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MTH1 suppression enhances the stemness of MCF7 through upregulation of STAT3

Jin Li1, Zi-Hui Wang2, Ya-Min Dang2

  • 1The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.

Free Radical Biology & Medicine
|July 9, 2022
PubMed

Insights

MTH1 inhibition boosts breast cancer stemness by increasing cancer stem cell populations and promoting tumor-initiating properties. This study reveals MTH1 suppression enhances stem cell markers and STAT3 phosphorylation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • MTH1 protein sanitizes the damaged nucleotide pool.
  • MTH1 inhibitors target rapidly proliferating tumor cells.
  • The impact of MTH1 inhibition on breast cancer stemness remains uninvestigated.

Purpose of the Study:

  • To investigate the effect of MTH1 suppression on breast cancer stemness.
  • To determine if MTH1 depletion influences cancer stem cell populations and properties.

Main Methods:

  • Stable MTH1-depleted breast cancer cell lines (MCF7, T47D) were constructed.
  • Flow cytometry assessed CD44+/CD24-/low subpopulations.
  • Tumorsphere formation assays evaluated stemness.
  • RNA expression profiling, RT-qPCR, and Western blotting analyzed gene and protein expression (Sox2, Oct4, Nanog, p-STAT3).
  • GSEA identified signaling pathways.

Main Results:

  • MTH1 suppression increased CD44+/CD24-/low subpopulations and tumorsphere formation.
  • Upregulation of stem cell transcription factors (Sox2, Oct4, Nanog) was observed.
  • MTH1 knockdown led to increased phosphorylated STAT3 (Tyr705).
  • 8-oxoGTP, not 8-oxo-dGTP, significantly increased STAT3 phosphorylation.

Conclusions:

  • MTH1 inhibition promotes breast cancer stemness.
  • MTH1 suppression increases the proportion of breast cancer stem cells (BCSCs).
  • The study elucidates a novel mechanism involving 8-oxoGTP and STAT3 phosphorylation in MTH1-mediated stemness.
Keywords:
BCSCsMCF7MTH1STAT3Stemness

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