The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer
Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153337 |
| _version_ | 1797634380032638976 |
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| author | Kilian B. Kennel Julius Burmeister Praveen Radhakrishnan Nathalia A. Giese Thomas Giese Martin Salfenmoser Jasper M. Gebhardt Moritz J. Strowitzki Cormac T. Taylor Ben Wielockx Martin Schneider Jonathan M. Harnoss |
| author_facet | Kilian B. Kennel Julius Burmeister Praveen Radhakrishnan Nathalia A. Giese Thomas Giese Martin Salfenmoser Jasper M. Gebhardt Moritz J. Strowitzki Cormac T. Taylor Ben Wielockx Martin Schneider Jonathan M. Harnoss |
| author_sort | Kilian B. Kennel |
| collection | DOAJ |
| description | Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1–/–, Phd2+/–, Phd3–/–, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1–/– mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3–/– mice, colitis activity and CAC growth remained unaltered. In Phd2+/– mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth. |
| first_indexed | 2024-03-11T12:06:51Z |
| format | Article |
| id | doaj.art-a20876b916204a5480cf7df3a59468fb |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:51Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-a20876b916204a5480cf7df3a59468fb2023-11-07T16:24:51ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01722The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancerKilian B. KennelJulius BurmeisterPraveen RadhakrishnanNathalia A. GieseThomas GieseMartin SalfenmoserJasper M. GebhardtMoritz J. StrowitzkiCormac T. TaylorBen WielockxMartin SchneiderJonathan M. HarnossColitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1–/–, Phd2+/–, Phd3–/–, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1–/– mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3–/– mice, colitis activity and CAC growth remained unaltered. In Phd2+/– mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.https://doi.org/10.1172/jci.insight.153337InflammationOncology |
| spellingShingle | Kilian B. Kennel Julius Burmeister Praveen Radhakrishnan Nathalia A. Giese Thomas Giese Martin Salfenmoser Jasper M. Gebhardt Moritz J. Strowitzki Cormac T. Taylor Ben Wielockx Martin Schneider Jonathan M. Harnoss The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer JCI Insight Inflammation Oncology |
| title | The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer |
| title_full | The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer |
| title_fullStr | The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer |
| title_full_unstemmed | The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer |
| title_short | The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer |
| title_sort | hif prolyl hydroxylases have distinct and nonredundant roles in colitis associated cancer |
| topic | Inflammation Oncology |
| url | https://doi.org/10.1172/jci.insight.153337 |
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