Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-021-00469-1 |
| _version_ | 1818647426886533120 |
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| author | Antonino Grassadonia Vincenzo Graziano Sara Pagotto Angelo Veronese Cesidio Giuliani Marco Marchisio Paola Lanuti Michele De Tursi Maurizia D’Egidio Pietro De Marino Davide Brocco Patrizia Vici Laura De Lellis Alessandro Cama Clara Natoli Nicola Tinari |
| author_facet | Antonino Grassadonia Vincenzo Graziano Sara Pagotto Angelo Veronese Cesidio Giuliani Marco Marchisio Paola Lanuti Michele De Tursi Maurizia D’Egidio Pietro De Marino Davide Brocco Patrizia Vici Laura De Lellis Alessandro Cama Clara Natoli Nicola Tinari |
| author_sort | Antonino Grassadonia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T01:02:21Z |
| format | Article |
| id | doaj.art-5fc24b252ab84a38bacd5f4f58aebc3f |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-17T01:02:21Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-5fc24b252ab84a38bacd5f4f58aebc3f2022-12-21T22:09:24ZengNature Publishing GroupCell Death Discovery2058-77162021-04-017111310.1038/s41420-021-00469-1Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progressionAntonino Grassadonia0Vincenzo Graziano1Sara Pagotto2Angelo Veronese3Cesidio Giuliani4Marco Marchisio5Paola Lanuti6Michele De Tursi7Maurizia D’Egidio8Pietro De Marino9Davide Brocco10Patrizia Vici11Laura De Lellis12Alessandro Cama13Clara Natoli14Nicola Tinari15Department of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medicine and Ageing Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medicine and Ageing Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medicine and Ageing Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medicine and Ageing Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDivision of Medical Oncology 2, IRCCS Regina Elena National Cancer InstituteDepartment of Pharmacy and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Pharmacy and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityDepartment of Medical, Oral and Biotechnological Sciences and Center for Advanced Studies and Technology (CAST), G. D’Annunzio UniversityAbstract 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.https://doi.org/10.1038/s41420-021-00469-1 |
| spellingShingle | Antonino Grassadonia Vincenzo Graziano Sara Pagotto Angelo Veronese Cesidio Giuliani Marco Marchisio Paola Lanuti Michele De Tursi Maurizia D’Egidio Pietro De Marino Davide Brocco Patrizia Vici Laura De Lellis Alessandro Cama Clara Natoli Nicola Tinari Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression Cell Death Discovery |
| title | Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression |
| title_full | Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression |
| title_fullStr | Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression |
| title_full_unstemmed | Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression |
| title_short | Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression |
| title_sort | tgf β1 transcriptionally promotes 90k expression possible implications for cancer progression |
| url | https://doi.org/10.1038/s41420-021-00469-1 |
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