Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Inflammation Oncology

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

  • Text
  • PDF
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

×

Figure 6

Lineage-specific deletion of Phd2 in the hematopoietic but not the epithelial cell compartment aggravates colitis-associated tumor growth.

Options: View larger image (or click on image) Download as PowerPoint
Lineage-specific deletion of Phd2 in the hematopoietic but not the epith...
(A) Macroscopic quantification of AOM/DSS-induced tumors. Number of tumors per mouse (Phd2fl/fl control: n = 8; and Vav:Cre-Phd2fl/fl: n = 7 mice) and size of individual tumors (control: n = 127; and Vav:Cre-Phd2fl/fl: n = 100 tumors), and representative macroscopic images (right) of colons from control and Vav:Cre-Phd2fl/fl mice (B) H&E staining of colons from control and Vav:Cre-Phd2fl/fl mice. Arrows indicate colitis-associated tumors. Scale bar: 2 mm. (C) Quantification of CC3 immunostaining in control (n = 32) and Vav:Cre-Phd2fl/fl (n = 53) tumors (top) and representative histological images (bottom). Scale bar: 50 μm. (D) Quantification of epithelial PCNA immunostaining in control (n = 9) and Vav:Cre-Phd2fl/fl (n = 11) tumors (top) and representative histological images (bottom). Scale bar: 25 μm. (E) Quantification of epithelial nuclear p-STAT3Y705 immunostaining in control (n = 14) and Vav:Cre-Phd2fl/fl (n = 14) tumors (top) and representative histological images (bottom). Scale bar: 25 μm. (F) Quantification of p-ERK1/2 immunostaining in control (n = 31) and Vav:Cre-Phd2fl/fl (n = 30) tumors (top) and representative histological images (bottom). Scale bar: 100 μm. (G) Quantification of F4/80 immunostaining in control (n = 38) and Vav:Cre-Phd2fl/fl (n = 45) tumors (top) and representative histological images (bottom). Scale bar: 100 μm. (H and I) qRT-PCR analysis of EGFR ligand Ereg in H and IL-6 and IL-11 in I in WT (n = 14) and Phd2+/– (n = 14) tumors. Statistical significance was calculated using 2-tailed Student’s t test. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts