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MEX3A Modulates PPARγ Pathway Activity and Colorectal Cancer Growth.

Ana R Silva1, Alexandre Coelho2, Vanessa Machado3

  • 1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine, University of Porto, Porto, Portugal.

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MEX3A protein promotes colorectal cancer growth and progression by downregulating PPARγ signaling. Reducing MEX3A in colorectal cancer models enhances tumor differentiation and chemotherapy sensitivity.

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Area of Science:

  • Molecular biology
  • Oncology
  • Gastroenterology

Background:

  • RNA-binding proteins (RBPs) regulate gene expression post-transcriptionally.
  • MEX3A maintains intestinal stem cell identity and epithelial renewal.
  • The role of MEX3A in colorectal cancer (CRC) requires further investigation.

Purpose of the Study:

  • To investigate the functional impact of MEX3A in colorectal cancer (CRC).
  • To explore MEX3A's role in tumor development and therapeutic response in CRC.

Main Methods:

  • MEX3A expression profiling in CRC mouse models and human CRC cases (n=172).
  • CRISPR/Cas9-mediated MEX3A knockout in patient-derived CRC tumoroids.
  • High-throughput HyperTRIBE technique to identify MEX3A RNA targets.
  • Analysis of peroxisome proliferator-activated receptor gamma (PPARγ) signaling.

Main Results:

  • Reduced tumor burden and area in mice with reduced Mex3a expression.
  • MEX3A overexpression in 85% of human CRC cases correlates with PPARγ downregulation.
  • MEX3A depletion in CRC tumoroids decreased LGR5, increased PPARγ, and enhanced sensitivity to FOLFOX chemotherapy.
  • HyperTRIBE identified direct interaction between MEX3A and PPARG transcripts.

Conclusions:

  • MEX3A promotes colorectal carcinogenesis by modulating PPARγ signaling.
  • MEX3A impacts CRC tumor development and response to chemotherapy.
  • Targeting MEX3A may offer a therapeutic strategy for colorectal cancer.