PBK as a Potential Biomarker and Therapeutic Target for Metastatic Pheochromocytomas and Paragangliomas

BACKGROUND: Metastasis is the major determinant of prognosis in pheochromocytomas and paragangliomas (PPGLs), yet reliable biomarkers remain lacking. PDZ-binding kinase (PBK), a serine-threonine kinase of the MAPK kinase family, regulates mitosis and oncogenic signaling and has been implicated in tumorigenesis and progression in multiple malignancies. However, its role in PPGLs has not been explored. METHODS: Bioinformatic analyses of public transcriptomes identified a novel metastasis-related molecule, PBK, and investigated its correlation with clinical features and prognosis, with findings further validated in clinical PPGL cohorts. A PBK index, defined as the percentage of positive PBK staining, was evaluated for independent significance and performance for metastasis prediction in multivariate logistic regression models. In vitro assays were conducted on PC-12 cells to explore the function of PBK and potential mechanisms. RESULTS: Elevated PBK expression showed correlations with metastasis, higher Ki-67 labeling index, SDHB mutations, and shorter metastasis-free survival in both public datasets and clinical cohorts. After adjusting for established risk factors, the PBK index remained an independent predictor for metastasis (odds ratio: 1.40, P = .016). The PBK index ≥ 3% substantially improved predictive performance when combined with established predictors (area under the curve = 0.951). In vitro, PBK silencing significantly impaired PC-12 cell viability, accompanied by S phase arrest and upregulation of p53 and p21. PBK silencing also suppressed cell migration and invasion by downregulating matrix metalloproteinase 2/9, disrupting epithelial-mesenchymal transition and other oncogenic pathways, including the MAPK, Rap1, and TGF-β signaling. CONCLUSION: PBK serves as a novel metastasis-related biomarker and a promising therapeutic target in PPGLs. Incorporation of the PBK index into risk models may refine metastasis prediction.