Role of PPP2R2B as a Promising Epigenetic and Signaling Modulator in Malignant Pleural Mesothelioma: In silico and In Vitro Profiling

PPP2R2B, the regulatory B subunit of protein phosphatase 2A, plays a crucial role in key phosphorylation-dependent signaling cascades in cancer. However, its exact function in Malignant Mesothelioma (MM) pathogenesis remains unexplored. We integrated multi-omic computational analyses of public MM datasets with preclinical in vitro investigation. In silico analyses evaluated transcriptomic and DNA methylation profiles, tumor immune infiltration, and drug sensitivity. In vitro silencing of PPP2R2B in MM cell lines (IST-MES2, MSTO-211H) and healthy controls (HMC) aimed to evaluate cell viability and transcriptional changes in apoptotic and inflammatory pathways. In silico analysis showed that PPP2R2B (mRNA expression) differentiated clinical stages and histological subtypes. Overall survival and PPP2R2B expression were negatively correlated with DNA methylation at N-Shore regions, with probe cg22642777 discriminating biphasic from epithelioid histotypes. Tumour immune infiltration was found to be directly correlated with the expression of PPP2R2B. OncoPredict predicted a correlation between PPP2R2B and sensitivity to targeted therapies in MM, such as JAK and PERK inhibitors. In vitro, PPP2R2B knockdown impaired cell viability in MSTO-211H and modulated the expression of apoptotic and inflammatory genes. These findings highlight PPP2R2B as a promising candidate for further investigation as a biomarker for histological/staging differentiation, immune profiling, and prognostic methylation stratification in MM.