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Published on: August 4, 2019

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Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome

Yao Zhang1, Ye Hu1,2, Jing-Yuan Fang1

  • 1State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China.

Oncotarget
|February 4, 2016
PubMed

Insights

Mutant p53 (mutp53) gain-of-function involves microRNAs (miRNAs). A mutp53-regulated miRNA signature predicts outcomes in gastric, breast, and liver cancers, revealing a novel oncogenic mechanism.

Area of Science:

  • Molecular oncology
  • Cancer genomics
  • Non-coding RNA research

Background:

  • Missense mutations in p53 impair tumor suppression and confer oncogenic gain-of-function (GOF).
  • The molecular mechanisms underlying mutp53 GOF, particularly the role of non-coding genes like microRNAs, remain incompletely understood.

Purpose of the Study:

  • To identify the microRNA expression profile regulated by mutant p53 (mutp53) at Arg282.
  • To investigate the prognostic significance of mutp53-regulated microRNAs in various human cancers.

Main Methods:

  • Controlled microarray experiments to profile microRNAome associated with mutp53 Arg282.
  • Non-negative matrix factorization (NMF) model to analyze microRNA signatures and patient outcomes.
  • Kaplan-Meier survival analysis and miRPath pathway analysis.

Main Results:

  • Mutant p53 predominantly represses microRNA expression, with 183 downregulated and 12 upregulated miRNAs identified.
  • A mutp53-regulated miRNA signature significantly predicted disease-free survival in gastric cancer (P = 0.013).
  • This signature also showed prognostic value in breast (P = 0.024) and hepatocellular cancers (P = 0.012), unlike models based on all miRNAs.

Conclusions:

  • Mutant p53 Arg282 exerts a predominant repressive effect on microRNA expression.
  • A specific mutp53-associated miRNA signature holds significant prognostic potential across multiple cancer types.
  • These findings suggest a microRNA-mediated mechanism contributing to mutp53 GOF and cancer progression.
Keywords:
cancer prognosismiRNAmutationnon-negative matrix factorizationp53

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