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      Mitochondrial DNA copy number in cervical exfoliated cells and risk of cervical cancer among HPV-positive women

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          Abstract

          Background

          Although human papillomavirus (HPV) infection has been regarded as the cause of cervical cancer in over 99% of cases, only a small fraction of HPV-infected women develop this malignancy. Emerging evidence suggests that alterations of mitochondrial DNA copy number (mtCN) may contribute to carcinogenesis. However, the relationship between mtCN and cervical cancer remains undetermined.

          Methods

          The current study included 591 cervical cancer cases and 373 cancer-free controls, all of whom were infected with high-risk HPV. Relative mtCN in cervical cancer exfoliated cells was measured by qRT-PCR assays, and logistic regression analysis was performed to compute odds ratios (ORs) and 95% confidence intervals (CIs). Interaction between mtCN and HPV types was assessed by using the Wald test in logistic regression models.

          Results

          HPV16, 18, 52, and 58 were the most common types in both case and control groups. Median mtCN in cases was significantly higher than that in controls (1.63 vs. 1.23, P = 0.03). After adjustment for age and HPV types, the highest quartile of mtCN was associated with increased odds of having cervical cancer (OR = 1.77, 95% CI = 1.19, 2.62; P < 0.01), as compared to the lowest quartile. A dose-response effect of mtCN on cervical cancer was also observed ( P trend < 0.001). The interaction between mtCN and HPV types was statistically nonsignificant.

          Conclusions

          In women who test HPV positive, the increase of mtCN in cervical exfoliated cells is associated with cervical cancer. This suggests a potential role of mtCN in cervical carcinogenesis.

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          Most cited references 33

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          p53 regulates mitochondrial respiration.

          The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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            Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress.

            A significant amount of reactive oxygen species (ROS) is generated during mitochondrial oxidative phosphorylation. Several studies have suggested that mtDNA may accumulate more oxidative DNA damage relative to nuclear DNA. This study used quantitative PCR to examine the formation and repair of hydrogen peroxide-induced DNA damage in a 16.2-kb mitochondrial fragment and a 17.7-kb fragment flanking the beta-globin gene. Simian virus 40-transformed fibroblasts treated with 200 microM hydrogen peroxide for 15 or 60 min exhibited 3-fold more damage to the mitochondrial genome compared with the nuclear fragment. Following a 60-min treatment, damage to the nuclear fragment was completely repaired within 1.5 hr, whereas no DNA repair in the mitochondrion was observed. Mitochondrial function, as assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, also showed a sharp decline. These cells displayed arrested-cell growth, large increases in p21 protein levels, and morphological changes consistent with apoptosis. In contrast, when hydrogen peroxide treatments were limited to 15 min, mtDNA damage was repaired with similar kinetics as the nuclear fragment, mitochondrial function was restored, and cells resumed division within 12 hr. These results indicate that mtDNA is a critical cellular target for ROS. A model is presented in which chronic ROS exposure, found in several degenerative diseases associated with aging, leads to decreased mitochondrial function, increased mitochondrial-generated ROS, and persistent mitochondrial DNA damage. Thus persistent mitochondrial DNA damage may serve as a useful biomarker for ROS-associated diseases.
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              Maintenance and Expression of Mammalian Mitochondrial DNA.

              Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
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                Author and article information

                Contributors
                hangdong@njmu.edu.cn
                Journal
                BMC Womens Health
                BMC Womens Health
                BMC Women's Health
                BioMed Central (London )
                1472-6874
                2 July 2020
                2 July 2020
                2020
                : 20
                Affiliations
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Epidemiology and Biostatistics, , School of Public Health, Nanjing Medical University, ; No. 101 Longmian Ave, Jiangning District, Nanjing, 211166 China
                [2 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Gynecology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210036 China
                [3 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, National Office for Cancer Prevention and Control, Cancer Institute and Hospital, , Chinese Academy of Medical Sciences, ; Beijing, 100021 China
                [4 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Department of Cancer Prevention, Cancer Institute and Hospital, , Chinese Academy of Medical Sciences, ; Beijing, 100021 China
                [5 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, , Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, ; Nanjing, 211166 China
                Article
                1001
                10.1186/s12905-020-01001-w
                7331179
                32615963
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81373079
                Award ID: 81402147
                Award ID: 81673265
                Award ID: 81502873
                Award Recipient :
                Funded by: Peking Union Medical College Youth Fund
                Award ID: 3332016131
                Award Recipient :
                Funded by: Natural Science Foundation of Jiangsu Province for Youth
                Award ID: BK20150997
                Award Recipient :
                Funded by: Natural Science Foundation of the Higher Education Institutions of Jiangsu Province
                Award ID: 15KJB330001
                Award Recipient :
                Funded by: Top-notch Academic Programs Project of Jiangsu Higher Education Institutions
                Award ID: PPZY2015A067
                Award Recipient :
                Funded by: Priority Academic Program for the Development of Jiangsu Higher Education Institutions
                Award ID: Public Health and Preventive Medicine
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

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