Aging-US: Growth factor beta type 1 and hypoxia-inducible factor 1 transcription complex12-15-2020
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."
Full Text - https://www.aging-us.com/article/202343/text
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.