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A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies.
Härkönen, Jouni; Pölönen, Petri; Deen, Ashik Jawahar; Selvarajan, Ilakya; Teppo, Hanna-Riikka; Dimova, Elitsa Y; Kietzmann, Thomas; Ahtiainen, Maarit; Väyrynen, Juha P; Väyrynen, Sara A; Elomaa, Hanna; Tynkkynen, Niko; Eklund, Tiia; Kuopio, Teijo; Talvitie, Eva-Maria; Taimen, Pekka; Kallajoki, Markku; Kaikkonen, Minna U; Heinäniemi, Merja; Levonen, Anna-Liisa.
Afiliación
  • Härkönen J; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland; Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland.
  • Pölönen P; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland; Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, 70210, Finland.
  • Deen AJ; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland.
  • Selvarajan I; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland.
  • Teppo HR; Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, 90220, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 90570, Finland; Department of Pathology, Oulu University Hospital, Oulu, 90220, Finland.
  • Dimova EY; Faculty of Biochemistry and Molecular Medicine, University of Oulu and Biocenter Oulu, Oulu, 90570, Finland.
  • Kietzmann T; Faculty of Biochemistry and Molecular Medicine, University of Oulu and Biocenter Oulu, Oulu, 90570, Finland.
  • Ahtiainen M; Department of Education and Research, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland.
  • Väyrynen JP; Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, 90220, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 90570, Finland; Department of Pathology, Oulu University Hospital, Oulu, 90220, Finland.
  • Väyrynen SA; Department of Internal Medicine, Oulu University Hospital, Oulu, 90220, Finland.
  • Elomaa H; Department of Education and Research, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland; Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland.
  • Tynkkynen N; Gerontology Research Center (GEREC), Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, 40014, Finland.
  • Eklund T; Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland.
  • Kuopio T; Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland; Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, 40100, Finland.
  • Talvitie EM; Department of Genomics, Turku University Hospital and University of Turku, Turku, 20520, Finland.
  • Taimen P; Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, 20520, Finland; Department of Pathology, Turku University Hospital, Turku, 20521, Finland.
  • Kallajoki M; Department of Pathology, Turku University Hospital, Turku, 20521, Finland.
  • Kaikkonen MU; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland.
  • Heinäniemi M; Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, 70210, Finland.
  • Levonen AL; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70210, Finland. Electronic address: anna-liisa.levonen@uef.fi.
Redox Biol ; 61: 102644, 2023 05.
Article en En | MEDLINE | ID: mdl-36867945
The NRF2 pathway is frequently activated in various cancer types, yet a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a NRF2 activity metric and utilized it to conduct a pan-cancer analysis of oncogenic NRF2 signaling. We identified an immunoevasive phenotype where high NRF2 activity is associated with low interferon-gamma (IFNγ), HLA-I expression and T cell and macrophage infiltration in squamous malignancies of the lung, head and neck area, cervix and esophagus. Squamous NRF2 overactive tumors comprise a molecular phenotype with SOX2/TP63 amplification, TP53 mutation and CDKN2A loss. These immune cold NRF2 hyperactive diseases are associated with upregulation of immunomodulatory NAMPT, WNT5A, SPP1, SLC7A11, SLC2A1 and PD-L1. Based on our functional genomics analyses, these genes represent candidate NRF2 targets, suggesting direct modulation of the tumor immune milieu. Single-cell mRNA data shows that cancer cells of this subtype exhibit decreased expression of IFNγ responsive ligands, and increased expression of immunosuppressive ligands NAMPT, SPP1 and WNT5A that mediate signaling in intercellular crosstalk. In addition, we discovered that the negative relationship of NRF2 and immune cells are explained by stromal populations of lung squamous cell carcinoma, and this effect spans multiple squamous malignancies based on our molecular subtyping and deconvolution data.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Escamosas / Factor 2 Relacionado con NF-E2 Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Redox Biol Año: 2023 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Escamosas / Factor 2 Relacionado con NF-E2 Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Redox Biol Año: 2023 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Países Bajos