Aging-US: Growth factor beta type 1 and hypoxia-inducible factor 1 transcription complex

12-15-2020

Aging-US recently published "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" which reported that for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 and activator protein 1 are involved in upregulation of transforming growth factor beta 1 expression, leading to activation of the transcription factor Smad3.

This process triggers upregulation of galectin-9 expression in both malignant and embryonic cells.

Dr. Vadim V. Sumbayev from The Universities of Kent and Greenwich and Dr. Elizaveta Fasler-Kan from The University of Bern as well as The University of Basel and University Hospital Basel said, "Galectin-9 is one of the crucial proteins used by various types of cancer cells to suppress cytotoxic immune responses and thus, escape immune surveillance"

Some cancer cells are capable of secreting this protein, while other cancer cells translocate galectin-9 onto the surface and use it to impair anti-cancer activities of cytotoxic lymphoid cells such as cytotoxic T lymphocytes and natural killer cells .

Figure 10. Proposed mechanism of the regulation of galectin-9 expression in human cancer and embryonic stage at low and normal oxygen availability stages. The figure depicts the key processes taking place in embryonic development and malignant tumour growth during the initial low oxygen availability (hypoxic) stage and later (normal oxygen availability) stages. The studied biochemical events are demonstrated in the right-hand panel. During the hypoxic stage, HIF-1 induces TGF-β expression, which then displays autocrine activity and triggers galectin-9 expression in a Smad3-dependent manner. During the normal oxygen availability stage, AP-1 contributes to TGF-β expression but it is also self-triggered by TGF-β. Galectin-9 upregulation is perpetually induced by the TGF-β-Smad3 pathway.

When complexed with Tim-3 on the cell surface, galectin-9 induces downstream signalling of differential intensity, depending on the type of human myeloid and lymphoid cells.

Human cancer cells express significantly higher levels of galectin-9 compared to healthy human cells.

Here the Aging-US authors report for the first time that in human breast cancer, AML and embryonic cells, HIF-1 and AP-1 upregulate the expression of TGF-β, leading to the activation of Smad3 through autocrine action.

This process subsequently upregulates galectin-9 expression in both malignant and embryonic cells, but not in mature healthy human cells.

The Sumbayev/Fasler-Kan Research Team concluded in their Aging-US Research Paper, "These finding demonstrate a self-supporting mechanism of galectin-9 expression operated by human AML, breast and colorectal cancer as well as embryonic cells. Our results suggest the possibility of using TGF-β signalling as a potential highly efficient target for cancer immunotherapy."

"The Aging-US authors report for the first time that in human breast cancer, AML and embryonic cells, HIF-1 and AP-1 upregulate the expression of TGF-β"

Full Text - https://www.aging-us.com/article/202343/text

Correspondence to: Vadim V. Sumbayev email: V.Sumbayev@kent.ac.uk and Elizaveta Fasler-Kan email: elizaveta.fasler@insel.ch

Keywords: galectin-9, immune escape, TGF-beta, HIF-1

About Aging-US:

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed CentralWeb of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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