NEUTROPHILS ALTER DSB REPAIR PATHWAY IN INFLAMED MUCOSA TO PROMOTE COLON CARCINOGENESIS

Autor: Triet Bui, Veronika Butin-Israeli, Stephen Hanauer, Julien Sebag, Ronen Sumagin
Rok vydání: 2021
Předmět:
Zdroj: Inflammatory Bowel Diseases. 27:S33-S33
ISSN: 1536-4844
1078-0998
DOI: 10.1093/ibd/izaa347.079
Popis: Due to exacerbated inflammation and recurring tissue injury patients with Inflammatory Bowel Disease (IBD) are at higher risk of developing colorectal cancer (CRC). Although, PMN infiltration of the intestinal mucosa is a hallmark of IBD, and is associated with tissue injury, the contribution of PMNs to CRC and more so to IBD associated CRC is not known. We recently showed that PMNs can acutely exacerbate tissue injury and promote genomic instability by promoting miR-23a and miR-155-dependent accumulation of double-strand breaks (DSBs) and inhibition of DSB-repair by homologous recombination (HR). We now demonstrate that in chronic gut inflammation and recurring epithelial injury, as seen in IBD, via similar miRNA-dependent mechanism, PMNs alter DNA damage responses (DDR) to promote CRC progression. In murine model of Colitis-associated CRC (Azoxymethane, AOM/Dextran sodium sulfate, DSS) and human CRC xenografts, intratumoral PMNs intriguingly, functional dualism, suppressing tumor onset, but promoting tumor cell survival and growth in progressive tumors. The observed PMN effects were mediated by persistent suppression of HR-mediated DSB repair. HR suppression by PMNs, initially resulted in elevated replication stress and increased tumor cell apoptosis, however, longer term, altered DDR transcriptional profile and facilitated the upregulation of DSB repair by non-homologous end-joining (NHEJ). NHEJ upregulation enhanced CRC progression and tumor cell survival. PMN depletion, CRSPER-mediated deletion of miR-155 responsive sequence in RAD51 (preserves HR activity) or inhibition of NHEJ by small molecule inhibitors increased tumor cell death and diminished tumor development. Collectively, our data define a novel link between PMN-mediated mucosal injury and colon carcinogenesis.
Databáze: OpenAIRE
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