PRELP Regulates Cell–Cell Adhesion and EMT and Inhibits Retinoblastoma Progression

Abstract

Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP−/− mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell–cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment.

PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity

“…Interestingly, gene sets related to inflammation such as “Interferon γ response”, “Interferon α response” and “Complement” were strongly affected in Prelp −/− meninges. Cell-cell adhesion related categories, “EMT” and “Apical Junction” were significantly affected ( Figure 5E ), which suggests that the functional role of PRELP as regulator of partial EMT may be conserved across tissues ( Papadaki et al, 2020 ; Hopkins et al, 2022 ). In summary, ontological analysis proposes two main biological roles of PRELP within the meninges: cell-cell adhesion and inflammation.…”

“…One of the proposed mechanisms of vascular leakage is activation of EndMT of vascular endothelial cells ( Sweeney et al, 2019 ), which is associated with a reduction in adherens and tight junctions. Recently, we demonstrated that PRELP has the ability to activate mesenchymal-to-epithelial transition (MET), resulting in the enhancement in bladder epithelial cell-cell and retinoblastoma cells ( Papadaki et al, 2020 ; Hopkins et al, 2022 ). As the EndMT/MEndT mechanism is largely conserved with EMT/MET, loss of PRELP may cause vascular leakage through activation of EndMT ( Saito, 2013 ; Hong et al, 2018 ).…”

“…These partial EMT states, pEMT, are important for understanding human diseases such as cancer ( Lamouille et al, 2014 ; Nieto et al, 2016 ; Aiello et al, 2018 ; Brabletz et al, 2018 ). Recently, we reported that PRELP regulates cell-cell adhesion of bladder umbrella epithelial cells and retinoblastoma cells through pEMT ( Papadaki et al, 2020 ; Hopkins et al, 2022 ). Similar mechanisms, endothelial-mesenchymal transition (EndMT) has been demonstrated in vascular cells ( Lamouille et al, 2014 ; Nieto et al, 2016 ; Kovacic et al, 2019 ).…”

“…Intriguingly, PRELP expression was regulated by epigenetically through acetylation of lysine residue 5 of histone H2B in the PRELP gene promoter region in bladder cancer ( Shozu et al, 2022 ). In addition, we demonstrated that Prelp was expressed in mouse retina and loss of Prelp contributed to retinoblastoma cell progression by reducing cell-cell adhesion and facilitated EMT ( Hopkins et al, 2022 ). We further investigated the roles in other tumors and identified that PRELP showed a tumor suppressive role by regulated PI3K-AKT signalling pathway in high-grade ovarian cancer ( Dozen et al, 2022 ).…”

All-in-One digital microfluidics pipeline for proteomic sample preparation and analysis

“…Among this group (differentially quanti-ed relative to healthy tissue), 15 proteins (higher quantities: PGS2, UGDH, ASPN, LUM, COEA1, PRELP; and lower quantitites: PDIA3, AMPL, PDIA4, B2MG, CALR, PLSL, 1A68, COR1A, D6RGG3) were commonly identied in both breast cancer tissue samples, and have been reported to be associated with the progression of breast cancer. [63][64][65][66][67][68][69][70][71][72][73][74][75][76] The quantitative trends for these proteins were consistent in both breast cancer tissues, which further validated the reliability of identication and quantication by the All-in-One pipeline.…”