Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death

Autores
Lamberti, María Julia; Montico, Barbara; Ravo, Maria; Nigro, Annunziata; Giurato, Giorgio; Iorio, Roberta; Tarallo, Roberta; Weisz, Alessandro; Stellato, Cristiana; Steffan, Agostino; Dolcetti, Riccardo; Casolaro, Vincenzo; Faè, Damiana Antonia; Dal Col, Jessica
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Biotecnología Ambiental y Salud - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Biotecnología Ambiental y Salud; Argentina. Universita di Salerno; Italia
Fil: Montico, Barbara. Irccs Centro Di Riferimento Oncologico Aviano. Immunopathology and Cancer Biomarkers; Italia
Fil: Ravo, Maria. Genomix Life Srl; Italia
Fil: Nigro, Annunziata. Universita di Salerno; Italia
Fil: Giurato, Giorgio. Universita di Salerno; Italia
Fil: Iorio, Roberta. Genomix Life Srl; Italia
Fil: Tarallo, Roberta. Universita di Salerno; Italia
Fil: Weisz, Alessandro. Universita di Salerno; Italia
Fil: Stellato, Cristiana. Universita di Salerno; Italia
Fil: Steffan, Agostino. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; Italia
Fil: Dolcetti, Riccardo. University of Melbourne; Australia. Peter Maccallum Cancer Centre; Australia
Fil: Casolaro, Vincenzo. Universita di Salerno; Italia
Fil: Faè, Damiana Antonia. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; Italia
Fil: Dal Col, Jessica. Universita di Salerno; Italia
Materia
ANTIGEN PRESENTATION PATHWAY
IMMUNOGENIC CELL DEATH
MHC-II
MIRNA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/210746
Acceder
id CONICETDig_0d9a8c2d5c0c2a9116bbddac806b152a
oai_identifier_str oai:ri.conicet.gov.ar:11336/210746
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell deathLamberti, María JuliaMontico, BarbaraRavo, MariaNigro, AnnunziataGiurato, GiorgioIorio, RobertaTarallo, RobertaWeisz, AlessandroStellato, CristianaSteffan, AgostinoDolcetti, RiccardoCasolaro, VincenzoFaè, Damiana AntoniaDal Col, JessicaANTIGEN PRESENTATION PATHWAYIMMUNOGENIC CELL DEATHMHC-IIMIRNAhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Biotecnología Ambiental y Salud - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Biotecnología Ambiental y Salud; Argentina. Universita di Salerno; ItaliaFil: Montico, Barbara. Irccs Centro Di Riferimento Oncologico Aviano. Immunopathology and Cancer Biomarkers; ItaliaFil: Ravo, Maria. Genomix Life Srl; ItaliaFil: Nigro, Annunziata. Universita di Salerno; ItaliaFil: Giurato, Giorgio. Universita di Salerno; ItaliaFil: Iorio, Roberta. Genomix Life Srl; ItaliaFil: Tarallo, Roberta. Universita di Salerno; ItaliaFil: Weisz, Alessandro. Universita di Salerno; ItaliaFil: Stellato, Cristiana. Universita di Salerno; ItaliaFil: Steffan, Agostino. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; ItaliaFil: Dolcetti, Riccardo. University of Melbourne; Australia. Peter Maccallum Cancer Centre; AustraliaFil: Casolaro, Vincenzo. Universita di Salerno; ItaliaFil: Faè, Damiana Antonia. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; ItaliaFil: Dal Col, Jessica. Universita di Salerno; ItaliaMDPI2022-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/210746Lamberti, María Julia; Montico, Barbara; Ravo, Maria; Nigro, Annunziata; Giurato, Giorgio; et al.; Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death; MDPI; Biomedicines; 10; 8; 8-2022; 1-252227-9059CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/biomedicines10081896info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2227-9059/10/8/1896info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:59:56Zoai:ri.conicet.gov.ar:11336/210746instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:59:57.001CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
title Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
spellingShingle Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
Lamberti, María Julia
ANTIGEN PRESENTATION PATHWAY
IMMUNOGENIC CELL DEATH
MHC-II
MIRNA
title_short Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
title_full Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
title_fullStr Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
title_full_unstemmed Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
title_sort Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death
dc.creator.none.fl_str_mv Lamberti, María Julia
Montico, Barbara
Ravo, Maria
Nigro, Annunziata
Giurato, Giorgio
Iorio, Roberta
Tarallo, Roberta
Weisz, Alessandro
Stellato, Cristiana
Steffan, Agostino
Dolcetti, Riccardo
Casolaro, Vincenzo
Faè, Damiana Antonia
Dal Col, Jessica
author Lamberti, María Julia
author_facet Lamberti, María Julia
Montico, Barbara
Ravo, Maria
Nigro, Annunziata
Giurato, Giorgio
Iorio, Roberta
Tarallo, Roberta
Weisz, Alessandro
Stellato, Cristiana
Steffan, Agostino
Dolcetti, Riccardo
Casolaro, Vincenzo
Faè, Damiana Antonia
Dal Col, Jessica
author_role author
author2 Montico, Barbara
Ravo, Maria
Nigro, Annunziata
Giurato, Giorgio
Iorio, Roberta
Tarallo, Roberta
Weisz, Alessandro
Stellato, Cristiana
Steffan, Agostino
Dolcetti, Riccardo
Casolaro, Vincenzo
Faè, Damiana Antonia
Dal Col, Jessica
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTIGEN PRESENTATION PATHWAY
IMMUNOGENIC CELL DEATH
MHC-II
MIRNA
topic ANTIGEN PRESENTATION PATHWAY
IMMUNOGENIC CELL DEATH
MHC-II
MIRNA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
Fil: Lamberti, María Julia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Biotecnología Ambiental y Salud - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Biotecnología Ambiental y Salud; Argentina. Universita di Salerno; Italia
Fil: Montico, Barbara. Irccs Centro Di Riferimento Oncologico Aviano. Immunopathology and Cancer Biomarkers; Italia
Fil: Ravo, Maria. Genomix Life Srl; Italia
Fil: Nigro, Annunziata. Universita di Salerno; Italia
Fil: Giurato, Giorgio. Universita di Salerno; Italia
Fil: Iorio, Roberta. Genomix Life Srl; Italia
Fil: Tarallo, Roberta. Universita di Salerno; Italia
Fil: Weisz, Alessandro. Universita di Salerno; Italia
Fil: Stellato, Cristiana. Universita di Salerno; Italia
Fil: Steffan, Agostino. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; Italia
Fil: Dolcetti, Riccardo. University of Melbourne; Australia. Peter Maccallum Cancer Centre; Australia
Fil: Casolaro, Vincenzo. Universita di Salerno; Italia
Fil: Faè, Damiana Antonia. Immunopathology and Cancer Biomarkers. Centro di Riferimento Oncologico di Aviano; Italia
Fil: Dal Col, Jessica. Universita di Salerno; Italia
description Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
publishDate 2022
dc.date.none.fl_str_mv 2022-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/210746
Lamberti, María Julia; Montico, Barbara; Ravo, Maria; Nigro, Annunziata; Giurato, Giorgio; et al.; Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death; MDPI; Biomedicines; 10; 8; 8-2022; 1-25
2227-9059
CONICET Digital
CONICET
url http://hdl.handle.net/11336/210746
identifier_str_mv Lamberti, María Julia; Montico, Barbara; Ravo, Maria; Nigro, Annunziata; Giurato, Giorgio; et al.; Integration of miRNA:mRNA Co-Expression revealed crucial mechanisms modulated in immunogenic cancer cell death; MDPI; Biomedicines; 10; 8; 8-2022; 1-25
2227-9059
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/biomedicines10081896
info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2227-9059/10/8/1896
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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