Pan-Cancer Analysis of PAPPA Gene Reveals Tumor-Specific Prognostic Effects

Pregnancy-associated plasma protein A (<i>PAPPA</i>) is a metalloproteinase that regulates insulin-like growth factor availability via cleavage of IGF-binding proteins, yet its role in cancer remains incompletely understood. Using integrated public datasets, we systematically examined <i>PAPPA</i> expression, prognostic relevance, cellular localization, and stromal associations across multiple tumor types. <i>PAPPA</i> was reduced in several cancers and primarily localized to stromal cells, whereas in cholangiocarcinoma and thyroid carcinoma it was elevated and also detected in malignant cells. High <i>PAPPA</i> expression was associated with poorer overall survival in bladder, cervical, lung squamous, mesothelioma, pancreatic, and gastric cancers, but exhibited a protective effect in lower-grade glioma. In tumors with adverse prognosis, <i>PAPPA</i> strongly correlated with cancer-associated fibroblast (CAF) infiltration and CAF marker genes; however, multivariable Cox analyses indicated that <i>PAPPA</i> generally retained an independent prognostic factor, whereas CAF infiltration was mostly not independently associated with overall survival. Interestingly, in LGG, despite negative <i>PAPPA</i>-CAF correlations, multivariable analysis showed that <i>PAPPA</i> remained protective while CAF infiltration was associated with worse survival. Pathway analyses linked <i>PAPPA</i>-associated genes to proteoglycans in cancer and PI3K-AKT and RAS signaling. Collectively, these findings establish <i>PAPPA</i> as an independent prognostic factor across most cancers, while its expression frequently coincides with high CAF infiltration in select tumor types, highlighting the need for further investigation.