Research Paper Advance Articles pp 23478—23496
Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells
- 1 Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, United Kingdom
- 2 Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 3 School of Biological Sciences, University of Essex, Colchester, United Kingdom
- 4 Division of Experimental Allergology and Immunodermatology, University of Oldenburg, Oldenburg, Germany
- 5 Dental Research Center, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
- 6 Department of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern, Bern, Switzerland
- 7 Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
- 8 Department of Biomedical Research, University of Bern, Bern, Switzerland
- 9 Department of Human Genetics, Children’s Hospital, Inselspital, University of Bern, Bern, Switzerland
Received: September 23, 2020 Accepted: November 15, 2020 Published: December 8, 2020https://doi.org/10.18632/aging.202343
How to Cite
Copyright: © 2020 Selnø et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Galectin-9 is one of the key proteins employed by a variety of human malignancies to suppress anti-cancer activities of cytotoxic lymphoid cells and thus escape immune surveillance. Human cancer cells in most cases express higher levels of galectin-9 compared to non-transformed cells. However, the biochemical mechanisms underlying this phenomenon remain unclear.
Here we report for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are involved in upregulation of transforming growth factor beta 1 (TGF-β1) expression, leading to activation of the transcription factor Smad3 through autocrine action. This process triggers upregulation of galectin-9 expression in both malignant (mainly in breast and colorectal cancer as well as acute myeloid leukaemia (AML)) and embryonic cells. The effect, however, was not observed in mature non-transformed human cells. TGF-β1-activated Smad3 therefore displays differential behaviour in human cancer and embryonic vs non-malignant cells. This study uncovered a self-supporting biochemical mechanism underlying high levels of galectin-9 expression operated by the human cancer and embryonic cells employed in our investigations. Our results suggest the possibility of using the TGF-β1 signalling pathway as a potential highly efficient target for cancer immunotherapy.