Neutrophil microRNAs promote genomic instability and carcinogenesis in inflamed intestinal tissue

Project: Research project

Project Details

Description

Inflammation and tissue damage are tightly linked to cancer. While immune cells and particularly PMNs, can drive tissue inflammation, their contribution to tumorigenesis is not clear. Patients with IBD, where en masse infiltration of the intestinal mucosa by PMNs leads to severe tissue injury and aberrant inflammation, are at a significantly higher risk of developing colorectal cancer (CRC) 1, suggesting a role for PMN-mediated inflammation in tumorigenesis. Our preliminary data suggest that tissue-infiltrating PMNs release membrane-derived microparticles (MPs) that effectively shuttle miRNAs to surrounding cells, leading to miRNA-dependent inhibition of the repair of DNA double-stranded breaks (DSB) by homologous recombination (HR, a primary DNA repair mechanism in healthy tissue2). The resulting accumulation of DSBs promote genomic instability (characterized by aneuploidy3-5, chromosomal aberrations6-8 and mutagenesis9,10), leading to carcinogenesis. Importantly, mutagenic inactivation of key tumor suppressor genes and cellular transformation can result from HR inhibition and paralleled upregulation of error-prone DSB repair by non-homologous end joining (NHEJ)7. Thus, in inflamed intestinal tissue, PMNs may shift the balance of cellular renewal and tissue homeostasis by promoting genomic instability, leading to increased mutagenesis, transformation and tumorigenesis.
StatusFinished
Effective start/end date9/1/178/31/18

Funding

  • Northwestern Memorial Hospital (Agmt 10/24/17)
  • Digestive Health Foundation (Agmt 10/24/17)

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