黏附 G 蛋白偶联受体，ELTD1，是治疗视网膜母细胞瘤迁移和侵袭的潜在靶点。
Adhesion G protein-coupled receptor, ELTD1, is a potential therapeutic target for retinoblastoma migration and invasion.
机构信息
Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
University of Puerto Rico, Rio Piedras Campus, Rio Piedras, Puerto Rico.
出版信息
BMC Cancer. 2021 Jan 11;21(1):53. doi: 10.1186/s12885-020-07768-3.
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.
背景
小儿转移性视网膜母细胞瘤（Rb）的预后较差，目前的治疗方法受到高全身毒性率和转移性 Rb 治疗效果不足的限制。肿瘤在脑内的扩散是由肿瘤内 Rb 细胞的异质黏附和侵袭特性所促进的。在这项研究中，我们首次评估了 ELTD1 和 GPR125 黏附 G 蛋白偶联受体（GPCR）在 Rb 细胞迁移、活力和侵袭中的表达和作用。
方法
我们使用圣裘德儿童研究医院儿童实体瘤网络数据库，比较了 64 例 Rb 肿瘤和 11 例胎儿视网膜的黏附 GPCR 的 RNA 表达，对其进行了特征描述。通过微阵列分析、细胞活力、Western blot 和迁移测定，以及 GPCR 亚细胞定位的成像，在体外研究了 ELTD1 和 GPR125 在 Rb 中的作用。为了阐明它们在体内的作用，我们利用 siRNA 技术在已建立的 Rb 原位异种移植小鼠模型中进行了研究。
结果
我们的研究首次表明，与胎儿视网膜相比，ELTD1 而不是 GPR125 在 Rb 肿瘤中显著增加。我们利用已建立的 Rb 细胞系 Y79 和 Weri-Rb-1，分别代表侵袭性、转移性和非转移性表型，进行了体外分析。研究表明，ELTD1 在 Weri-Rb-1 细胞中富集，而 GPR125 在 Y79 细胞中富集。这些差异还扩展到它们的亚细胞定位，因为 ELTD1 标记在 Weri-Rb-1 细胞的细胞间黏附部位显示出点状簇，而 GPR125 在 Y79 细胞中显示出极化分布。最后，我们证明缺乏这两种黏附受体不会影响 Rb 细胞活力，但抑制 ELTD1 可减少 Y79 细胞的体外迁移和体内侵袭。
结论
综上所述，我们的数据表明，ELTD1 可能是预防眼外 Rb 的潜在靶点。研究结果表明，ELTD1 是转移性 Rb 的潜在治疗靶点。
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