دورية أكاديمية
أعرض في EDS

Disruption of hypoxia-inducible factor-2α in neutrophils decreases colitis-associated colon cancer.

التفاصيل البيبلوغرافية
العنوان: Disruption of hypoxia-inducible factor-2α in neutrophils decreases colitis-associated colon cancer.
المؤلفون: Singhal R; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States., Kotla NK; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States., Solanki S; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States., Huang W; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States.; Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, United States., Bell HN; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States., El-Derany MO; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States.; Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt., Castillo C; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States., Shah YM; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States.; Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
المصدر: American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2024 Jan 01; Vol. 326 (1), pp. G53-G66. Date of Electronic Publication: 2023 Nov 07.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD : American Physiological Society
مواضيع طبية MeSH: Colitis-Associated Neoplasms*/genetics , Colonic Neoplasms*/genetics , Colonic Neoplasms*/pathology, Animals ; Mice ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Body Weight ; Carcinogenesis/pathology ; Cell Transformation, Neoplastic/pathology ; Cytokines ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Inflammation ; Neutrophils ; Tumor Microenvironment
مستخلص: Neutrophils are abundant immune cells in the colon tumor microenvironment. Studies have shown that neutrophils are recruited into hypoxic foci in colon cancer. However, the impact of hypoxia signaling on neutrophil function and its involvement in colon tumorigenesis remain unclear. To address this, we generated mice with a deletion of hypoxia-inducible factor (HIF)-1α or HIF-2α in neutrophils driven by the MRP8Cre ( HIF-1α ΔNeu ) or ( HIF-2α ΔNeu ) and littermate controls. In an azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colon cancer, the disruption of neutrophils-HIF-1α did not result in any significant changes in body weight, colon length, tumor size, proliferation, or burden. However, the disruption of HIF-2α in neutrophils led to a slight increase in body weight, a significant decrease in the number of tumors, and a reduction in tumor size and volume compared with their littermate controls. Histological analysis of colon tissue from mice with HIF-2α-deficient neutrophils revealed notable reductions in proliferation as compared with control mice. In addition, we observed reduced levels of proinflammatory cytokines, such as TNF-α and IL-1β, in neutrophil-specific HIF-2α-deficient mice in both the tumor tissue as well as the neutrophils. Importantly, it is worth noting that the reduced tumorigenesis associated with HIF-2α deficiency in neutrophils was not evident in already established syngeneic tumors or a DSS-induced inflammation model, indicating a potential role of HIF-2α specifically in colon tumorigenesis. In conclusion, we found that the loss of neutrophil-specific HIF-2α slows colon tumor growth and progression by reducing the levels of inflammatory mediators. NEW & NOTEWORTHY Despite the importance of hypoxia and neutrophils in colorectal cancer (CRC), the contribution of neutrophil-specific HIFs to colon tumorigenesis is not known. We describe that neutrophil HIF-1α has no impact on colon cancer, whereas neutrophil HIF-2α loss reduces CRC growth by decreasing proinflammatory and immunosuppressive cytokines. Furthermore, neutrophil HIF-2α does not reduce preestablished tumor growth or inflammation-induced colitis. The present study offers novel potential of neutrophil HIF-2α as a therapeutic target in CRC.
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معلومات مُعتمدة: R01 CA148828 United States CA NCI NIH HHS; R01 DK095201 United States DK NIDDK NIH HHS; P30 CA046592 United States CA NCI NIH HHS; F30 CA257292 United States CA NCI NIH HHS; P30 DK034933 United States DK NIDDK NIH HHS; R01 CA245546 United States CA NCI NIH HHS; F30 DK131851 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: HIF-2α; colitis; colorectal cancer; inflammation; neutrophil
المشرفين على المادة: 0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Cytokines)
1B37H0967P (endothelial PAS domain-containing protein 1)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
تواريخ الأحداث: Date Created: 20231107 Date Completed: 20240108 Latest Revision: 20240731
رمز التحديث: 20240731
مُعرف محوري في PubMed: PMC11208019
DOI: 10.1152/ajpgi.00182.2023
PMID: 37933447
قاعدة البيانات: MEDLINE
الوصف
تدمد:1522-1547
DOI:10.1152/ajpgi.00182.2023