Background/Objectives: Retinoblastoma (RB) and uveal melanoma (UM) remain vision-threatening and lethal ocular malignancies with limited molecular markers of differentiation state and prognosis. We investigated whether proteins governing endocytosis and signaling, including Megalin (LRP2), Cubilin (CUBN), Caveolin-1, GAIP-interacting protein C-terminus 1 (GIPC1), and Disabled homolog 2-interacting protein (DAB2IP), exhibit subtype-specific expression patterns in ocular tumors and whether these patterns are related to transcriptomic profiles and survival.Methods: Formalin-fixed, paraffin-embedded human ocular tissues included controls (n= 10), retinoblastoma (n= 10), and UM subtypes (epithelioid, spindle, mixoid; totaln= 30). Immunofluorescence for LRP2, CUBN, CAV1, GIPC1, and DAB2IP was quantified using ImageJ (version 1.54g) across standardized high-power fields; per-specimen means were used for statistical analysis (Shapiro–Wilk test; one-way ANOVA with Tukey’s post hoc test). Public data analyses comprised: (i) overall survival in TCGA-UVM using GEPIA2; (ii) differential expression in GEO datasets (GSE62075: melanocytes vs. UM cell lines; GSE208143: retinoblastoma vs. pediatric control retina) and (iii) multivariate Cox proportional hazards regression analysis using the GEPIA3 online platform.Results: LRP2 expression was uniformly reduced across retinoblastoma and all UM subtypes versus control. CUBN expression decreased in retinoblastoma and epithelioid melanoma, was retained in spindle melanoma, and increased in mixoid-cell melanoma. CAV1 expression was increased in epithelioid melanoma but reduced in retinoblastoma, mixoid, and spindle melanomas. GIPC1 and DAB2IP expression were preserved in epithelioid melanoma yet significantly reduced in retinoblastoma and mixoid/spindle melanomas. In TCGA-UVM, higherCAV1andGIPC1mRNA expression was associated with worse overall survival (p≈ 0.025 and 0.036), whereasLRP2,CUBN, andDAB2IPexpression were not significant. GEO analyses revealed no significant differences for the five genes in UM cell lines versus melanocytes (GSE62075). However, in retinoblastoma (GSE208143),LRP2was downregulated, whileCUBN,CAV1,GIPC1, andDAB2IPwere upregulated.Conclusions: Endocytic/signaling proteins exhibit distinct, subtype-linked expression in ocular tumors. Integration with public datasets highlightsCAV1andGIPC1as adverse survival correlates in UM and positions LRP2/CUBN/DAB2IP dysregulation as features of ocular tumor biology, nominating candidate biomarkers and mechanistic targets.
背景/目的：视网膜母细胞瘤（RB）和葡萄膜黑色素瘤（UM）仍是威胁视力及生命的眼部恶性肿瘤，其分化状态和预后的分子标志物有限。本研究旨在探讨调控内吞和信号传导的蛋白，包括Megalin（LRP2）、Cubilin（CUBN）、Caveolin-1、GAIP相互作用蛋白C末端1（GIPC1）和Disabled同源物2相互作用蛋白（DAB2IP），在眼部肿瘤中是否呈现亚型特异性表达模式，以及这些模式是否与转录组谱和生存相关。方法：研究样本为福尔马林固定、石蜡包埋的人眼组织，包括对照组（n=10）、视网膜母细胞瘤组（n=10）和UM亚型组（上皮样、梭形、混合型；总计n=30）。使用ImageJ（版本1.54g）在标准化高倍视野下对LRP2、CUBN、CAV1、GIPC1和DAB2IP的免疫荧光强度进行定量；以每样本均值进行统计分析（Shapiro-Wilk检验；单因素方差分析及Tukey事后检验）。公共数据分析包括：（i）使用GEPIA2分析TCGA-UVM数据中的总生存期；（ii）分析GEO数据集中的差异表达（GSE62075：黑色素细胞 vs. UM细胞系；GSE208143：视网膜母细胞瘤 vs. 儿童对照视网膜）；（iii）使用GEPIA3在线平台进行多变量Cox比例风险回归分析。结果：与对照组相比，LRP2在视网膜母细胞瘤和所有UM亚型中表达均一致降低。CUBN在视网膜母细胞瘤和上皮样黑色素瘤中表达降低，在梭形黑色素瘤中保留，在混合细胞黑色素瘤中表达增加。CAV1在上皮样黑色素瘤中表达增加，但在视网膜母细胞瘤、混合型和梭形黑色素瘤中表达降低。GIPC1和DAB2IP在上皮样黑色素瘤中表达保留，但在视网膜母细胞瘤和混合型/梭形黑色素瘤中显著降低。在TCGA-UVM中，较高的CAV1和GIPC1 mRNA表达与较差的总生存期相关（p≈0.025和0.036），而LRP2、CUBN和DAB2IP的表达无显著相关性。GEO分析显示，在UM细胞系与黑色素细胞比较中（GSE62075），五个基因均无显著差异。然而，在视网膜母细胞瘤中（GSE208143），LRP2表达下调，而CUBN、CAV1、GIPC1和DAB2IP表达上调。结论：内吞/信号传导蛋白在眼部肿瘤中呈现独特的、与亚型相关的表达模式。结合公共数据集分析，突出了CAV1和GIPC1是UM不良生存的相关因素，并将LRP2/CUBN/DAB2IP的失调定位为眼部肿瘤生物学的特征，从而提名了潜在的生物标志物候选和机制靶点。
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