Linking Megalin, Cubilin, Caveolin-1, GIPC1 and Dab2IP Expression to Ocular Tumorigenesis: Profiles in Retinoblastoma, Choroidal Melanoma, and the Normal Human Eye

<b>Background/Objectives</b>: 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. <b>Methods</b>: Formalin-fixed, paraffin-embedded human ocular tissues included controls (<i>n</i> = 10), retinoblastoma (<i>n</i> = 10), and UM subtypes (epithelioid, spindle, mixoid; total <i>n</i> = 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. <b>Results</b>: 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, higher <i>CAV1</i> and <i>GIPC1</i> mRNA expression was associated with worse overall survival (<i>p</i> ≈ 0.025 and 0.036), whereas <i>LRP2</i>, <i>CUBN</i>, and <i>DAB2IP</i> expression were not significant. GEO analyses revealed no significant differences for the five genes in UM cell lines versus melanocytes (GSE62075). However, in retinoblastoma (GSE208143), <i>LRP2</i> was downregulated, while <i>CUBN</i>, <i>CAV1</i>, <i>GIPC1</i>, and <i>DAB2IP</i> were upregulated. <b>Conclusions</b>: Endocytic/signaling proteins exhibit distinct, subtype-linked expression in ocular tumors. Integration with public datasets highlights <i>CAV1</i> and <i>GIPC1</i> as adverse survival correlates in UM and positions LRP2/CUBN/DAB2IP dysregulation as features of ocular tumor biology, nominating candidate biomarkers and mechanistic targets.