FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis
Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhea...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9730 |
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| author | Jenisha Ghimire Rida Iftikhar Harrison M. Penrose Patricia Snarski Emmanuelle Ruiz Suzana D. Savkovic |
| author_facet | Jenisha Ghimire Rida Iftikhar Harrison M. Penrose Patricia Snarski Emmanuelle Ruiz Suzana D. Savkovic |
| author_sort | Jenisha Ghimire |
| collection | DOAJ |
| description | Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs’ coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3<sub>389</sub>) separated transcriptomes of affected tissue in IBD (<i>p</i> = 0.00018) and colon cancer (<i>p</i> = 0.0037) from control. Increased PMN-FOXO3<sub>389</sub> presence predicted colon cancer invasion (lymphovascular <i>p</i> = 0.015; vascular <i>p</i> = 0.046; perineural <i>p</i> = 0.03) and poor survival. Validated DEGs from PMN-FOXO3<sub>389</sub> (<i>P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7</i>) are involved in metabolism, inflammation, and tumorigenesis (<i>p</i> < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology. |
| first_indexed | 2024-03-11T03:04:49Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:04:49Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9025387fd6c4439aa9ed162655b02fa02023-11-18T08:03:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-012411973010.3390/ijms24119730FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and TumorigenesisJenisha Ghimire0Rida Iftikhar1Harrison M. Penrose2Patricia Snarski3Emmanuelle Ruiz4Suzana D. Savkovic5Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USADepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USADepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USADepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USADepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USADepartment of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USAInflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs’ coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3<sub>389</sub>) separated transcriptomes of affected tissue in IBD (<i>p</i> = 0.00018) and colon cancer (<i>p</i> = 0.0037) from control. Increased PMN-FOXO3<sub>389</sub> presence predicted colon cancer invasion (lymphovascular <i>p</i> = 0.015; vascular <i>p</i> = 0.046; perineural <i>p</i> = 0.03) and poor survival. Validated DEGs from PMN-FOXO3<sub>389</sub> (<i>P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7</i>) are involved in metabolism, inflammation, and tumorigenesis (<i>p</i> < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology.https://www.mdpi.com/1422-0067/24/11/9730IBDcolon cancerPMNsLDsFOXO3 |
| spellingShingle | Jenisha Ghimire Rida Iftikhar Harrison M. Penrose Patricia Snarski Emmanuelle Ruiz Suzana D. Savkovic FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis International Journal of Molecular Sciences IBD colon cancer PMNs LDs FOXO3 |
| title | FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis |
| title_full | FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis |
| title_fullStr | FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis |
| title_full_unstemmed | FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis |
| title_short | FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis |
| title_sort | foxo3 deficiency in neutrophils drives colonic inflammation and tumorigenesis |
| topic | IBD colon cancer PMNs LDs FOXO3 |
| url | https://www.mdpi.com/1422-0067/24/11/9730 |
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