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

Abstract

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.

Identification of heterogeneity and prognostic key genes associated with uveal melanoma using single-cell RNA-sequencing technology

“…Overexpression of EphB1 promoted the migration and invasion of lung cancer cells [32]. MH Vazquez-Levin and et al found an association between higher EphB1 expression and higher stage and tumor grade of Bladder cancer [33]. ITGB2 encodes integrin subunit β2, which acts like a cancer cell's mechanical anchor to the ECM.…”

The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy

“…Ephrin B1 binds to Eph receptor tyrosine kinase and potentiates tumor growth [32]. Ephrin B silencing in invasive MB49 bladder cancer cells (MB49-I) resulted in lower migratory and invasive capacity [33].…”

A comprehensive prognostic and immunological analysis of ephrin family genes in hepatocellular carcinoma

“…Substantial evidence indicates that ephrins play a vital role in tumor angiogenesis, invasion, metastasis, and tumor stemness maintenance ( Lodola et al, 2017 ). Many ephrin ligands have been shown to be upregulated in multiple tumors and associated with poor prognosis, such as lung adenocarcinoma ( Deng et al, 2021 ), breast cancer ( Kaenel et al, 2012 ), colorectal cancer ( Papadakos et al, 2022 ), prostate cancer ( Zhao et al, 2021 ), bladder cancer ( Mencucci et al, 2020 ), and other cancers ( Surawska et al, 2004 ). Lin et al (2021) reported that EFNA4 is highly expressed in cancer tissues and leads to poor prognosis in patients with HCC.…”