Prognostic Value, Immune Signature, and Molecular Mechanisms of the PHLDA Family in Pancreatic Adenocarcinoma

Background: Increasing evidence supports the belief that the pleckstrin homology domain family A (PHLDA) family is associated with the development of a variety of cancers. However, the function of the PHLDA family members in PAAD is still unclear. Methods: Comprehensive bioinformatic analyses using R (version 3.6.3), Cytoscape (version 3.9.1), UALCAN, etc., were performed to study the clinicopathological characteristics, prognostic value, immune features, and functional mechanisms of the PHLDA family members in PAAD. Results: The PHLDA family members showed significantly elevated expression in PAAD compared with paracancerous or normal tissues. Their high expression or amplification were significantly correlated with worse clinicopathological characteristics and prognosis in PAAD patients. In addition, the role of the PHLDA family members in the immune regulation is diverse and complex. Mechanistically, TP53 mutations were significantly associated with the promoter methylation and expression levels of the PHLDA family members, which were activated in multiple oncogenic pathways, including the EMT, RAS/MAPK, and TSC/mTOR pathways. Moreover, we found that their expression levels were significantly correlated with the sensitivity of multiple traditional chemotherapeutic drugs and novel targeted MEK1/2 inhibitors. Conclusion: The PHLDA family members play an oncogenic role in the development of PAAD and might serve as new biomarkers or therapeutic targets.