S100 Calcium-Binding Protein P and Cathepsin E as Key Mediators in Pancreatic Cancer Tumorigenesis

<b>Background/Objectives:</b> Pancreatic cancer (PC) remains one of the deadliest malignancies, with challenges that hinder early detection and few actionable molecular targets. In this study, we aimed to identify biomarkers predictive of PC to support its diagnosis and treatment. <b>Methods:</b> Proteins from formalin-fixed, paraffin-embedded pooled samples of PC (n = 15; 5 pools) and chronic pancreatitis (n = 10; 5 pools) tissues were analyzed via label-free quantitative proteomics using liquid chromatography-tandem mass spectrometry. Immunohistochemistry (IHC) was performed on PC tissue microarrays to assess S100 calcium-binding protein P (S100P) and cathepsin E (CTSE) expression (IHC evaluable pairs: n = 78 for S100P; n = 82 for CTSE). Transwell invasion assays were conducted to evaluate the effects of these proteins on PC cell invasiveness, and Western blotting was used to validate protein expression and elucidate associated molecular mechanisms. <b>Results:</b> Both S100P and CTSE were overexpressed in PC tissues compared with those in adjacent normal tissues. Elevated S100P expression correlated with poor prognosis, whereas higher CTSE expression predicted favorable outcomes; both served as independent prognostic factors in PC. Functionally, S100P promoted PC cell invasion, whereas CTSE suppressed it. Mechanistically, both proteins appeared to regulate epithelial-mesenchymal transition (EMT) and invasive capacity through activation or inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. <b>Conclusions:</b> Elevated expression of S100P and CTSE in PC tissues serves as independent indicators in our model of patient survival. Both proteins regulate EMT and invasion, potentially via the PI3K-AKT pathway, and hold significant promise as prognostic biomarkers and therapeutic targets in PC.