Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C–C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.
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Acknowledgements We thank Dr. Joonbeom Bae, Dr. Chang-Yong Choi, and Sang-Pil Choi from Korea University for their advice on experiments related to immune cells, and Ock Ran Kim (Seoul National University Hospital) for advice on histological analyses. This work was supported by grants to Hyunggee Kim from the National Research Foundation (NRF) (2015R1A5A1009024 and 2017M3A9A8031425), Next-Generation Biogreen 21 Program (PJ01107701), Brain Korea 21 Plus, and Korea University, from the Korea Health Industry Development Institute (KHIDI) (HI14C3418) to D-HN, and from the NRF (2016M3C7A1913844) to SHK. The bio-specimens for this study were provided by Samsung Medical Center Biobank.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology