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SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction

Ying Feng1, Ningxin Zhu1, Karan Bedi2

  • 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America.

The Journal of Clinical Investigation
|April 3, 2025
PubMed

Insights

Loss of SOX9 gene expression promotes colorectal cancer (CRC) progression and invasion. Reduced SOX9 is linked to poor prognosis, increased metastasis, and epithelial-mesenchymal transition (EMT) in CRC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The Wnt/β-catenin pathway is crucial in cell regulation and is frequently dysregulated in colorectal cancer (CRC) due to APC mutations.
  • SOX9, a transcription factor regulated by Wnt/β-catenin, plays a role in cell differentiation and may influence tumor progression.

Purpose of the Study:

  • To investigate the role of SOX9 inactivation in colorectal cancer (CRC) biology.
  • To determine the impact of SOX9 loss on tumor invasiveness, metastasis, and patient prognosis.

Main Methods:

  • Utilized mouse models of colorectal cancer (CRC) with combined genetic defects (Apc, Sox9, Kras, Trp53).
  • Analyzed SOX9 protein and gene expression in human CRC patient cohorts (n=171 and n=376).
  • Assessed correlations between SOX9 expression, tumor grade, survival, lymph node involvement, and promoter methylation.

Main Results:

  • Combined Apc and Sox9 inactivation in mice led to more invasive tumors with epithelial-mesenchymal transition (EMT) and SOX2 upregulation.
  • Sox9 inactivation in another mouse CRC model promoted SOX2 induction and distant metastases.
  • Loss of SOX9 protein was observed in ~20% of human CRCs, correlating with higher tumor grade.
  • Low SOX9 gene expression in patients was linked to poor survival, earlier diagnosis, and increased lymph node metastasis.
  • SOX9 expression reduction in human CRCs was associated with promoter methylation and prominent EMT pathway gene expression changes.

Conclusions:

  • SOX9 exhibits tumor suppressor functions in colorectal cancer (CRC).
  • Loss of SOX9 can promote CRC progression, invasion, and poor prognosis.
  • SOX9 downregulation may enhance EMT and stem cell phenotypes, contributing to CRC advancement.
Keywords:
Colorectal cancerGastroenterologyGeneticsMouse modelsOncologyTumor suppressors

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