A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer
Background and Aims: Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer dev...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Gastro Hep Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S277257232200156X |
| _version_ | 1798022570900979712 |
|---|---|
| author | David W. Basta Mandy Vong Adolat Beshimova Brooke N. Nakamura Iulia Rusu Michael G. Kattah Ling Shao |
| author_facet | David W. Basta Mandy Vong Adolat Beshimova Brooke N. Nakamura Iulia Rusu Michael G. Kattah Ling Shao |
| author_sort | David W. Basta |
| collection | DOAJ |
| description | Background and Aims: Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer development. In this report, we investigate whether A20 also acts as a tumor suppressor in a model of colitis-associated cancer. Methods: Colitis and colitis-associated tumors were induced in wild-type and A20 intestinal epithelial cell-specific knockout (A20dIEC) mice using dextran sodium sulfate and azoxymethane. Clinicopathologic markers of inflammation were assessed in conjunction with colonic tumor burden. Gene expression analyses and immunohistochemistry were performed on colonic tissue and intestinal enteroids. Nitric oxide (NO) production and activity were assessed in whole colonic lysates and mouse embryonic fibroblasts. Results: A20dIEC mice develop larger tumors after treatment with dextran sodium sulfate and azoxymethane than wild-type mice. In addition to elevated markers of inflammation, A20dIEC mice have significantly enhanced expression of inducible nitric oxide synthase (iNOS), a well-known driver of neoplasia. Enhanced iNOS expression is associated with the formation of reactive nitrogen species and DNA damage. Loss of A20 also enhances NO-dependent cell death directly. Conclusion: Mechanistically, we propose that A20 normally restricts tumor necrosis factor–induced nuclear factor kappa B–dependent production of iNOS in intestinal epithelial cells, thereby protecting against colitis-associated tumorigenesis. We also propose that A20 plays a direct role in regulating NO-dependent cell death. |
| first_indexed | 2024-04-11T17:32:05Z |
| format | Article |
| id | doaj.art-3c9d21c9040843689582793516145867 |
| institution | Directory Open Access Journal |
| issn | 2772-5723 |
| language | English |
| last_indexed | 2024-04-11T17:32:05Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj.art-3c9d21c90408436895827935161458672022-12-22T04:11:59ZengElsevierGastro Hep Advances2772-57232023-01-012196107A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated CancerDavid W. Basta0Mandy Vong1Adolat Beshimova2Brooke N. Nakamura3Iulia Rusu4Michael G. Kattah5Ling Shao6Division of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaDivision of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaDivision of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaDivision of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaDivision of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaDivision of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaCorrespondence: Address correspondence to: Ling Shao, MD, PhD, Division of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Hoffman Medical Research 600, Los Angeles, California 90033.; Division of Gastroenterology and Liver Disease, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CaliforniaBackground and Aims: Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer development. In this report, we investigate whether A20 also acts as a tumor suppressor in a model of colitis-associated cancer. Methods: Colitis and colitis-associated tumors were induced in wild-type and A20 intestinal epithelial cell-specific knockout (A20dIEC) mice using dextran sodium sulfate and azoxymethane. Clinicopathologic markers of inflammation were assessed in conjunction with colonic tumor burden. Gene expression analyses and immunohistochemistry were performed on colonic tissue and intestinal enteroids. Nitric oxide (NO) production and activity were assessed in whole colonic lysates and mouse embryonic fibroblasts. Results: A20dIEC mice develop larger tumors after treatment with dextran sodium sulfate and azoxymethane than wild-type mice. In addition to elevated markers of inflammation, A20dIEC mice have significantly enhanced expression of inducible nitric oxide synthase (iNOS), a well-known driver of neoplasia. Enhanced iNOS expression is associated with the formation of reactive nitrogen species and DNA damage. Loss of A20 also enhances NO-dependent cell death directly. Conclusion: Mechanistically, we propose that A20 normally restricts tumor necrosis factor–induced nuclear factor kappa B–dependent production of iNOS in intestinal epithelial cells, thereby protecting against colitis-associated tumorigenesis. We also propose that A20 plays a direct role in regulating NO-dependent cell death.http://www.sciencedirect.com/science/article/pii/S277257232200156XColonUlcerative colitisInflammationNitric oxideA20Tnfaip3 |
| spellingShingle | David W. Basta Mandy Vong Adolat Beshimova Brooke N. Nakamura Iulia Rusu Michael G. Kattah Ling Shao A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer Gastro Hep Advances Colon Ulcerative colitis Inflammation Nitric oxide A20 Tnfaip3 |
| title | A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer |
| title_full | A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer |
| title_fullStr | A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer |
| title_full_unstemmed | A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer |
| title_short | A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer |
| title_sort | a20 restricts nos2 expression and intestinal tumorigenesis in a mouse model of colitis associated cancer |
| topic | Colon Ulcerative colitis Inflammation Nitric oxide A20 Tnfaip3 |
| url | http://www.sciencedirect.com/science/article/pii/S277257232200156X |
| work_keys_str_mv | AT davidwbasta a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT mandyvong a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT adolatbeshimova a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT brookennakamura a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT iuliarusu a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT michaelgkattah a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer AT lingshao a20restrictsnos2expressionandintestinaltumorigenesisinamousemodelofcolitisassociatedcancer |