Cargando…

Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system

Activation of the Simulator of Interferon Genes (STING) system by mitochondrial (mt) DNA can upregulate type 1 interferon genes and enhance immune responses to combat bacterial and viral infections. In cancers, the tumor‐derived DNA activates STING leading to upregulation of IFN‐beta and induction o...

Descripción completa

Detalles Bibliográficos
Autores principales: Schneider, Kevin, Chwa, Marilyn, Atilano, Shari R., Nashine, Sonali, Udar, Nitin, Boyer, David S., Jazwinski, S. Michal, Miceli, Michael V., Nesburn, Anthony B., Kuppermann, Baruch D., Kenney, M. Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536090/
https://www.ncbi.nlm.nih.gov/pubmed/36238361
http://dx.doi.org/10.1096/fba.2019-00044
_version_ 1784802916128784384
author Schneider, Kevin
Chwa, Marilyn
Atilano, Shari R.
Nashine, Sonali
Udar, Nitin
Boyer, David S.
Jazwinski, S. Michal
Miceli, Michael V.
Nesburn, Anthony B.
Kuppermann, Baruch D.
Kenney, M. Cristina
author_facet Schneider, Kevin
Chwa, Marilyn
Atilano, Shari R.
Nashine, Sonali
Udar, Nitin
Boyer, David S.
Jazwinski, S. Michal
Miceli, Michael V.
Nesburn, Anthony B.
Kuppermann, Baruch D.
Kenney, M. Cristina
author_sort Schneider, Kevin
collection PubMed
description Activation of the Simulator of Interferon Genes (STING) system by mitochondrial (mt) DNA can upregulate type 1 interferon genes and enhance immune responses to combat bacterial and viral infections. In cancers, the tumor‐derived DNA activates STING leading to upregulation of IFN‐beta and induction of antitumor T cells. The entire mtDNA from the cell lines was sequenced using next‐generation sequencing (NGS) technology with independent sequencing of both strands in both directions, allowing identification of low‐frequency heteroplasmy SNPs. There were 15 heteroplasmy SNPs showing a range from 3.4% to 40.5% occurrence in the K cybrid cell lines. Three H haplogroup cybrids possessed SNP heteroplasmy that ranged from 4.39% to 30.7%. The present study used qRT‐PCR to determine if cybrids of H and K haplogroups differentially regulate expression levels of five cancer genes (BRAC1, ALK, PD1, EGFR, and HER2) and seven STING subunits genes (CGAS, TBK1, IRF3, IκBa, NFκB, TRAF2, and TNFRSF19). Some cybrids underwent siRNA knockdown of STING followed by qRT‐PCR in order to determine the impact of STING on gene expression. Rho0 (lacking mtDNA) ARPE‐19 cells were used to determine if mtDNA is required for the expression of the cancer genes studied. Our results showed that (a) K cybrids have lower expression levels for BRAC1, ALK, PD1, EGFR, IRF3, and TNFRSF19 genes but increased transcription for IκBa and NFκB compared to H cybrids; (b) STING KD decreases expression of EGFR in both H and K cybrids, and (c) PD1 expression is negligible in Rho0 cells. Our findings suggest that the STING DNA sensing pathway may be a previously unrecognized pathway to target modulation of cancer‐related genes and the PD1 expression requires the presence of mtDNA.
format Online
Article
Text
id pubmed-9536090
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-95360902022-10-12 Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system Schneider, Kevin Chwa, Marilyn Atilano, Shari R. Nashine, Sonali Udar, Nitin Boyer, David S. Jazwinski, S. Michal Miceli, Michael V. Nesburn, Anthony B. Kuppermann, Baruch D. Kenney, M. Cristina FASEB Bioadv Research Articles Activation of the Simulator of Interferon Genes (STING) system by mitochondrial (mt) DNA can upregulate type 1 interferon genes and enhance immune responses to combat bacterial and viral infections. In cancers, the tumor‐derived DNA activates STING leading to upregulation of IFN‐beta and induction of antitumor T cells. The entire mtDNA from the cell lines was sequenced using next‐generation sequencing (NGS) technology with independent sequencing of both strands in both directions, allowing identification of low‐frequency heteroplasmy SNPs. There were 15 heteroplasmy SNPs showing a range from 3.4% to 40.5% occurrence in the K cybrid cell lines. Three H haplogroup cybrids possessed SNP heteroplasmy that ranged from 4.39% to 30.7%. The present study used qRT‐PCR to determine if cybrids of H and K haplogroups differentially regulate expression levels of five cancer genes (BRAC1, ALK, PD1, EGFR, and HER2) and seven STING subunits genes (CGAS, TBK1, IRF3, IκBa, NFκB, TRAF2, and TNFRSF19). Some cybrids underwent siRNA knockdown of STING followed by qRT‐PCR in order to determine the impact of STING on gene expression. Rho0 (lacking mtDNA) ARPE‐19 cells were used to determine if mtDNA is required for the expression of the cancer genes studied. Our results showed that (a) K cybrids have lower expression levels for BRAC1, ALK, PD1, EGFR, IRF3, and TNFRSF19 genes but increased transcription for IκBa and NFκB compared to H cybrids; (b) STING KD decreases expression of EGFR in both H and K cybrids, and (c) PD1 expression is negligible in Rho0 cells. Our findings suggest that the STING DNA sensing pathway may be a previously unrecognized pathway to target modulation of cancer‐related genes and the PD1 expression requires the presence of mtDNA. John Wiley and Sons Inc. 2022-08-26 /pmc/articles/PMC9536090/ /pubmed/36238361 http://dx.doi.org/10.1096/fba.2019-00044 Text en ©2022 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Schneider, Kevin
Chwa, Marilyn
Atilano, Shari R.
Nashine, Sonali
Udar, Nitin
Boyer, David S.
Jazwinski, S. Michal
Miceli, Michael V.
Nesburn, Anthony B.
Kuppermann, Baruch D.
Kenney, M. Cristina
Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title_full Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title_fullStr Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title_full_unstemmed Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title_short Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
title_sort differential modulation of cancer‐related genes by mitochondrial dna haplogroups and the sting dna sensing system
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536090/
https://www.ncbi.nlm.nih.gov/pubmed/36238361
http://dx.doi.org/10.1096/fba.2019-00044
work_keys_str_mv AT schneiderkevin differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT chwamarilyn differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT atilanosharir differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT nashinesonali differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT udarnitin differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT boyerdavids differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT jazwinskismichal differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT micelimichaelv differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT nesburnanthonyb differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT kuppermannbaruchd differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem
AT kenneymcristina differentialmodulationofcancerrelatedgenesbymitochondrialdnahaplogroupsandthestingdnasensingsystem