The dual role of PCDH9 in tumors, neurological and developmental diseases.

Protocadherin 9 (PCDH9), a member of the δ1-protocadherin family, plays a crucial role in regulating cell polarity, tumor suppression, and neurodevelopment. This is achieved through its dual functions of extracellular calcium-dependent adhesion and intracellular signal transduction. In the context of tumors, PCDH9 inhibits epithelial-mesenchymal transition and cell cycle progression in various cancer types, such as liver cancer and glioma, via the GSK-3β/Snail1 axis. However, in Group 4 medulloblastoma, functionally acquired mutations in PCDH9 drive cancer development through the non-classical Wnt pathway. The expression of PCDH9 is tightly regulated by microRNAs (e.g., miR-589-3p) and epigenetic silencing mechanisms. Within the nervous system, PCDH9 deficiency gives rise to abnormal autistic behaviors, disruptions in hippocampal migration, and abnormal cerebrospinal fluid circulation. Its potential for clinical translation is evident in several areas, including the use of methylation as a prognostic marker, β-eucalyptol-mediated therapy to restore PCDH9, and strategies that target the piRNA-PI3K/AKT axis. Looking ahead, it is essential to conduct in-depth analyses of its evolutionary adaptability and formulate strategies targeting the adherent-signal interface.