may be translocated to the nucleus, where it acts as co-transcription factor of tumor invasion associated genes. This investigation further characterizes E-cadherin and β-catenin associated changes in BC, by combining bioinformatics, an experimental murine cell model (MB49/MB49-I) and human BC samples. In in silico studies, a DisGeNET (gene-disease associations database) analysis identified CDH1 (E-cadherin gene) as one with highest score among 130 BC related-genes. COSMIC mutation analysis revealed CDH1 low mutations rates. Compared to MB49 control BC cells, MB49-I invasive cells showed decreased E-cadherin expression, E-to P-cadherin switch, higher β-catenin nuclear signal and lower cytoplasmic p-Ser33-β-catenin signal, higher Ephrin-B1 ligand and EphB2 receptor expression, higher Phospho-Stat3 and Urokinase-type Plasminogen Activator (UPA), and UPA receptor expression. MB49-I cells transfected with Ephrin-B1 siRNA showed lower migratory and invasive capacity than control cells (scramble siRNA). By immunohistochemistry, orthotopic MB49-I tumors had lower E-cadherin, increased nuclear β-catenin, lower pSer33-β-catenin cytoplasmic signal, and higher Ephrin-B1 expression than MB49 tumors. Similar changes were found in human BC tumors, and 83% of infiltrating tumors depicted a high Ephrin-B1 stain. An association between higher Ephrin-B1 expression and higher stage and tumor grade was found. No association was found between abnormal E-cadherin signal, Ephrin-B1 expression or clinical-pathological parameter. This study thoroughly analyzed E-cadherin and associated changes in BC, and reports Ephrin-B1 as a new marker of tumor aggressiveness.

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Prognostic role of N-cadherin expression in patients with non–muscle-invasive bladder cancer

Cited by 22 publications

References 22 publications

Intensity of Nuclear Staining for Ki-67, p53 and Survivin as a New Prognostic Factor in Non-muscle Invasive Bladder Cancer

Intensity of Nuclear Staining for Ki-67, p53 and Survivin as a New Prognostic Factor in Non-muscle Invasive Bladder Cancer

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

Ephrin-B1 Is a Novel Biomarker of Bladder Cancer Aggressiveness. Studies in Murine Models and in Human Samples

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