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Transforming growth factor beta type 1 (TGF-B) 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

Selno, Anette Teo Hansen, Schlichtner, Stephanie, Yasinska, Inna M., Sakhnevych, Svetlana S., Fiedler, Walter, Wellbrock, Jasmin, Klenova, Elena, Pavlova, Ludmila, Gibbs, Bernhard F., Degen, Martin, and others. (2020) Transforming growth factor beta type 1 (TGF-B) 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. Aging, 12 (23). pp. 23478-23496. E-ISSN 1945-4589. (doi:10.18632/aging.202343) (KAR id:85301)

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

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.

Item Type: Article
DOI/Identification number: 10.18632/aging.202343
Uncontrolled keywords: galectin-9, immune escape, TGF-beta, HIF-1
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Depositing User: Vadim Sumbayev
Date Deposited: 04 Jan 2021 09:50 UTC
Last Modified: 16 Feb 2021 14:17 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/85301 (The current URI for this page, for reference purposes)
Sumbayev, Vadim V.: https://orcid.org/0000-0002-9404-5626
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