Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system
Abstract 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 in...
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Wiley
2022-10-01
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Series: | FASEB BioAdvances |
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Online Access: | https://doi.org/10.1096/fba.2019-00044 |
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author | Kevin Schneider Marilyn Chwa Shari R. Atilano Sonali Nashine Nitin Udar David S. Boyer S. Michal Jazwinski Michael V. Miceli Anthony B. Nesburn Baruch D. Kuppermann M. Cristina Kenney |
author_facet | Kevin Schneider Marilyn Chwa Shari R. Atilano Sonali Nashine Nitin Udar David S. Boyer S. Michal Jazwinski Michael V. Miceli Anthony B. Nesburn Baruch D. Kuppermann M. Cristina Kenney |
author_sort | Kevin Schneider |
collection | DOAJ |
description | Abstract 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. |
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institution | Directory Open Access Journal |
issn | 2573-9832 |
language | English |
last_indexed | 2024-04-13T20:12:23Z |
publishDate | 2022-10-01 |
publisher | Wiley |
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spelling | doaj.art-09bf357e9bfd42d796eda35f47c0bc9b2022-12-22T02:31:48ZengWileyFASEB BioAdvances2573-98322022-10-0141067568910.1096/fba.2019-00044Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing systemKevin Schneider0Marilyn Chwa1Shari R. Atilano2Sonali Nashine3Nitin Udar4David S. Boyer5S. Michal Jazwinski6Michael V. Miceli7Anthony B. Nesburn8Baruch D. Kuppermann9M. Cristina Kenney10Department of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USARetina‐Vitreous Associates Medical Group Beverly Hills California USATulane Center for Aging and Department of Medicine Tulane University New Orleans Louisiana USATulane Center for Aging and Department of Medicine Tulane University New Orleans Louisiana USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USADepartment of Ophthalmology, Gavin Herbert Eye Institute University of California Irvine Irvine California USAAbstract 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.https://doi.org/10.1096/fba.2019-00044cancer genesmitochondrial DNA haplogroupssimulator of interferon genes (STING) |
spellingShingle | Kevin Schneider Marilyn Chwa Shari R. Atilano Sonali Nashine Nitin Udar David S. Boyer S. Michal Jazwinski Michael V. Miceli Anthony B. Nesburn Baruch D. Kuppermann M. Cristina Kenney Differential modulation of cancer‐related genes by mitochondrial DNA haplogroups and the STING DNA sensing system FASEB BioAdvances cancer genes mitochondrial DNA haplogroups simulator of interferon genes (STING) |
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 | cancer genes mitochondrial DNA haplogroups simulator of interferon genes (STING) |
url | https://doi.org/10.1096/fba.2019-00044 |
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