Article the p72r polymorphism in r248q/w p53 mutants modifies the mutant effect on epithelial to mesenchymal transition phenotype and cell invasion via cxcl1 expression

Cristabelle De Souza, Jill A. Madden, Dennis Minn, Vigneshwari Easwar Kumar, Dennis J. Montoya, Roshni Nambiar, Zheng Zhu, Wen Wu Xiao, Neeki Tahmassebi, Harikumara Kathi, Nina Nelson, Anthony Karnezis, Jeremy Chien

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number8025
Pages (from-to)1-18
Number of pages18
JournalInternational journal of molecular sciences
Volume21
Issue number21
DOIs
StatePublished - Nov 1 2020

Keywords

  • CXCL1
  • Mutant p53
  • Ovarian cancer
  • P72R polymorphism
  • Tumor invasion

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Article the p72r polymorphism in r248q/w p53 mutants modifies the mutant effect on epithelial to mesenchymal transition phenotype and cell invasion via cxcl1 expression'. Together they form a unique fingerprint.

Cite this