Cancers (Dec 2022)
A Critical Role of the IL-22–IL-22 Binding Protein Axis in Hepatocellular Carcinoma
- Anastasios D. Giannou,
- Jöran Lücke,
- Dörte Kleinschmidt,
- Ahmad Mustafa Shiri,
- Babett Steglich,
- Mikolaj Nawrocki,
- Tao Zhang,
- Dimitra E. Zazara,
- Jan Kempski,
- Lilan Zhao,
- Olympia Giannou,
- Theodora Agalioti,
- Leonie Brockmann,
- Franziska Bertram,
- Morsal Sabihi,
- Marius Böttcher,
- Florian Ewald,
- Kornelius Schulze,
- Johann von Felden,
- Andres Machicote,
- Ioannis C. Maroulis,
- Petra C. Arck,
- Julia-Kristin Graß,
- Baris Mercanoglu,
- Matthias Reeh,
- Stefan Wolter,
- Michael Tachezy,
- Hannes Seese,
- Myrto Theodorakopoulou,
- Panagis M. Lykoudis,
- Asmus Heumann,
- Faik G. Uzunoglu,
- Tarik Ghadban,
- Oliver Mann,
- Jakob R. Izbicki,
- Jun Li,
- Anna Duprée,
- Nathaniel Melling,
- Nicola Gagliani,
- Samuel Huber
Affiliations
- Anastasios D. Giannou
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Jöran Lücke
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Dörte Kleinschmidt
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Ahmad Mustafa Shiri
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Babett Steglich
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Mikolaj Nawrocki
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Tao Zhang
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Dimitra E. Zazara
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Jan Kempski
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Lilan Zhao
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Olympia Giannou
- Department of Computer Engineering & Informatics, University of Patras, 26500 Patras, Greece
- Theodora Agalioti
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Leonie Brockmann
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Franziska Bertram
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Morsal Sabihi
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Marius Böttcher
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Florian Ewald
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Kornelius Schulze
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Andres Machicote
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Ioannis C. Maroulis
- Department of Surgery, University of Patras Medical School, 26500 Patras, Greece
- Petra C. Arck
- Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Julia-Kristin Graß
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Baris Mercanoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Matthias Reeh
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Stefan Wolter
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Michael Tachezy
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Hannes Seese
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Myrto Theodorakopoulou
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Panagis M. Lykoudis
- 3rd Department of Surgery, National & Kapodistrian University of Athens, 11527 Athens, Greece
- Asmus Heumann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Faik G. Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Tarik Ghadban
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Oliver Mann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Jun Li
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Anna Duprée
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Nicola Gagliani
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Samuel Huber
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- DOI
- https://doi.org/10.3390/cancers14246019
- Journal volume & issue
-
Vol. 14,
no. 24
p. 6019
Abstract
Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC.
Keywords