Proteomics reveals protein phosphatase 1γ as a biomarker associated with Hippo signal pathway in glioma

Hub proteins related with Hippo signal pathway in glioma were investigated using proteomics methods (Tandem Mass Tag, TMT) to determine the differentially expressed proteins in glioblastoma (GBM). Ingenuity Pathway Analysis (IPA) was performed to complement proteomic findings by identifying the top canonical pathways as well as to suggest novel proteins for the targeted therapy of glioma. A total of 222 formalin-fixed paraffin -embedded (FFPE) glioma tissue samples were used to verify the expression of protein phosphatase 1 gamma (PP1 gamma), Yes-associated protein 1 (YAP1), and SOX2 via immunohistochemistry. Bioinformatics analysis revealed these proteins as crucial in the Hippo signaling pathway in GBM. Spearman correlation was performed to analyze the relationship of these three proteins, and survival analysis was conducted to investigate their effects on prognosis. Among the 5808 proteins identified by TMT with the standard of P-value 0.05 and fold change (FC) of 1.2 or <0.83, 1398 upregulated and 1060 downregulated differentially expressed proteins were found. IPA revealed that the Hippo signaling was activated in the top 10 canonical pathways, and PP1 gamma was activated in the Hippo signaling. Immunohistochemistry analysis indicated that PP1 gamma, YAP1, and SOX2 were highly and positively expressed in glioma. PP1 gamma expression was related to WHO grade (p = 0.003) and ki-67 expression (p = 0.012). Low PP1 gamma expression was associated with IDH1-mut in low-grade glioma (LGG; WHO grades II and III) (p = 0.037). PP1 gamma was positively correlated with YAP1 (p < 0.001; r = 0.259) and SOX2 (p = 0.009; r = 0.175). In survival analysis, age, WHO grade, ki-67 expression, and PP1 gamma expression independently predicted a short OS in total cohort (p < 0.05). Therefore, PP1 gamma is a hub protein associated with Hippo signal pathway in glioma, and its expression indicates poor prognosis in patients with glioma. Therefore, PP1 gamma may be a promising prognostic biomarker and a therapeutic target in glioma.