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The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer
Kilian B. Kennel, … , Martin Schneider, Jonathan M. Harnoss
Kilian B. Kennel, … , Martin Schneider, Jonathan M. Harnoss
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e153337. https://doi.org/10.1172/jci.insight.153337.
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Research Article Inflammation Oncology

The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer

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Abstract

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.

Authors

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

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Figure 1

Loss of Phd1 but not Phd2 or Phd3 selectively protects mice against chronic colitis.

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Loss of Phd1 but not Phd2 or Phd3 selectively protects mice against chro...
(A) Model of chronic colitis and colitis-associated tumorigenesis induced by AOM and repeated cycles of DSS in WT control, Phd1–/–, Phd2+/–, and Phd3–/– mice. (B) BW change relative to baseline from WT (n = 10), Phd1–/– (n = 6), Phd2+/– (n = 5), and Phd3–/– (n = 9) mice over the course of AOM/DSS treatment. BW was measured every other day. (C) Colon length of AOM/DSS-treated WT (n = 10), Phd1–/– (n = 7), Phd2+/– (n = 5), and Phd3–/– (n = 10) mice after termination of the experiment at day 84. (D) Histological scoring of mucosal damage (top) as previously described by Katakura et al. (62) and representative H&E staining (bottom) of colons from WT (n = 7), Phd1–/– (n = 6), Phd2+/– (n = 5), and Phd3–/– (n = 8) mice after termination of the experiment on day 84. Scale bar: 100 μm. Statistical significance was calculated using 2-way ANOVA (B) or 1-way ANOVA with Dunnett’s multiple comparisons test in C and D. *P < 0.05, ****P < 0.0001.

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