Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated apoptotic and inflammatory signaling, yet the tissue-level behavior of several candidate regulators remains poorly defined. Materials and Methods: We quantified ectodysplasin A2 receptor (EDA2R), TNF-receptor-associated factor 7 (TRAF7) and the apoptotic fragments cleaved-PARP1 and cleaved-CASP3 by immunofluorescence in 49 ccRCC and 27 matched non-tumoral cortex samples and analyzed the corresponding transcripts in TCGA-KIRC and GTEx. Results: TRAF7 protein was higher in tumor than in control tissue (median 0.81% vs. 0.63% positive area, p = 0.015), an increase concentrated in grade 2–3 tumors, whereas EDA2R and the apoptotic fragments did not differ (all p > 0.59). The positive EDA2R–cleaved-PARP1 correlation in low-grade tumors (ρ = +0.54, p = 0.002) was attenuated in high-grade tumors (ρ = +0.06, p = 0.84). In TCGA-KIRC, EDA2R mRNA was overexpressed in tumors, and higher expression was associated with better overall survival (HR = 0.60, p = 0.0011), including after mutual adjustment for the four transcripts (HR = 0.66, p = 5.3 × 10⁻⁵) and after adjustment for age, sex, stage and grade (HR per standard deviation = 0.83, p = 0.008). TRAF7 mRNA did not differ between tumor and normal tissue, but higher levels were associated with worse overall survival after the same adjustment (HR = 1.38, p < 0.001). Conclusions: TRAF7 and EDA2R show opposite, marker-specific discordance between protein- and transcript-level data across cohorts, consistent with, but not demonstrating, regulation beyond transcription. EDA2R is a candidate transcript-level prognostic marker requiring validation, and TRAF7 is a protein-level feature of ccRCC; paired RNA–protein and functional studies are needed.

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, characterized by frequent metastasis and poor prognosis. Epithelial–mesenchymal transition (EMT) plays a pivotal role in tumor progression. Protocadherin 9 (PCDH9) has emerged as a potential tumor suppressor, but its relationship with EMT markers in ccRCC remains unclear. This study aimed to investigate the expression patterns and prognostic significance of PCDH9, β-catenin (CTNNB1), Snail (SNAI1), and Vimentin (VIM) in ccRCC. Methods: Immunofluorescence analysis was performed on formalin-fixed paraffin-embedded tissue sections from 48 ccRCC patients (31 low-grade, 17 high-grade) and adjacent normal renal cortex. Findings were validated using The Cancer Genome Atlas (TCGA-KIRC) dataset via GEPIA2/GEPIA3 platforms, including differential expression, correlation, and survival analyses. Results:PCDH9 mRNA was significantly downregulated in ccRCC tumors (TCGA-KIRC), while VIM was upregulated at the transcriptomic level. Tissue-level immunofluorescence quantification revealed discordant patterns, highlighting the influence of cellular heterogeneity on bulk protein assessment. The strong positive correlation between PCDH9 and CDH1 observed in normal kidney was completely lost in tumor tissue. Unexpectedly, PCDH9 showed positive correlations with EMT transcription factors (ZEB1, SNAI1) in tumors. In univariate survival analysis, high PCDH9 and CTNNB1 expression were associated with improved overall survival. Multivariate Cox regression revealed endpoint-specific prognostic signatures: VIM independently predicted disease progression, while SNAI1 predicted overall mortality. CTNNB1 was consistently protective across both endpoints. Conclusions: Our findings support a tumor-suppressive role for PCDH9 in ccRCC and reveal disruption of epithelial adhesion molecule co-regulation during tumorigenesis. The identification of endpoint-specific prognostic signatures has implications for patient stratification and suggests that ccRCC exhibits a partial EMT phenotype rather than classical EMT.