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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 5

Phd2-deficient BMDMs stimulate tumor proliferation and show increased Ereg expression in vitro.

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Phd2-deficient BMDMs stimulate tumor proliferation and show increased E...
(A) qRT-PCR analysis of Ereg in WT and Phd2+/– BMDMs upon stimulation with control, LPS (100 ng/mL), TNF-α (20 ng/mL), or IL-4 (20 ng/mL) for 24 hours. Dots represent biological replicates. Data represent 4 independent experiments. (B) t-Distributed stochastic neighbor embedding (tSNE) plots showing analysis of Ereg expression in myeloid cells from human CRC samples. Analysis was performed with publicly available scRNA-Seq data (36). (C) tSNE plots showing analysis of Ereg expression in immune cells from human UC mucosa samples. Analysis was performed with publicly available scRNA-Seq data (37). (D) Crystal violet viability assay of murine CMT-93 rectal cancer cells after 48 hours of treatment with control (RPMI medium + 1% FCS) or conditioned media from BMDMs stimulated with control, LPS, TNF-α, or IL-4. Dots represent technical replicates. Data represent 2 independent experiments. Statistical significance was calculated using Student’s t test. *P < 0.05.

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