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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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2022-10-01
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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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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