ArticleCellular and molecular gastroenterology and hepatology2019
Loss of Forkhead Box O3 Facilitates Inflammatory Colon Cancer: Transcriptome Profiling of the Immune Landscape and Novel Targets.
Article in Cellular and molecular gastroenterology and hepatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 31 citations in OpenAlex.
- Regulation of Inducible Nitric Oxide Synthase (NOS2) Expression in Healthy and Inflamed Bowel: A Narrative Review.International journal of molecular sciences · 2026Review
- FOXO3: at the crossroads of metabolic, inflammatory, and tumorigenic remodeling in the colon.American journal of physiology. Gastrointestinal and liver physiology · 2024Review
- MicroRNAs-associated with FOXO3 in cellular senescence and other stress responses.Biogerontology · 2024Review
- Genome-Wide Association Studies of Diarrhea Frequency and Duration in the First Year of Life in Bangladeshi Infants.The Journal of infectious diseases · 2023Article
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- FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis.International journal of molecular sciences · 2023Article
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- Sialyltransferases and Neuraminidases: Potential Targets for Cancer Treatment.Diseases (Basel, Switzerland) · 2022Review
- Review
- FOXO3 Expression in Macrophages Is Lowered by a High-Fat Diet and Regulates Colonic Inflammation and Tumorigenesis.Metabolites · 2022Article
- FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.Aging and cancer · 2021Article
- Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity.Oncogenesis · 2021Article
- Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.Cell & bioscience · 2021Review
- Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/βCancer communications (London, England) · 2021Article
- S1P Lyase Regulates Intestinal Stem Cell Quiescence via Ki-67 and FOXO3.International journal of molecular sciences · 2021Article
- FOXO3 is a latent tumor suppressor for FOXO3-positive and cytoplasmic-type gastric cancer cells.Oncogene · 2021Article
- Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.Nature communications · 2021Article
- The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology.Frontiers in immunology · 2021Review
- Metformin Attenuates ROSFrontiers in immunology · 2021Article
- Molecular modulation of autophagy: New venture to target resistant cancer stem cells.World journal of stem cells · 2020Review
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsDiminished forkhead box O3 (FOXO3) function drives inflammation and cancer growth; however, mechanisms fostering these pathobiologies are unclear. Here, we aimed to identify in colon loss of FOXO3-dependent cellular and molecular changes that facilitate inflammation-mediated tumor growth.
methodsFOXO3 knockout (KO) and wild-type (WT) mice were used in the AOM/DSS model of inflammation-mediated colon cancer. Bioinformatics were used for profiling of mRNA sequencing data from human and mouse colon and tumors; specific targets were validated in human colon cancer cells (shFOXO3).
resultsIn mice, FOXO3 deficiency led to significantly elevated colonic tumor burden (incidence and size) compared with WT (P < .05). In FOXO3 KO colon, activated molecular pathways overlapped with those associated with mouse and human colonic inflammation and cancer, especially human colonic tumors with inflammatory microsatellite instability (false discovery rate < 0.05). FOXO3 KO colon, similar to tumors, had increased neutrophils, macrophages, B cells, T cells, and decreased natural killer cells (false discovery rate < 0.05). Moreover, in KO colon differentially expressed transcripts were linked to activation of inflammatory nuclear factor kappa B, tumorigenic cMyc, and bacterial Toll-like receptor signaling. Among differentially expressed transcripts, we validated altered expression of integrin subunit alpha 2 (ITGA2), ADAM metallopeptidase with thrombospondin type 1 motif 12, and ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5 in mouse WT and FOXO3 KO colon and tumors (P < .05). Similarly, their altered expression was found in human inflammatory bowel disease and colon cancer tissues and linked to poor patient survival. Ultimately, in human colon cancer cells, FOXO3 knockdown (shFOXO3) led to significantly increased ITGA2, and silencing ITGA2 (siRNA) alone diminished cell growth.
conclusionsWe identified the loss of FOXO3-mediated immune landscape, pathways, and transcripts that could serve as biomarkers and new targets for inflammatory colon cancer treatment.
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