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Published on: April 18, 2025

Hypoxia induced DNMT3B and SHP2 signaling promoted HCC via suppressing P53 and MYH11 protein expression

Hongxun Ruan1, Wei Huang1, Yanle Fang1

  • 1The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Frontiers in Oncology
|June 30, 2026
PubMed
Abstract

Insights

CBFβ-MYH11 suppresses hepatocellular carcinoma (HCC) by regulating the AKT/DNMT3B/SHP2 pathway in hypoxic conditions. This pathway modulation impacts P53 expression, hindering tumor progression and improving patient prognosis in HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) remains a significant global health challenge.
  • Hypoxia is a critical factor influencing HCC progression and treatment resistance.
  • Understanding the molecular mechanisms underlying HCC suppression is crucial for developing novel therapies.

Purpose of the Study:

  • To investigate the role of CBFβ-MYH11 in suppressing hepatocellular carcinoma under hypoxic conditions.
  • To elucidate the molecular pathways regulated by CBFβ-MYH11 in HCC.
  • To evaluate the prognostic value of a composite molecular axis score in HCC patients.

Main Methods:

  • Analysis of three independent HCC cohorts (TCGA-LIHC, GSE14520, ICGC LIRI-JP).
  • Gene correlation, hypoxia-based expression, and prognostic stratification analyses.
  • Establishment of a composite HIF1A/AKT/SHP2/DNMT3B/P53/MYH11 axis score.
  • In vivo studies using nude mouse models with quantitative assessments of tumor characteristics and molecular markers.
  • In vitro assays including scratch and invasion assays, Western blot, and immunoprecipitation.

Main Results:

  • A negative correlation between DNMT3B and MYH11 was observed, with high HIF1A correlating with DNMT3B upregulation and MYH11 silencing.
  • A high composite axis score was associated with shorter overall survival and identified as an independent adverse prognostic factor.
  • CBFβ-MYH11 overexpression in HCC cells reduced tumor volume, vascular density, invasion, and migration.
  • CBFβ-MYH11 modulated the expression of key genes including HIF1α, VEGF, MMP2, and RUNX1.
  • AKT inhibition under hypoxia significantly increased P53 and CBFβ-MYH11 expression, normalizing DNMT3B, HIF1α, and MMP2 levels.

Conclusions:

  • CBFβ-MYH11 plays a crucial role in suppressing HCC progression in hypoxic environments.
  • The AKT/DNMT3B/SHP2 pathway is a key target regulated by CBFβ-MYH11 to modulate P53 expression.
  • The findings highlight CBFβ-MYH11 as a potential therapeutic target for HCC, particularly in hypoxic tumors.
Keywords:
AKTCBFβ-MYH11DNMT3BHIF1αSHP2angiogenesishepatocellular carcinomahypoxia

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