Research Paper|Volume 12, Issue 23|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

Anette Teo Hansen Selnø¹, Stephanie Schlichtner¹, Inna M. Yasinska¹, Svetlana S. Sakhnevych¹, Walter Fiedler², Jasmin Wellbrock², Elena Klenova³, Ludmila Pavlova³, Bernhard F. Gibbs^1,⁴, Martin Degen⁵, Isabelle Schnyder^6,⁷, Nijas Aliu⁸, Steffen M. Berger^6,⁷, Elizaveta Fasler-Kan^6,^7,⁹, Vadim V. Sumbayev¹

¹Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, United Kingdom
²Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
³School of Biological Sciences, University of Essex, Colchester, United Kingdom
⁴Division of Experimental Allergology and Immunodermatology, University of Oldenburg, Oldenburg, Germany
⁵Dental Research Center, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
⁶Department of Pediatric Surgery, Children’s Hospital, Inselspital Bern, University of Bern, Bern, Switzerland
⁷Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
⁸Department of Biomedical Research, University of Bern, Bern, Switzerland
⁹Department of Human Genetics, Children’s Hospital, Inselspital, University of Bern, Bern, Switzerland

Received: September 23, 2020Accepted: November 15, 2020Published: December 8, 2020

https://doi.org/10.18632/aging.202343

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.

Abstract

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.