The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression

Authors

Cristabelle De Souza, University of California, DavisFollow
Jill A. Madden, The Manton Center for Orphan Disease Research and The Division of Genetics and GenomicsFollow
Dennis Minn, University of Massachusetts AmherstFollow
Vigneshwari Easwar Kumar, University of California, DavisFollow
Dennia J. Montoya, University of California, DavisFollow
Roshni Nambiar, University of California, DavisFollow
Zheng Zhu, University of California, DavisFollow
Wen-Wu Xiao, University of California, DavisFollow
Neeki Tahmassebi, University of California, DavisFollow
Harikumara Kathi, University of California, DavisFollow
Nina Nelson, University of California, DavisFollow
Anthony N. Karnezis, University of California, DavisFollow
Jeremy Chien, University of California, DavisFollow

Publication Date

2020

Journal or Book Title

International Journal of Molecular Sciences

Abstract

High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread TP53 mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP (rs1042522) in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties. Most importantly, RNA sequencing studies identified CXCL1 a critical factor that is differentially affected by P72R SNP in R248Q and R248W mutants and is responsible for differences in cellular morphology and functional properties observed in these p53 mutants. We show that the mutants with the P72 SNP promote a reversion of the EMT phenotype to epithelial characteristics, whereas its R72 counterpart promotes a mesenchymal transition via the chemokine CXCL1. These studies reveal a new role of the P72R SNP in modulating the neomorphic properties of p53 mutants via CXCL1, which has significant implications for tumor invasion and metastasis.

DOI

https://doi.org/10.3390/ijms21218025

Volume

21

Issue

21

License

UMass Amherst Open Access Policy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Souza, Cristabelle De; Madden, Jill A.; Minn, Dennis; Kumar, Vigneshwari Easwar; Montoya, Dennia J.; Nambiar, Roshni; Zhu, Zheng; Xiao, Wen-Wu; Tahmassebi, Neeki; Kathi, Harikumara; Nelson, Nina; Karnezis, Anthony N.; and Chien, Jeremy, "The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression" (2020). International Journal of Molecular Sciences. 1351.
https://doi.org/10.3390/ijms21218025