PMNs promote Non‐Homologous End‐Joining (NHEJ)‐mediated survival of colorectal cancer cells in inflammatory setting

• DOI: 10.1096/fasebj.2019.33.1_supplement.368.11
• Publication Date: 2021-06-22T00:58:35Z
• Authors: Triet M Bui; Hannah Wiesolek; Veronika Butin‐Is...; Ronen Sumagin
• Keywords: Camptothecin

Exacerbated Inflammation that can be driven by neutrophil (PMN) infiltration is one of the major risk factors for development and progression colorectal cancer (CRC). Using a biopsy‐based acute‐injury model, we previously showed miRNAs derived from PMN‐ m icro p articles (MPs) inhibit H omologous R ecombination (HR), leading to accumulation D ouble‐ S trand B reaks (DSBs). These observations led us investigate effects long‐term exposure intestinal epithelial cells HCT116 PMNs PMN‐MPs. Consistent with PMN‐MP treatment HR suppression concomitant DSBs, increased aneuploidy apoptosis within 7 population doublings (PD7). With continued inhibition PMN‐MPs, PD12 observed an upregulation N on‐ E nd‐ J oining (NHEJ) activity. Importantly, DSBs cell were also significantly decreased at PD12, despite elevated aneuploidy, suggesting PMN‐induced NHEJ activation promotes tumor survival aneuploidy. To test this in vivo , employed xenograft model conjunction antibody‐based PMN depletion strategy. vitro observations, inhibition, upregulation, apoptosis, confirmed PMN‐infiltrated (PMN+) tumors as compared PMN‐depleted (PMN−) tumors. examine whether indeed provide advantage help them overcome DSB accumulation, performed ex clonogenicity assay, where challenged DSB‐inducing agents Camptothecin (CMPT). PMN+ resistant CMPT able more efficiently re‐propagate parental cells, which underwent response CMPT‐induced genotoxic stress. Consistently, H2AX cycle regulatory genes ( p16INK4a p27Kip1 TP53 p21Cip1 ) was observed, indicating inefficient DNA Damage repair. As such, our findings define new role promoting CRC during carcinogenesis. Support or Funding Information This work supported grants National Institutes Health (NIH) DK101675, Digestive Foundation, Chicago Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant) American Society Ronen Sumagin. abstract Experimental Biology 2019 Meeting. There no full text article associated published The FASEB Journal .