Prevalence of germline MSH3 polymorphisms in ulcerative colitis and early-onset colorectal cancer patients that

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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer

Published on: July 28, 2010

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Stephanie S Tseng-Rogenski1, Anand Venugopal1, Minoru Koi1,2

  • 1Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, United States.

Human Molecular Genetics
|November 27, 2025
PubMed

Insights

The DNA repair protein MSH3 relocates from the nucleus to the cytosol upon IL-6 signaling, increasing colorectal cancer aggressiveness. A specific MSH3 polymorphism exacerbates this shift, impacting DNA repair and cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The DNA mismatch repair protein MSH3 plays a crucial role in maintaining genomic stability.
  • IL-6 signaling is implicated in various inflammatory conditions and cancer progression.
  • MSH3's nuclear-cytosolic localization is critical for its function and regulation.

Purpose of the Study:

  • To investigate the effect of IL-6 signaling on MSH3 localization and its functional consequences in colorectal cancer (CRC).
  • To examine the role of a specific MSH3 polymorphism (Δ27bpMSH3) in altering MSH3 localization and its association with CRC and ulcerative colitis (UC).
  • To elucidate the molecular mechanism linking inflammation, MSH3 stability, and DNA repair dysfunction.

Main Methods:

  • Analysis of MSH3 localization in response to IL-6 signaling in cell models.
  • Genotyping of MSH3 NLS polymorphisms in patient cohorts (UC, early-onset CRC, late-onset CRC, and controls).
  • Co-immunoprecipitation assays to study protein-protein interactions between MSH3, MSH2, and NEMO/IKKγ.

Main Results:

  • IL-6 signaling induces MSH3 translocation from the nucleus to the cytosol, impairing its DNA repair function.
  • A MSH3 NLS polymorphism (Δ27bpMSH3) leads to enhanced cytosolic accumulation upon IL-6 stimulation.
  • MSH3 NLS polymorphisms were found at higher frequencies in UC and early-onset CRC patients compared to controls, and in advanced CRC stages.
  • IL-6 promotes MSH3 stabilization in the cytosol by facilitating its binding to the NEMO/IKKγ complex, independent of MSH2.

Conclusions:

  • IL-6-induced MSH3 cytosolic shift, particularly in the presence of specific polymorphisms, contributes to colorectal cancer aggressiveness and metastatic potential.
  • The study identifies a novel link between inflammatory signaling (IL-6), DNA repair protein stability (MSH3), and cancer development.
  • Targeting MSH3 localization or stability could represent a therapeutic strategy for inflammation-associated colorectal cancers.
Keywords:
IKKγMSH3NEMONFκBcolorectal cancerinflammationinterleukin-6microsatellite instabilitymismatch repairoxidative stressreactive oxygen speciesulcerative colitis

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