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Investigating the Expression and Function of PPP2R1A in Hepatocellular Carcinoma: A Multi-Omics Analysis with in vitro Validation

Year: 2026

Type: article

Abstract: Background: Hepatocellular carcinoma (HCC) remains difficult to diagnose early and to treat effectively. Protein Phosphatase 2A Regulatory Subunit Aα ( PPP2R1A ), the scaffolding (Aα) subunit of the PP2A holoenzyme, is altered in several cancer types, but its expression pattern, functional significance, and translational relevance in HCC are incompletely understood. Methods: Public transcriptomic, single-cell, and spatial transcriptomic datasets (TCGA-LIHC, GTEx, GEO, ICGC-LIHC, HPA, TISCH2) and drug-sensitivity databases were integrated to characterize PPP2R1A expression and its associations with survival, biological pathways, and tumor immune infiltration in HCC. Functional effects of PPP2R1A knockdown were assessed in Huh7 cells by RT-qPCR, CCK-8, Transwell, flow-cytometric cell-cycle, and β-galactosidase assays. Results: PPP2R1A was significantly overexpressed in HCC tissues relative to normal liver and was also elevated across several other cancer types. High PPP2R1A expression was associated with shorter overall and disease-specific survival in Kaplan–Meier analysis, although it was not an independent prognostic factor after multivariate adjustment (hazard ratio [HR] = 1.051, p = 0.789). PPP2R1A expression correlated positively with transcriptional programs related to cell cycle, MYC, EGFR, MAPK, and WNT signaling, and negatively with p53 pathway activity. At single-cell and spatial resolution, PPP2R1A was enriched in malignant cells and in tumor regions, and its expression correlated with the abundance of several computationally inferred immune cell populations. PPP2R1A knockdown in Huh7 cells reduced proliferation and invasion, induced G2-phase arrest, and decreased MYC, CDK1, and CCNB1 mRNA expression without inducing senescence. Drug-sensitivity screens suggested candidate agents, such as AT-7519, that warrant further investigation in PPP2R1A -high HCC. Conclusion: PPP2R1A is consistently overexpressed in HCC and contributes to the malignant phenotype at least partly through cell-cycle regulation. These findings are hypothesis-generating, and the potential diagnostic, prognostic, or therapeutic value of PPP2R1A in HCC requires dedicated prospective and functional validation. Keywords: hepatocellular carcinoma, PPP2R1A, PP2A, multi-omics analysis, cell-cycle regulation

Source: Journal of Hepatocellular Carcinoma

DOI: 10.2147/jhc.s641006