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

MENCUCCI, MARÍA VICTORIA; BESSO, MARÍA JOSÉ; VANZULLI, SILVIA; TEJERIZO, JUAN CARLOS; VAZQUEZ-LEVIN, MÓNICA HEBE; LAPYCKYJ, LARA; BELGOROSKY, DENISE; LODILLINSKY, CATALINA; GONZALEZ, MATÍAS IGNACIO; ROSSO, MARINA; ISOLA, MARIANA; EIJÁN, ANA MARÍA; ZUBIETA, MARÍA ERCILIA

Frontiers in Oncology

Frontiers

Lugar: Lausanne; Año: 2020 vol. 10 p. 1 - 17

Bladder cancer (BC) is the ninth most common cancer worldwide, but molecularchanges are still under study. During tumor progression, Epithelial cadherin (E-cadherin)expression is altered and β-catenin may be translocated to the nucleus, where itacts as co-transcription factor of tumor invasion associated genes. This investigationfurther characterizes E-cadherin and β-catenin associated changes in BC, by combiningbioinformatics, an experimental murine cell model (MB49/MB49-I) and human BCsamples. In in silico studies, a DisGeNET (gene-disease associations database)analysis identified CDH1 (E-cadherin gene) as one with highest score among 130BC related-genes. COSMIC mutation analysis revealed CDH1 low mutations rates.Compared to MB49 control BC cells, MB49-I invasive cells showed decreasedE-cadherin expression, E- to P-cadherin switch, higher β-catenin nuclear signal andlower cytoplasmic p-Ser33-β-catenin signal, higher Ephrin-B1 ligand and EphB2receptor expression, higher Phospho-Stat3 and Urokinase-type Plasminogen Activator(UPA), and UPA receptor expression. MB49-I cells transfected with Ephrin-B1 siRNAshowed lower migratory and invasive capacity than control cells (scramble siRNA).By immunohistochemistry, orthotopic MB49-I tumors had lower E-cadherin, increasednuclear β-catenin, lower pSer33-β-catenin cytoplasmic signal, and higher Ephrin-B1expression than MB49 tumors. Similar changes were found in human BC tumors, and83% of infiltrating tumors depicted a high Ephrin-B1 stain. An association between higherEphrin-B1 expression and higher stage and tumor grade was found. No association wasfound between abnormal E-cadherin signal, Ephrin-B1 expression or clinical-pathologicalparameter. This study thoroughly analyzed E-cadherin and associated changes in BC,and reports Ephrin-B1 as a new marker of tumor aggressiveness.