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.
Smoljo et al. (2026) studied this question.