ACS Omega · 2 authors, 4 centres
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This study analyzed phosphoproteomic data from 159 hepatocellular carcinoma (HCC) patients and found that 28 protein phosphatase genes were upregulated and 3 were downregulated in tumor tissue. Elevated expression of CDC25C, PPP1R13L, and PPP1CA was significantly associated with worse overall and disease-free survival, suggesting these proteins could serve as prognostic biomarkers and therapeutic targets for HCC.
**Background:** Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Protein phosphorylation and dephosphorylation, regulated by kinases and phosphatases, are critical for cellular processes. While kinases are well-studied in cancer, the role of protein phosphatases in HCC is less understood. This study aimed to investigate the expression and prognostic significance of protein phosphatases in HCC using phosphoproteomic data.
**Methods:** The study analyzed publicly available phosphoproteomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database, comprising 159 HCC patients. A total of 11,547 phosphorylation sites associated with 4043 phosphoproteins were quantified. Differentially expressed phosphorylation sites between tumor and paired nontumor tissues were identified using a paired t-test with Benjamini-Hochberg false discovery rate correction (adjusted p < 0.05, fold change ≥ 1.5 or ≤ 0.667). Bioinformatics analyses included Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) network construction using STRING. Kaplan-Meier survival analysis and Cox regression were used to assess the association between gene expression and overall survival (OS) and disease-free survival (DFS).
**Key Results:** Among the 11,547 phosphorylation sites, 9994 were differentially expressed (8198 upregulated, 1796 downregulated) in tumor vs. nontumor tissue. Focusing on protein phosphatases, 105 phosphorylation sites (corresponding to 31 unique genes) showed significant changes: 28 genes were upregulated and 3 were downregulated. Key upregulated genes included PTPN1, CDC25C, DUSP9, PPP1R12A, PPP1CA, PPP1R13L, and PTEN. Downregulated genes were PTPN13, PPP1R12B, and PPP1R3E. KEGG pathway analysis of the 31 genes highlighted enrichment in insulin resistance, oocyte meiosis, oxytocin signaling, and vascular smooth muscle contraction pathways. GSEA identified proteoglycans in cancer, cGMP-PKG, and cAMP signaling pathways. The PPI network identified 15 hub genes, including PTPN1, CDC25C, and PPP1CA. Survival analysis showed that elevated expression of 10 genes (PTP1B, CDC25C, PTPN12, PTPRF, PTPRO, PPP1R12A, PPP1R13L, PPP2R5D, PPP1R37, and PPP1CA) was significantly associated with worse OS (p < 0.05). For example, CDC25C had a hazard ratio (HR) of 2 (p = 6.8 × 10⁻⁵) for OS and HR = 2 (p = 5.0 × 10⁻⁶) for DFS. PPP1CA had HR = 1.6 (p = 0.01) for OS. Immunohistochemistry from the Human Protein Atlas confirmed higher protein expression of several hub genes in HCC vs. normal liver tissue.
**Clinical Implications:** This study provides a comprehensive phosphoproteomic landscape of protein phosphatases in HCC. The identified dysregulated phosphatases, particularly CDC25C, PPP1R13L, and PPP1CA, represent potential diagnostic and prognostic biomarkers. Their elevated expression correlates with poor survival, suggesting they could be used to stratify patients and guide treatment decisions. Furthermore, these phosphatases may serve as novel therapeutic targets, as inhibitors for some (e.g., CDC25C) have not yet been explored in HCC. The findings underscore the importance of protein phosphatases in HCC progression and highlight avenues for future research into targeted therapies.