Adhesion G protein-coupled receptor, ELTD1, is a potential therapeutic target for retinoblastoma migration and invasion

Abstract

Background Prognosis for pediatric metastatic Retinoblastoma (Rb) is poor and current therapies are limited by high systemic toxicity rates and insufficient therapeutic efficacy for metastatic Rb. Tumor dissemination to the brain is promoted by the heterogeneous adhesive and invasive properties of Rb cells within the tumor. In this study we evaluate, for the first time, the expression, and roles of the ELTD1 and GPR125 adhesion G protein-coupled receptors (GPCRs) in Rb cell migration, viability and invasion. Methods We characterized the RNA expression of adhesion-GPCRs in 64 Rb tumors compared to 11 fetal retinas using the database from the Childhood Solid Tumor Network from St Jude Children’s Research Hospital. The role of ELTD1 and GPR125 in Rb were investigated ex vivo by microarray analysis, in vitro by cell viability, Western blot and migration assays, in addition to imaging of the subcellular localization of the GPCRs. To elucidate their role in vivo we utilized siRNA technology in an established Rb orthotopic xenograft murine model. Results Our investigation demonstrates, for the first time, that ELTD1 but not GPR125, is significantly increased in Rb tumors compared to fetal retinas. We utilized established the Rb cell lines Y79 and Weri-Rb-1, which represent an aggressive, metastatic, and non-metastatic phenotype, respectively, for the in vitro analyses. The studies demonstrated that ELTD1 is enriched in Weri-Rb-1 cells, while GPR125 is enriched in Y79 cells. The measured differences extended to their subcellular localization as ELTD1 labeling displayed punctate clusters in cell-to-cell adhesion sites of Weri-Rb-1 cells, while GPR125 displayed a polarized distribution in Y79 cells. Lastly, we demonstrated the lack of both adhesion receptors does not affect Rb cell viability, yet inhibition of ELTD1 decreases Y79 cell migration in vitro and invasion in vivo. Conclusion Taken together, our data suggest that ELTD1, is a potential target to prevent extraocular Rb. The results within establish ELTD1 as a potential therapeutic target for metastatic Rb.

MicroRNA‑153‑3p suppresses retinoblastoma cell growth and invasion via targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways

“…In the future, other target genes of miR-153 or other differentially expressed miRNAs found in the present study also need to be carefully examined for their role in RB development. In addition, the expression level of miR-153 was detected in the RB cell lines, Y79 and WERI-RB-1, which have somewhat different characteristics, with the Y79 cells exhibiting inherent metastatic properties and the WERI-RB-1 cells exhibiting non-metastatic properties ( 47 ). The results of the present study revealed that the expression levels of miR-153 in the Y79 cells were higher than those in the Weri-RB1 cells ( Fig.…”

ELTD1 Promotes Gastric Cancer Cell Proliferation, Invasion and Epithelial–Mesenchymal Transition Through MAPK/ERK Signaling by Regulating CSK

“… 9 Moreover, the role of ELTD1 in pathological conditions is also explored, especially in malignancies. It has been reported that ELTD1 is upregulated in retinoblastoma, 24 glioma, 13 hepatocellular carcinoma, 12 etc. In spite of this, the role of ELTD1 in gastrointestinal tumors remains unclear.…”

ELTD1—An Emerging Silent Actor in Cancer Drama Play

“…By using cell lines and orthotopic xenograft mouse model, Santiago and colleagues recently demonstrated that ELTD1 is a potential target in retinoblastoma. They found that, without affecting normal cell viability, cell migration, and metastasis were reduced by ELTD1 disruption [ 52 ].…”

“…Retinoblastoma: In January 2021, Guihurt Santiago and colleagues reported differences regarding the expression and functional roles of ELTD1 and G–protein receptor 125 (GPR125/ADRGRA3)—two adhesion–GPCRs in retinoblastoma (Rb) [ 52 ]. The investigation demonstrated for the first time, that ELTD1, and not GPR125, was overexpressed in Rb compared to fetal retinas.…”

“…By disrupting ELTD1, in vitro cell migration and in vivo metastasis were reduced without affecting cell viability. This data suggests that ELTD1 may be a potential target for prevention of extraocular Rb and for treatment ofmetastatic Rb [ 52 ].…”