Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor.

Dual Blockage of P-cadherin and C-met Synergistically Inhibits the Growth of Head and Neck Cancer

“…However, the role of P-cadherin in cancer cells remains a topic of ongoing debate. P-cadherin has been observed to induce aggressive behavior in several types of cancer, including prostate, colon, breast, ovarian, gastric, pancreatic cancer, and glioblastoma [20,[37][38][39]. In contrast, some reports suggest that P-cadherin functions as a tumor suppressor in other tumor models, such as melanoma, cholangiocarcinoma, hepatocarcinoma, and oral squamous cell carcinoma (OSCC) [37,[40][41][42].…”

3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer

“…Our data suggest that E- to P-cadherin switch is a common event in gastric cancers. The impact of P-cadherin overexpression in cancer is still controversial, as this molecule seems to act as tumour-promoting and a marker of a bad prognosis in several cancer types—namely, in breast, glioblastoma, and gastric cancer [ 36 ]—but may also act as a marker of a good prognosis—namely, in colon cancer [ 37 ]. Breast cancer cells presenting E- to P-cadherin switch, and those expressing both cadherins, reveal increased migration capacity in vitro [ 38 ], while breast cancer epithelial cells expressing E-cadherin and lacking P-cadherin expression, resembling the normal breast, and cells lacking both cadherins display reduced migration [ 38 ].…”

GPX4 is a potential diagnostic and therapeutic biomarker associated with diffuse large B lymphoma cell proliferation and B cell immune infiltration

“…Partial stably growing DLBCL cancer cells were divided into two groups randomly: the empty control group and the GPX4 overexpression group. The nonsense sequence GPX4 plasmid vector and The GPX4 overexpression plasmid vector were transfected into DLBCL cancer cells, respectively [ 26 ].…”