TP53 gain-of-function mutation promotes inflammation in glioblastoma

Seok Won Ham, Hee Young Jeon, Xiong Jin, Eun Jung Kim, Jun Kyum Kim, Yong Jae Shin, Yeri Lee, Se Hoon Kim, Seon Yong Lee, Sunyoung Seo, Min Gi Park, Hye Mi Kim, Do Hyun Nam, Hyunggee Kim

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24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - 2018 May 21

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Ham, S. W., Jeon, H. Y., Jin, X., Kim, E. J., Kim, J. K., Shin, Y. J., Lee, Y., Kim, S. H., Lee, S. Y., Seo, S., Park, M. G., Kim, H. M., Nam, D. H., & Kim, H. (Accepted/In press). TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death and Differentiation, 1-17. https://doi.org/10.1038/s41418-018-0126-3