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Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression

Authors :
Marco Marchisio
Sara Pagotto
Laura De Lellis
Nicola Tinari
Paola Lanuti
Alessandro Cama
Michele De Tursi
Pietro Di Marino
Cesidio Giuliani
Angelo Veronese
Clara Natoli
Antonino Grassadonia
Maurizia D'Egidio
Davide Brocco
Vincenzo Graziano
Patrizia Vici
Graziano, Vincenzo [0000-0001-7656-824X]
Pagotto, Sara [0000-0003-2457-6648]
Veronese, Angelo [0000-0002-1451-1392]
Apollo - University of Cambridge Repository
Source :
Cell Death Discovery, Cell Death Discovery, Vol 7, Iss 1, Pp 1-13 (2021)
Publication Year :
2020

Abstract

The 90K protein, also known as Mac-2 BP or LGALS3BP, can activate the immune response in part by increasing major histocompatibility (MHC) class I levels. In studies on a non-immune cell model, the rat FRTL-5 cell line, we observed that transforming growth factor (TGF)-β1, like γ-interferon (IFN), increased 90K levels, despite its immunosuppressive functions and the ability to decrease MHC class I. To explain this paradoxical result, we investigated the mechanisms involved in the TGF-β1 regulation of 90K expression with the aim to demonstrate that TGF-β1 utilizes different molecular pathways to regulate the two genes. We found that TGF-β1 was able to increase the binding of Upstream Stimulatory Factors, USF1 and USF2, to an E-box element, CANNTG, at −1926 to −1921 bp, upstream of the interferon response element (IRE) in the 90K promoter. Thyrotropin (TSH) suppressed constitutive and γ-IFN-induced 90K expression by decreasing USF binding to the E-box. TGF-β1 was able to overcome TSH suppression at the transcriptional level by increasing USF binding to the E-box. We suggest that the ability of TGF-β1 to increase 90K did not result in an increase in MHC class I because of a separate suppressive action of TGF-β1 directly on the MHC class I gene. We propose that the increased levels of 90K may play a role, rather than in immune response, in the context of the TGF-β1-induced changing of the cellular microenvironment that predisposes to cell motility and cancer progression. Consistently, analyzing the publicly available cancer patient data sets cBioPortal, we found that 90K expression directly correlated with TGF-β1 and USFs and that high levels of 90K were significantly associated with increased mortality in patients affected by different types of cancer.

Details

ISSN :
20587716
Volume :
7
Issue :
1
Database :
OpenAIRE
Journal :
Cell death discovery
Accession number :
edsair.doi.dedup.....2b8706f0687a401c9f4ee15676b70c0a