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1
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Ghadyani F, Sharif S, Morovvati S. Evaluation of mtDNA common deletion in esophageal squamous cell carcinoma. Indian J Cancer 2024; 61:363-367. [PMID: 39044636 DOI: 10.4103/ijc.ijc_324_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 12/04/2023] [Indexed: 07/25/2024]
Abstract
BACKGROUND Mitochondrial defects are thought to play a role in cancer initiation and progression for a long time. Because of the absence of protective histones and an inefficiency in the DNA repair process, mitochondrial DNA is known to be prone to mutations. The deletion of 4977bp is one of the most common mutations in human cancers. This study aimed to investigate the relationship between 4977bp common deletion and Esophageal Squamous Cell Carcinoma Disease (SCC) to provide prognostic information. METHODS By using a PCR protocol, this study identified the 4977bp deletion of mtDNA. A PCR method was used on tumor samples from 41 squamous cell carcinoma patients and blood samples from 50 healthy individuals to detect DNA. RESULTS Among the 41 tumor samples (80.5%), 33 were found to have the 4977bp deletion, while none of the blood samples from healthy individuals contained it. CONCLUSIONS It is shown that the deletion of 4977bp of mtDNA correlates significantly with SCC in this study. A 4977bp deletion could be used as an effective cancer screening indicator and biomarker for early diagnosis and prevention of cancer.
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Affiliation(s)
- Fatemeh Ghadyani
- Department of Cellular and Molecular, Faculty of Biology Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Shahrbanoo Sharif
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Saeid Morovvati
- School of Advanced Sciences and Technology, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran
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2
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Xu YC, Su J, Zhou JJ, Yuan Q, Han JS. Roles of MT-ND1 in Cancer. Curr Med Sci 2023; 43:869-878. [PMID: 37642864 DOI: 10.1007/s11596-023-2771-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 06/12/2023] [Indexed: 08/31/2023]
Abstract
The energy shift toward glycolysis is one of the hallmarks of cancer. Complex I is a vital enzyme complex necessary for oxidative phosphorylation. The mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1 (MT-ND1) is the largest subunit coded by mitochondria of complex I. The present study summarizes the structure and biological function of MT-ND1. From databases and literature, the expressions and mutations of MT-ND1 in a variety of cancers have been reviewed. MT-ND1 may be a biomarker for cancer diagnosis and prognosis. It is also a potential target for cancer therapy.
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Affiliation(s)
- Yi-Chun Xu
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China.
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China.
| | - Jun Su
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China
| | - Jia-Jing Zhou
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
| | - Qing Yuan
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China
| | - Jun-Song Han
- Department of Pathology, Shanghai Tongji Hospital, Tongji Hospital Affiliated to Tongji University, Shanghai, 200065, China.
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, 201203, China.
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3
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Alexiou A, Tsagkaris C, Chatzichronis S, Koulouris A, Haranas I, Gkigkitzis I, Zouganelis G, Mukerjee N, Maitra S, Jha NK, Batiha GES, Kamal MA, Nikolaou M, Ashraf GM. The Fractal Viewpoint of Tumors and Nanoparticles. Curr Med Chem 2023; 30:356-370. [PMID: 35927901 DOI: 10.2174/0929867329666220801152347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 04/02/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
Even though the promising therapies against cancer are rapidly improved, the oncology patients population has seen exponential growth, placing cancer in 5th place among the ten deadliest diseases. Efficient drug delivery systems must overcome multiple barriers and maximize drug delivery to the target tumors, simultaneously limiting side effects. Since the first observation of the quantum tunneling phenomenon, many multidisciplinary studies have offered quantum-inspired solutions to optimized tumor mapping and efficient nanodrug design. The property of a wave function to propagate through a potential barrier offer the capability of obtaining 3D surface profiles using imaging of individual atoms on the surface of a material. The application of quantum tunneling on a scanning tunneling microscope offers an exact surface roughness mapping of tumors and pharmaceutical particles. Critical elements to cancer nanotherapeutics apply the fractal theory and calculate the fractal dimension for efficient tumor surface imaging at the atomic level. This review study presents the latest biological approaches to cancer management based on fractal geometry.
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Affiliation(s)
- Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia.,AFNP Med, 1030 Wien, Austria
| | - Christos Tsagkaris
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia.,European Student Think Tank, Public Health and Policy Working Group, 1058, Amsterdam, Netherlands
| | - Stylianos Chatzichronis
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
| | - Andreas Koulouris
- Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, 17177 Stockholm, Sweden.,Faculty of Medicine, University of Crete, 70013 Heraklion, Greece
| | - Ioannis Haranas
- Department of Physics and Computer Science, Wilfrid Laurier University, Waterloo, ON, N2L-3C5, Canada
| | - Ioannis Gkigkitzis
- NOVA Department of Mathematics, 8333 Little River Turnpike, Annandale, VA 22003 USA
| | - Georgios Zouganelis
- Human Sciences Research Centre, College of Life and Natural Sciences, University of Derby, East Midlands, DE22 1GB England, UK
| | - Nobendu Mukerjee
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia.,Department of Microbiology; Ramakrishna Mission Vivekananda Centenary College, Akhil Mukherjee Rd, Chowdhary Para, Rahara, Khardaha, West Bengal, Kolkata- 700118, India
| | - Swastika Maitra
- Department of Microbiology, Adamas University, Kolkata, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India.,Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India.,Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh.,Enzymoics, 7 Peterlee place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia
| | - Michail Nikolaou
- 1st Oncology Department, "Saint Savas" Anticancer, Oncology Hospital, 11522 Athens, Greece
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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4
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Keerthiga R, Pei DS, Fu A. Mitochondrial dysfunction, UPR mt signaling, and targeted therapy in metastasis tumor. Cell Biosci 2021; 11:186. [PMID: 34717757 PMCID: PMC8556915 DOI: 10.1186/s13578-021-00696-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/02/2021] [Indexed: 12/13/2022] Open
Abstract
In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.
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Affiliation(s)
| | - De-Sheng Pei
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.
| | - Ailing Fu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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5
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Tan YQ, Zhang X, Zhang S, Zhu T, Garg M, Lobie PE, Pandey V. Mitochondria: The metabolic switch of cellular oncogenic transformation. Biochim Biophys Acta Rev Cancer 2021; 1876:188534. [PMID: 33794332 DOI: 10.1016/j.bbcan.2021.188534] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023]
Abstract
Mitochondria, well recognized as the "powerhouse" of cells, are maternally inherited organelles with bacterial ancestry that play essential roles in a myriad of cellular functions. It has become profoundly evident that mitochondria regulate a wide array of cellular and metabolic functions, including biosynthetic metabolism, cell signaling, redox homeostasis, and cell survival. Correspondingly, defects in normal mitochondrial functioning have been implicated in various human malignancies. Cancer development involves the activation of oncogenes, inactivation of tumor suppressor genes, and impairment of apoptotic programs in cells. Mitochondria have been recognized as the site of key metabolic switches for normal cells to acquire a malignant phenotype. This review outlines the role of mitochondria in human malignancies and highlights potential aspects of mitochondrial metabolism that could be targeted for therapeutic development.
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Affiliation(s)
- Yan Qin Tan
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, Guangdong, PR China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China
| | - Xi Zhang
- Shenzhen Bay Laboratory, Shenzhen 518055, Guangdong, PR China
| | - Shuwei Zhang
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, Guangdong, PR China
| | - Tao Zhu
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230000, Anhui, PR China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230000, Anhui, PR China
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Sector-125, Noida 201313, India
| | - Peter E Lobie
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, Guangdong, PR China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Shenzhen Bay Laboratory, Shenzhen 518055, Guangdong, PR China.
| | - Vijay Pandey
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, Guangdong, PR China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China.
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6
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Mohamed Yusoff AA, Mohd Khair SZN, Abd Radzak SM, Idris Z, Lee HC. Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: A first report from a Malaysian study group. J Chin Med Assoc 2020; 83:838-844. [PMID: 32732530 PMCID: PMC7478208 DOI: 10.1097/jcma.0000000000000401] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The 4977-bp common deletion (mtDNA) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA in brain tumors have been reported. The present study aimed to determine mtDNA prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated. METHODS A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing. RESULTS Overall, mtDNA was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients. CONCLUSION The prevalence of mtDNA in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.
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Affiliation(s)
- Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
- Address correspondence. Dr. Abdul Aziz Mohamed Yusoff, Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia. E-mail address: (A.A. Mohamed Yusoff)
| | - Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Zamzuri Idris
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
| | - Hsin-Chen Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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7
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Wang SF, Chen S, Tseng LM, Lee HC. Role of the mitochondrial stress response in human cancer progression. Exp Biol Med (Maywood) 2020; 245:861-878. [PMID: 32326760 PMCID: PMC7268930 DOI: 10.1177/1535370220920558] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
IMPACT STATEMENT Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.
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Affiliation(s)
- Sheng-Fan Wang
- Department of Pharmacy, Taipei Veterans General Hospital, 112 Taipei
- School of Pharmacy, Taipei Medical University, 110 Taipei
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, 112 Taipei
| | - Shiuan Chen
- Department of Cancer Biology, Beckman Research Institute of the City of Hope, CA 91010, USA
| | - Ling-Ming Tseng
- Division of General Surgery, Department of Surgery, Comprehensive Breast Health Center, Taipei Veterans General Hospital, 112 Taipei
- Department of Surgery, School of Medicine, National Yang-Ming University, 112 Taipei
| | - Hsin-Chen Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, 112 Taipei
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8
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Abstract
Mitochondria play various important roles in energy production, metabolism, and apoptosis. Mitochondrial dysfunction caused by alterations in mitochondrial DNA (mtDNA) can lead to the initiation and progression of cancers and other diseases. These alterations include mutations and copy number variations. Especially, the mutations in D-loop, MT-ND1, and MT-ND5 affect mitochondrial functions and are widely detected in various cancers. Meanwhile, several other mutations have been correlated with muscular and neuronal diseases, especially MT-TL1 is deeply related. These pieces of evidence indicated mtDNA alterations in diseases show potential as a novel therapeutic target. mtDNA repair enzymes are the target for delaying or stalling the mtDNA damage-induced cancer progression and metastasis. Moreover, some mutations reveal a prognosis ability of the drug resistance. Current efforts aim to develop mitochondrial transplantation technique as a direct cure for deregulated mitochondria-associated diseases. This review summarizes the implications of mitochondrial dysfunction in cancers and other pathologies; and discusses the relevance of mitochondria-targeted therapies, along with their contribution as potential biomarkers.
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Affiliation(s)
- Ngoc Ngo Yen Nguyen
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea.,Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea
| | - Sung Soo Kim
- Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Yong Hwa Jo
- Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
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9
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Mahalaxmi I, Santhy K. An overview about mitochondrial DNA mutations in ovarian cancer. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2017.05.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Iyer Mahalaxmi
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, India
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10
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Yusoff AAM, Abdullah WSW, Khair SZNM, Radzak SMA. A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies. Oncol Rev 2019; 13:409. [PMID: 31044027 PMCID: PMC6478002 DOI: 10.4081/oncol.2019.409] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 02/19/2019] [Indexed: 01/04/2023] Open
Abstract
Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA4977) and it has been explored since two decades. In spite of that, its implication in carcinogenesis still unknown and its predictive and prognostic impact remains controversial. This review article provides an overview of some of the cellular and molecular mechanisms underlying mDNA4977 formation and a detailed summary about mDNA4977 reported in various types of cancers. The current knowledges of mDNA4977 as a prognostic and predictive marker are also discussed.
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Affiliation(s)
- Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Wan Salihah Wan Abdullah
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | | | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
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11
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Zhu Y, Dean AE, Horikoshi N, Heer C, Spitz DR, Gius D. Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy. J Clin Invest 2018; 128:3682-3691. [PMID: 30168803 DOI: 10.1172/jci120844] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mammalian cells use a complex network of redox-dependent processes necessary to maintain cellular integrity during oxidative metabolism, as well as to protect against and/or adapt to stress. The disruption of these redox-dependent processes, including those in the mitochondria, creates a cellular environment permissive for progression to a malignant phenotype and the development of resistance to commonly used anticancer agents. An extension of this paradigm is that when these mitochondrial functions are altered by the events leading to transformation and ensuing downstream metabolic processes, they can be used as molecular biomarkers or targets in the development of new therapeutic interventions to selectively kill and/or sensitize cancer versus normal cells. In this Review we propose that mitochondrial oxidative metabolism is altered in tumor cells, and the central theme of this dysregulation is electron transport chain activity, folate metabolism, NADH/NADPH metabolism, thiol-mediated detoxification pathways, and redox-active metal ion metabolism. It is proposed that specific subgroups of human malignancies display distinct mitochondrial transformative and/or tumor signatures that may benefit from agents that target these pathways.
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Affiliation(s)
- Yueming Zhu
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Angela Elizabeth Dean
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Nobuo Horikoshi
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Collin Heer
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Douglas R Spitz
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - David Gius
- Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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12
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Rodrigues-Antunes S, Borges BN. Alterations in mtDNA, gastric carcinogenesis and early diagnosis. Mitochondrial DNA A DNA Mapp Seq Anal 2018; 30:226-233. [DOI: 10.1080/24701394.2018.1475478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- S. Rodrigues-Antunes
- Laboratório de Biologia Molecular “Francisco Mauro Salzano”, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil
| | - B. N. Borges
- Laboratório de Biologia Molecular “Francisco Mauro Salzano”, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil
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13
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Chatre L, Fernandes J, Michel V, Fiette L, Avé P, Arena G, Jain U, Haas R, Wang TC, Ricchetti M, Touati E. Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA-independent mechanisms. Sci Rep 2017; 7:15901. [PMID: 29162845 PMCID: PMC5698309 DOI: 10.1038/s41598-017-15567-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 10/30/2017] [Indexed: 12/31/2022] Open
Abstract
Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis.
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Affiliation(s)
- Laurent Chatre
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS UMR3738, Paris, France
| | - Julien Fernandes
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS ERL3526, Paris, France.,UTechS PBI-CiTech, Institut Pasteur, Paris, 75015, France
| | - Valérie Michel
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,CNRS ERL3526, Paris, France
| | - Laurence Fiette
- Unit of Human Pathology and Animal Models, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,Paris Descartes University, PRES Sorbonne-Paris-Cité, Paris, France
| | - Patrick Avé
- Unit of Human Pathology and Animal Models, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,Paris Descartes University, PRES Sorbonne-Paris-Cité, Paris, France
| | - Giuseppe Arena
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France.,IRCM (Institut de Recherche en Cancérologie de Montpellier), Université de Montpellier, 34298, Montpellier, France.,INSERM U1194, Montpellier, France
| | - Utkarsh Jain
- Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Pettenkoferstraße 9a, D-80336, Munich, Germany.,Amity Institute of Nanotechnology, Amity University, Sector 125, Noida, Uttar Pradesh, 201313, India
| | - Rainer Haas
- Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Pettenkoferstraße 9a, D-80336, Munich, Germany.,German Center for Infection Research [DZIF], LMU, Munich, Germany
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, College of Physicians and Surgeons, Columbia University, New York, USA
| | - Miria Ricchetti
- Stem Cells and Development, Team Stability of Nuclear and Mitochondrial DNA, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France. .,CNRS UMR3738, Paris, France.
| | - Eliette Touati
- Unit of Helicobacter Pathogenesis, Team Genotoxicity, Infection and Cancer, Institut Pasteur, 25-28 Rue du Dr. Roux, Paris, France. .,CNRS ERL3526, Paris, France.
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14
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N Zekri AR, Salama H, Medhat E, Hamdy S, Hassan ZK, Bakr YM, Youssef ASED, Saleh D, Saeed R, Omran D. Potential Diagnostic and Prognostic Value of Lymphocytic Mitochondrial DNA Deletion in Relation to Folic Acid Status in HCV-Related Hepatocellular Carcinoma. ASIAN PACIFIC JOURNAL OF CANCER PREVENTION : APJCP 2017; 18:2451-2457. [PMID: 28952275 PMCID: PMC5720650 DOI: 10.22034/apjcp.2017.18.9.2451] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Objective: We assessed the possibility of using mitochondrial (mt) DNA deletion as a molecular biomarker for disease progression in HCV-related hepatocellular carcinoma (HCC) and to identify its association with folic acid status. Methods: Serum folic acid and lymphocytic mtDNA deletions were assessed in 90 patients; 50 with HCC, 20 with liver cirrhosis (LC), and 20 with chronic hepatitis C (CHC) compared to 10 healthy control subjects. The diagnostic accuracy of mtDNA deletions frequency was evaluated using receiver-operating characteristic (ROC) curve analysis Survival analysis was performed using the Kaplan-Meier method. Differences in the survival rates were compared using log-rank test. Result: Our data revealed a significant elevation of mtDNA deletions frequency in the HCC group compared to the other groups (P-value <0.01). Also, our data showed a significant correlation between folate deficiency and high frequency of mtDNA deletions in patients with HCV-related HCC when compared to the other groups (r= -0.094 and P-value <0.05). Moreover, the size of the hepatic focal lesion in the HCC patients was positively correlated with mtDNA deletions (r= 0.09 and P-value <0.01). The median survival time for the HCC patients with high frequency of mtDNA deletions (∆Ct ≥3.9; 5.7+ 0.6 months) was significantly shorter than those with low mtDNA deletions frequency (∆Ct < 3.9; 11.9+ 0.04 months, P-value <0.01). Conclusion: Our data provided an evidence that lymphocytic mtDNA deletion could be used as non-invasive biomarker for disease progression and patients’ survival in HCV-related HCC. Also, our findings implied a causal relationship between the folate deficiency and the high mtDNA deletions frequency among Egyptian patients with HCV related HCC.
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Affiliation(s)
- Abdel Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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15
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Hashemi S, Nowzari Dalini A, Jalali A, Banaei-Moghaddam AM, Razaghi-Moghadam Z. Cancerouspdomains: comprehensive analysis of cancer type-specific recurrent somatic mutations in proteins and domains. BMC Bioinformatics 2017; 18:370. [PMID: 28814324 PMCID: PMC5559820 DOI: 10.1186/s12859-017-1779-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/02/2017] [Indexed: 01/19/2023] Open
Abstract
Background Discriminating driver mutations from the ones that play no role in cancer is a severe bottleneck in elucidating molecular mechanisms underlying cancer development. Since protein domains are representatives of functional regions within proteins, mutations on them may disturb the protein functionality. Therefore, studying mutations at domain level may point researchers to more accurate assessment of the functional impact of the mutations. Results This article presents a comprehensive study to map mutations from 29 cancer types to both sequence- and structure-based domains. Statistical analysis was performed to identify candidate domains in which mutations occur with high statistical significance. For each cancer type, the corresponding type-specific domains were distinguished among all candidate domains. Subsequently, cancer type-specific domains facilitated the identification of specific proteins for each cancer type. Besides, performing interactome analysis on specific proteins of each cancer type showed high levels of interconnectivity among them, which implies their functional relationship. To evaluate the role of mitochondrial genes, stem cell-specific genes and DNA repair genes in cancer development, their mutation frequency was determined via further analysis. Conclusions This study has provided researchers with a publicly available data repository for studying both CATH and Pfam domain regions on protein-coding genes. Moreover, the associations between different groups of genes/domains and various cancer types have been clarified. The work is available at http://www.cancerouspdomains.ir. Electronic supplementary material The online version of this article (doi:10.1186/s12859-017-1779-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | - Adrin Jalali
- Max Planck Institute for Informatics, Saarland Informatics, Campus, 66123, Saarbrücken, Germany
| | | | - Zahra Razaghi-Moghadam
- Faculty of New Sciences and Technologies, University of Tehran, North Kargar St, Tehran, Tehran, 1439957131, Iran.
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Strickertsson JAB, Desler C, Rasmussen LJ. Bacterial infection increases risk of carcinogenesis by targeting mitochondria. Semin Cancer Biol 2017; 47:95-100. [PMID: 28754330 DOI: 10.1016/j.semcancer.2017.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 01/19/2023]
Abstract
As up to a fifth of all cancers worldwide, have now been linked to microbial infections, it is essential to understand the carcinogenic nature of the bacterial/host interaction. This paper reviews the bacterial targeting of mediators of mitochondrial genomic fidelity and of mitochondrial apoptotic pathways, and compares the impact of the bacterial alteration of mitochondrial function to that of cancer. Bacterial virulence factors have been demonstrated to induce mutations of mitochondrial DNA (mtDNA) and to modulate DNA repair pathways of the mitochondria. Furthermore, virulence factors can induce or impair the intrinsic apoptotic pathway. The effect of bacterial targeting of mitochondria is analogous to behavior of mitochondria in a wide array of tumours, and this strongly suggests that mitochondrial targeting of bacteria is a risk factor for carcinogenesis.
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Affiliation(s)
| | - Claus Desler
- Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Lene Juel Rasmussen
- Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
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17
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Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1320241. [PMID: 28744336 PMCID: PMC5506471 DOI: 10.1155/2017/1320241] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 04/10/2017] [Accepted: 05/10/2017] [Indexed: 02/06/2023]
Abstract
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
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18
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Jiang J, Zhao JH, Wang XL, DI JI, Liu ZB, Li GY, Wang MZ, Li Y, Chen R, Ge RL. Analysis of mitochondrial DNA in Tibetan gastric cancer patients at high altitude. Mol Clin Oncol 2015; 3:875-879. [PMID: 26171199 DOI: 10.3892/mco.2015.539] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 10/07/2014] [Indexed: 12/20/2022] Open
Abstract
The highest risk areas of gastric cancer are currently Japan, Korea and China; Qinghai, a high-altitude area, has one of the highest gastric cancer rates in China. The incidence of gastric cancer is higher in the Tibetan ethnic group compared to that in the Han ethnic group in Qinghai. This study was conducted to determine the clinical characteristics of mitochondrial DNA (mtDNA) mutations and copy numbers among Tibetans with gastric cancer residing at high altitudes and investigate the association between adaptations to hypoxic conditions and oncogenesis. A total of 23 Tibetan gastric cancer patients and 40 matched controls were recruited in this study. Leukocyte mtDNA genes and copy numbers were analyzed. The haplogroups were classified based on mitochondrial gene sequences. A total of 56.5% of the study participants had used alcohol at some point in their lives and 73.9% were positive for Helicobacter pylori (H. pylori). Eight mutations in 8 mitochondrial genes were identified in 43.4% of the Tibetan cancer patient group. There were no significant differences in leukocyte mtDNA copy number levels based on smoking status, alchohol consumption, obesity or H. pylori infection between the control and cancer groups. Statistical differences were also not found between gastric cancer patients with and those without mtDNA mutations. The majority of Tibetan patients with gastric cancer belonged to the mitochondrial haplogroup M9. In conclusion, Tibetans with gastric cancer residing at high altitudes exhibited a wide spectrum of mtDNA mutations. However, leukocyte mtDNA copy numbers in stage II gastric cancer were not statistically different compared to those in healthy Tibetans.
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Affiliation(s)
- Jun Jiang
- Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai 810001, P.R. China ; Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Jun-Hui Zhao
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Xue-Lian Wang
- Department of Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - J I DI
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Zhi-Bo Liu
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Guo-Yuan Li
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Miao-Zhou Wang
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Yan Li
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Rong Chen
- Department of Oncology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Ri-Li Ge
- Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai 810001, P.R. China
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19
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Lee JH, Kim DK. Microsatellite Instability of Nuclear and Mitochondrial DNAs in Gastric Carcinogenesis. Asian Pac J Cancer Prev 2014. [DOI: 10.7314/apjcp.2014.15.19.8027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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20
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Fernandes J, Michel V, Camorlinga-Ponce M, Gomez A, Maldonado C, De Reuse H, Torres J, Touati E. Circulating mitochondrial DNA level, a noninvasive biomarker for the early detection of gastric cancer. Cancer Epidemiol Biomarkers Prev 2014; 23:2430-8. [PMID: 25159292 DOI: 10.1158/1055-9965.epi-14-0471] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Gastric cancer represents a major health burden worldwide and is often diagnosed at an advanced stage. Biomarkers for screening and prevention of gastric cancer are missing. Changes in peripheral blood mitochondrial DNA (mtDNA) have emerged as a potential preventive/diagnosis biomarker for cancer risk. We aimed to determine whether peripheral leukocytes mtDNA levels are associated with stages of the gastric carcinogenesis cascade. METHODS We measured mtDNA by quantitative real-time PCR assay in peripheral leukocytes of 28 patients with non-atrophic gastritis (NAG), 74 patients with gastric cancer, and 48 matched asymptomatic controls. In parallel, the serologic level of IL8 was determined. RESULTS Mean mtDNA level was higher in patients with gastric cancer (P = 0.0095) than in controls, with values >8.46 significantly associated with gastric cancer (OR, 3.93). Three ranges of mtDNA values were identified: interval I, <2.0; interval II, 2.0-20; and interval III, >20. Interval I included mainly NAG cases, and few gastric cancer samples and interval III corresponded almost exclusively to patients with gastric cancer. All controls fell in interval II, together with some NAG and gastric cancer cases. IL8 levels were significantly higher in patients with gastric cancer (P < 0.05), with levels >50 pg/mL observed exclusively in patients with gastric cancer, allowing to distinguish them within interval II. We validated mtDNA results in a second cohort of patients, confirming that mtDNA was significantly higher in gastric cancer than in patients with preneoplasia. CONCLUSIONS Circulating levels of mtDNA and IL8 constitute a potential biomarker for the early detection of gastric cancer. IMPACT Our findings lead us to propose a new noninvasive method to detect patients with gastric cancer risk.
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Affiliation(s)
- Julien Fernandes
- Institut Pasteur, Department of Microbiology, Helicobacter Pathogenesis Unit. CNRS, Paris, France. CNRS, ERL3526, Paris, France
| | - Valérie Michel
- Institut Pasteur, Department of Microbiology, Helicobacter Pathogenesis Unit. CNRS, Paris, France. CNRS, ERL3526, Paris, France
| | | | - Alejandro Gomez
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, IMSS, Mexico City, Mexico
| | | | - Hilde De Reuse
- Institut Pasteur, Department of Microbiology, Helicobacter Pathogenesis Unit. CNRS, Paris, France. CNRS, ERL3526, Paris, France
| | - Javier Torres
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, IMSS, Mexico City, Mexico
| | - Eliette Touati
- Institut Pasteur, Department of Microbiology, Helicobacter Pathogenesis Unit. CNRS, Paris, France. CNRS, ERL3526, Paris, France.
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21
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Ye F, Samuels DC, Clark T, Guo Y. High-throughput sequencing in mitochondrial DNA research. Mitochondrion 2014; 17:157-63. [PMID: 24859348 PMCID: PMC4149223 DOI: 10.1016/j.mito.2014.05.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 04/04/2014] [Accepted: 05/13/2014] [Indexed: 12/14/2022]
Abstract
Next-generation sequencing, also known as high-throughput sequencing, has greatly enhanced researchers' ability to conduct biomedical research on all levels. Mitochondrial research has also benefitted greatly from high-throughput sequencing; sequencing technology now allows for screening of all 16,569 base pairs of the mitochondrial genome simultaneously for SNPs and low level heteroplasmy and, in some cases, the estimation of mitochondrial DNA copy number. It is important to realize the full potential of high-throughput sequencing for the advancement of mitochondrial research. To this end, we review how high-throughput sequencing has impacted mitochondrial research in the categories of SNPs, low level heteroplasmy, copy number, and structural variants. We also discuss the different types of mitochondrial DNA sequencing and their pros and cons. Based on previous studies conducted by various groups, we provide strategies for processing mitochondrial DNA sequencing data, including assembly, variant calling, and quality control.
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Affiliation(s)
- Fei Ye
- Department of Biostatistics, Vanderbilt University, Nashville, TN 37232, USA
| | - David C Samuels
- Center for Human Genetics, Vanderbilt University, Nashville, TN 37232, USA
| | - Travis Clark
- Vanderbilt Technology for Advanced Genomics, Vanderbilt University, Nashville, TN 37232, USA
| | - Yan Guo
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
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22
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Mottaghi-Dastjerdi N, Soltany-Rezaee-Rad M, Sepehrizadeh Z, Roshandel G, Ebrahimifard F, Setayesh N. Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization. Hum Exp Toxicol 2014; 34:3-11. [PMID: 24812152 DOI: 10.1177/0960327114532386] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC.
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Affiliation(s)
- N Mottaghi-Dastjerdi
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Pharmaceutical Sciences Research Center, Sari School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Islamic Republic of Iran
| | - M Soltany-Rezaee-Rad
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Pharmaceutical Sciences Research Center, Sari School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Islamic Republic of Iran
| | - Z Sepehrizadeh
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - G Roshandel
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Golestan, Islamic Republic of Iran
| | - F Ebrahimifard
- Department of General Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - N Setayesh
- Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
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Dai JG, Zhang ZY, Liu QX, Min JX. Mitochondrial genome microsatellite instability and copy number alteration in lung carcinomas. Asian Pac J Cancer Prev 2013; 14:2393-9. [PMID: 23725147 DOI: 10.7314/apjcp.2013.14.4.2393] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Mitochondrial DNA (mtDNA) is considered a hotspot of mutations in various tumors. However, the relationship between microsatellite instability (MSI) and mtDNA copy number alterations in lung cancer has yet to be fully clarifieds. In the current study, we investigated the copy number and MSI of mitochondrial genome in lung carcinomas, as well as their significance for cancer development. METHODS The copy number and MSI of mtDNA in 37 matched lung carcinoma/adjacent histological normal lung tissue samples were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays for sequence variation, followed by sequence analysis and fluorogenic 5'-nuclease real-time PCR. Student's t test and linear regression analyses were employed to analyze the association between mtDNA copy number alterations and mitochondrial MSI (mtMSI). RESULTS The mean copy number of mtDNA in lung carcinoma tissue samples was significantly lower than that of the adjacent histologically normal lung tissue samples (p < 0.001). mtMSI was detected in 32.4% (12/37) of lung carcinoma samples. The average copy number of mtDNA in lung carcinoma samples containing mtMSI was significantly lower than that in the other lung carcinoma samples (P < 0.05). CONCLUSIONS Results suggest that mtMSI may be an early and important event in the progression of lung carcinogenesis, particularly in association with variation in mtDNA copy number.
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Affiliation(s)
- Ji-Gang Dai
- Department of Thoracic Cardiovascular Surgery of Xinqiao Hospital, the Third Military Medical University, Chongqing, China
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24
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Tipirisetti NR, Lakshmi RK, Govatati S, Govatati S, Vuree S, Singh L, Raghunadha Rao D, Bhanoori M, Vishnupriya S. Mitochondrial genome variations in advanced stage breast cancer: A case–control study. Mitochondrion 2013; 13:372-8. [DOI: 10.1016/j.mito.2013.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 02/09/2013] [Accepted: 04/19/2013] [Indexed: 12/19/2022]
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25
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Strickertsson JAB, Desler C, Martin-Bertelsen T, Machado AMD, Wadstrøm T, Winther O, Rasmussen LJ, Friis-Hansen L. Enterococcus faecalis infection causes inflammation, intracellular oxphos-independent ROS production, and DNA damage in human gastric cancer cells. PLoS One 2013; 8:e63147. [PMID: 23646188 PMCID: PMC3639970 DOI: 10.1371/journal.pone.0063147] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 04/02/2013] [Indexed: 12/31/2022] Open
Abstract
Background Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. Methods To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. Results Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up-regulated while DNA damage repair and cell cycle control genes were down-regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. Conclusions Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-κB inflammatory response as well as impaired DNA damage response and cell cycle control gene expression. Transcript profiling Array Express accession number E-MEXP-3496.
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Affiliation(s)
- Jesper A. B. Strickertsson
- Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Claus Desler
- Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tomas Martin-Bertelsen
- Department of Biology and Biotech Research and Innovation Centre, The Bioinformatics Centre, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Ana Manuel Dantas Machado
- Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Torkel Wadstrøm
- Department of Clinical Microbiology, University of Lund, Lund, Sweden
| | - Ole Winther
- Department of Biology and Biotech Research and Innovation Centre, The Bioinformatics Centre, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- DTU Informatics, Technical University of Denmark, Copenhagen, Denmark
| | - Lene Juel Rasmussen
- Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lennart Friis-Hansen
- Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
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Parr RL, Jakupciak JP, Birch-Machin MA, Dakubo GD. The mitochondrial genome: a biosensor for early cancer detection? ACTA ACUST UNITED AC 2013; 1:169-82. [PMID: 23489304 DOI: 10.1517/17530059.1.2.169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Mutations in the mitochondrial genome have been reported as biomarkers for the detection of cancer. Hallmarks of cancer development include the accumulation of genetic alterations in the mitochondrial and nuclear genomes. Damage to mitochondria affects energy metabolism, generation of reactive oxygen species, apoptosis, cell growth and other processes that contribute to the neoplastic process. Furthermore, mitochondrial DNA mutations occur frequently in cancer. Little work has been done to link a pathway between mitochondrial mutations and cancer etiology. Volumes of work have been reported on the association of mitochondrial mutations and almost all types of cancer including the use of body fluids for early detection. This review examines the measurement of mitochondrial mutations for the application of detecting human tumor tissue.
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Affiliation(s)
- Ryan L Parr
- Vice President of Research, Genesis Genomics, Inc., 290 Munro Street, Ste 1000, Thunder Bay, Ontario, P7A 7T1, Canada +1 807 346 8100; +1 807 346 8105 ;
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27
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Govatati S, Tipirisetti NR, Perugu S, Kodati VL, Deenadayal M, Satti V, Bhanoori M, Shivaji S. Mitochondrial genome variations in advanced stage endometriosis: a study in South Indian population. PLoS One 2012; 7:e40668. [PMID: 22815783 PMCID: PMC3398934 DOI: 10.1371/journal.pone.0040668] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 06/11/2012] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Endometriosis is a chronic gynecological benign disease that shares several features similar to malignancy. Mitochondrial DNA (mtDNA) mutations have been reported in all most all types of tumors. However, it is not known as to whether mtDNA mutations are associated with endometriosis. METHODOLOGY We sequenced the entire mitochondrial genome of analogous ectopic and eutopic endometrial tissues along with blood samples from 32 advanced stage endometriosis patients to analyze the role of somatic and germ-line mtDNA variations in pathogenesis of endometriosis. All ectopic tissues were screened for tumor-specific mtDNA deletions and microsatellite instability (MSI). We also performed mtDNA haplogrouping in 128 patients and 90 controls to identify its possible association with endometriosis risk. PRINCIPAL FINDINGS We identified 51 somatic (novel: 31; reported: 20) and 583 germ-line mtDNA variations (novel: 53; reported: 530) in endometriosis patients. The A13603G, a novel missense mutation which leads to a substitution from serine to glycine at the codon 423 of ND5 gene showed 100% incidence in ectopic tissues. Interestingly, eutopic endometrium and peripheral leukocytes of all the patients showed heteroplasmy (A/G; 40-80%) at this locus, while their ectopic endometrium showed homoplasmic mutant allele (G/G). Superimposition of native and mutant structures of ND5 generated by homology modeling revealed no structural differences. Tumor-specific deletions and MSI were not observed in any of the ectopic tissues. Haplogrouping analysis showed a significant association between haplogroup M5 and endometriosis risk (P: 0.00069) after bonferroni correction. CONCLUSIONS Our findings substantiate the rationale for exploring the mitochondrial genome as a biomarker for the diagnosis of endometriosis.
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Affiliation(s)
- Suresh Govatati
- Department of Biochemistry, Osmania University, Hyderabad, Andhra Pradesh, India
| | | | - Shyam Perugu
- Department of Biochemistry, Osmania University, Hyderabad, Andhra Pradesh, India
| | | | - Mamata Deenadayal
- Infertility Institute and Research Centre, Secundrabad, Andhra Pradesh, India
| | - Vishnupriya Satti
- Department of Genetics, Osmania University, Hyderabad, Andhra Pradesh, India
| | - Manjula Bhanoori
- Department of Biochemistry, Osmania University, Hyderabad, Andhra Pradesh, India
| | - S. Shivaji
- Centre for Cellular and Molecular Biology, Hyderabad, Andhra Pradesh, India
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Hung WY, Huang KH, Wu CW, Chi CW, Kao HL, Li AFY, Yin PH, Lee HC. Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells. Biochim Biophys Acta Gen Subj 2012; 1820:1102-10. [PMID: 22561002 DOI: 10.1016/j.bbagen.2012.04.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 03/19/2012] [Accepted: 04/18/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Mitochondrial dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear. METHODS Mitochondria specific inhibitors, oligomycin and antimycin A, were used to induce mitochondrial dysfunction and to enhance cell migration of human gastric cancer SC-M1 cells. Antioxidant N-acetylcysteine (NAC) was used for evaluating the effect of reactive oxygen species (ROS). Protein expressions of epithelial-to-mesenchymal transition (EMT) markers and the cell-extracellular matrix (ECM) adhesion molecules, the integrin family, were analyzed. A migratory subpopulation of SC-M1 cells (SC-M1-3rd) was selected using a transwell assay for examining the association of mitochondrial bioenergetic function, intracellular ROS content and β5-integrin expression. Clinicopathologic characteristics of β5-integrin expression were analyzed in GC specimens by immunohistochemical staining. RESULTS Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of β5-integrin and cell surface expression of αvβ5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-αvβ5-integrin neutralizing antibody respectively prevented the mitochondrial dysfunction-induced cell migration. The selected migratory SC-M1-3rd cells showed impaired mitochondrial function, higher mitochondria-generated ROS, and increased β5-integrin expression. The migration ability was also repressed by anti-αvβ5-integrin neutralizing antibody. In clinical specimens, GCs with higher β5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated β5-integrin expression. GENERAL SIGNIFICANCE These results support the role of mitochondrial dysfunction in GC progression.
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Affiliation(s)
- Wen-Yi Hung
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, and Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
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Abstract
Mitochondria are ubiquitous organelles in eukaryotic cells principally responsible for regulating cellular energy metabolism, free radical production, and the execution of apoptotic pathways. Abnormal oxidative phosphorylation (OXPHOS) and aerobic metabolism as a result of mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. In the past decades, numerous somatic mutations in both the coding and control regions of mitochondrial DNA (mtDNA) have been extensively examined in a broad range of primary human cancers, underscoring that accumulation of mtDNA alterations may be a critical factor in eliciting persistent mitochondrial defects and consequently contributing to cancer initiation and progression. However, the roles of these mtDNA mutations in the carcinogenic process remain largely unknown. This review outlines a wide variety of somatic mtDNA mutations identified in common human malignancies and highlights recent advances in understanding the causal roles of mtDNA variations in neoplastic transformation and tumor progression. In addition, it briefly illustrates how mtDNA alterations activate mitochondria-to-nucleus retrograde signaling so as to modulate the expression of relevant nuclear genes or induce epigenetic changes and promote malignant phenotypes in cancer cells. The present state of our knowledge regarding how mutational changes in the mitochondrial genome could be used as a diagnostic biomarker for early detection of cancer and as a potential target in the development of new therapeutic approaches is also discussed. These findings strongly indicate that mtDNA mutations exert a crucial role in the pathogenic mechanisms of tumor development, but continued investigations are definitely required to further elucidate the functional significance of specific mtDNA mutations in the etiology of human cancers.
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Potenza L, Calcabrini C, Bellis RD, Mancini U, Polidori E, Zeppa S, Alloni R, Cucchiarini L, Dacha M. Effect of surgical stress on nuclear and mitochondrial DNA from healthy sections of colon and rectum of patients with colorectal cancer. J Biosci 2011; 36:243-51. [PMID: 21654079 DOI: 10.1007/s12038-011-9064-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Surgical resection at any location in the body leads to stress response with cellular and subcellular change, leading to tissue damage. The intestine is extremely sensitive to surgical stress with consequent postoperative complications. It has been suggested that the increase of reactive oxygen species as subcellular changes plays an important role in this process. This article focuses on the effect of surgical stress on nuclear and mitochondrial DNA from healthy sections of colon and rectum of patients with colorectal cancer. Mitochondrial DNA copy number, mitochondrial common deletion and nuclear and mitochondrial 8-oxo-2'-deoxyguanosine content were measured. Both the colon and rectal tissue were significantly damaged either at the nuclear or mitochondrial level. In particular, mitochondrial DNA was more damaged in rectum than in colon. The present investigation found an association between surgical stress and nuclear and mitochondrial DNA damage, suggesting that surgery may generate an increase in free radicals, which trigger a cascade of molecular changes, including alterations in DNA.
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Affiliation(s)
- Lucia Potenza
- Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino 'Carlo Bo', Urbino, Italy.
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Effects of oxidative stress on mitochondrial content and integrity of human anastomotic colorectal dehiscence: a preliminary DNA study. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2011; 25:433-9. [PMID: 21912768 DOI: 10.1155/2011/741073] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Anastomotic dehiscence is one of the most severe complications of colorectal surgery. Gaining insight into the molecular mechanisms responsible for the development of anastomotic dehiscence following colorectal surgery is important for the reduction of postoperative complications. OBJECTIVE Based on the close relationship between surgical stress and oxidative stress, the present study aimed to determine whether a correlation exists between increased levels of reactive oxygen species and colorectal anastomotic dehiscence. METHODS Patients who underwent surgical resection for colorectal cancer were divided into three groups: patients with anastomotic dehiscence (group 1); patients without dehiscence who underwent neoadjuvant radiochemotherapy (group 2); and patients without anastomotic dehiscence who did not undergo neoadjuvant radiochemotherapy (group 3). Quantitative polymerase chain reaction and real-time polymerase chain reaction assays were performed to measure nuclear DNA and mitochondrial DNA (mtDNA) content, and possible oxidative damage to nonmalignant colon and rectal tissues adjacent to the anastomoses. RESULTS mtDNA content was reduced in the colon tissue of patients in groups 1 and 2. Rectal mtDNA was found to be more damaged than colonic mtDNAs in all groups. The 4977 bp common deletion was observed in the mtDNA of tissues from both the colon and rectum of all patients. DISCUSSION Patients in groups 1 and 2 were more similar to one another than to group 3, probably due to higher levels of reactive oxygen species in the mitochondria; the greater damage found in the rectum suggests that dehiscence originates primarily from the rectal area. CONCLUSIONS The present study of mtDNA analyses of normal human colon and rectal tissues from patients with colorectal cancer is among the first of its kind.
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Kassem AM, El-Guendy N, Tantawy M, Abdelhady H, El-Ghor A, Abdel Wahab AH. Mutational hotspots in the mitochondrial D-loop region of cancerous and precancerous colorectal lesions in Egyptian patients. DNA Cell Biol 2011; 30:899-906. [PMID: 21612400 DOI: 10.1089/dna.2010.1186] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Mutations in the mitochondrial genome (mtDNA) are associated with different types of cancer, specifically colorectal cancer (CRC). However, few studies have been performed on precancerous lesions, such as ulcerative colitis (UC) lesions and adenomatous polyps (AP). The aim of this study was to identify mtDNA mutations in the cancerous and precancerous lesions of Egyptian patients. An analysis of the mutations found in six regions of the mtDNA genome (ND1, ND5, COI, tRNAser, D-loop 1, and 2) in 80 Egyptian patients (40 CRC, 20 UC, and 20 AP) was performed using polymerase chain reaction-single-strand conformational polymorphism techniques and followed up by direct sequencing. The overall incidence of mutations was 25%, 25%, and 35% in CRC, UC, and AP cases, respectively. Although there was no common mutation pattern within each group, a large number of mutations were detected in the D-loop region in all of the groups. Some mutations (e.g., T414G) were detected repeatedly in precancerous (UC and AP) and cancerous lesions. Mutations detected in patients with CRC were predominantly found in the ND1 gene (40%). Our preliminary study suggests that Egyptian patients with CRC have a large number of mtDNA mutations, especially in the D-loop region, which have not been previously reported. Mutations in the mtDNA of precancerous lesions (i.e., AP and UC) may contribute to transformation events that lead to CRC.
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Affiliation(s)
- Abdel Meguid Kassem
- Tropical Medicine Department, Faculty of Medicine, Cairo University, New Maadi, Cairo, Egypt.
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Lee HC, Chang CM, Chi CW. Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 2010; 9 Suppl 1:S47-58. [PMID: 20816876 DOI: 10.1016/j.arr.2010.08.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mitochondria are intracellular organelles responsible for generating ATP through respiration and oxidative phosphorylation (OXPHOS), producing reactive oxygen species, and initiating and executing apoptosis. Mitochondrial dysfunction has been observed to be an important hallmark of aging and cancer. Because mitochondrial DNA (mtDNA) is important in maintaining functionally competent organelles, accumulation of mtDNA mutations can affect energy production, oxidative stress, and cell survival, which may contribute to aging and/or carcinogenesis. This review outlines a variety of somatic mtDNA mutations identified in aging tissues and human cancers, as well as recent advances in understanding the causal role of mtDNA mutations in the aging process and cancer progression. Mitochondrial dysfunction elicited by somatic mutations in mtDNA could induce apoptosis in aging cells and some cancer cells with severe mtDNA mutations. In addition, it could activate mitochondria-to-nucleus retrograde signaling to modulate the expression of nuclear genes involved in a metabolic shift from OXPHOS to glycolysis, facilitate cells to adapt to altered environments and develop resistance to chemotherapeutic agents, or promote metastatic properties of cancer cells. These findings suggest that accumulation of somatic mtDNA mutations is not only an important contributor to human aging but also plays a critical role in cancer progression.
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Yadav DS, Devi TR, Ihsan R, Mishra AK, Kaushal M, Chauhan PS, Bagadi SAR, Sharma J, Zamoawia E, Verma Y, Nandkumar A, Saxena S, Kapur S. Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population. Genet Test Mol Biomarkers 2010; 14:715-23. [PMID: 20854097 DOI: 10.1089/gtmb.2010.0087] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Widespread use of tobacco and betel quid consumption and a high incidence of tobacco-associated aerodigestive tract cancers have been reported in different ethnic groups from several regions of Northeast (NE) India. This study was done to explore the possibility of phase II metabolic enzymes being responsible for the high prevalence of cancers in this region of India. METHODS Samples from 370 cases with oral, gastric, and lung cancers and 270 controls were analyzed for polymorphism of glutathione-S-transferase (GST) genes using polymerase chain reaction-restriction fragment length polymorphism-based methods. RESULTS AND CONCLUSIONS Tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was found to be a risk factor for oral cancer but not for gastric or lung cancer. The variant genotypes of GSTP1 were not associated with any of the aerodigestive tract cancers. GSTT1 and GSTM1 null genotypes appeared to play a protective role for lung cancer (odds ratio [OR] = 0.47, 95% confidence interval [95% CI]: 0.24-0.93, p = 0.03) and (OR = 0.52, 95% CI: 0.28-0.96, p = 0.04), but they were not associated with oral and gastric cancers. However, when data was analyzed in different geographic regions the GSTT1 null genotype was found to be a significant risk factor for oral (OR = 2.58, 95% CI 1.01-6.61, p = 0.05) as well as gastric cancer (OR = 3.08, 95% CI 1.32-7.19, p = 0.009) in samples obtained from the Assam region of NE India. This is the first study on the association of GST polymorphisms and aerodigestive tract cancers in the high-risk region of NE India.
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Touati E. When bacteria become mutagenic and carcinogenic: lessons from H. pylori. Mutat Res 2010; 703:66-70. [PMID: 20709622 DOI: 10.1016/j.mrgentox.2010.07.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Accepted: 07/30/2010] [Indexed: 12/24/2022]
Abstract
More and more convincing data link bacteria to the development of cancers. How bacteria act as mutagens by altering host genomes, what are the different strategies they develop and what consequences do they have on infection-associated pathogenesis are the main questions addressed in this review, which focuses in particular on Helicobacter pylori infection. H. pylori is a major risk factor for gastric cancer development. Its oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa, associated with its capacity to persistently colonize the human stomach. However, direct genotoxicity of H. pylori through the action of bacterial cytotoxin or resulting from a DNA damaging effect of its metabolic derivatives as nitroso compounds cannot be excluded. Numerous studies have investigated inflammation-associated DNA damaging activity and mutagenic response due to H. pylori infection in both human and animal models. Recent findings on its mutagenic effects at the nuclear and mitochondrial genome and related DNA damage are reviewed. This genotoxic activity associated with oxidative species produced during inflammation is linked to the decreased efficiency of DNA repair systems. DNA methylation, which plays an important role in the regulation of the host response to H. pylori infection, is also documented. Furthermore, H. pylori affects genome integrity by increasing activation-induced cytidine deaminase (AID), a DNA/RNA editing cytidine deaminase linking mutagenesis and tumorigenesis. These different strategies occurring during bacteria-host cell interaction, lead to nucleotide modifications and genome instabilities recognized as early events in the carcinogenesis process and contribute to the oncogenic properties of H. pylori infection.
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Affiliation(s)
- Eliette Touati
- Institut Pasteur, Unité de Pathogenèse de Helicobacter, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.
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Wu IC, Ohsawa I, Fuku N, Tanaka M. Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann N Y Acad Sci 2010; 1201:111-20. [DOI: 10.1111/j.1749-6632.2010.05636.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Machado AMD, Figueiredo C, Seruca R, Rasmussen LJ. Helicobacter pylori infection generates genetic instability in gastric cells. Biochim Biophys Acta Rev Cancer 2010; 1806:58-65. [PMID: 20122996 DOI: 10.1016/j.bbcan.2010.01.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 01/16/2010] [Accepted: 01/24/2010] [Indexed: 01/02/2023]
Abstract
The discovery that Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which H. pylori induces carcinogenesis. Gastric cancer shows genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair pathways. As such, this review highlights the consequences of H. pylori infection on the integrity of DNA in the host cells. By down-regulating major DNA repair pathways, H. pylori infection has the potential to generate mutations. In addition, H. pylori infection can induce direct changes on the DNA of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly, H. pylori infection generates genetic instability in nuclear and mitochondrial DNA. Based on the reviewed literature we conclude that H. pylori infection promotes gastric carcinogenesis by at least three different mechanisms: (1) a combination of increased endogenous DNA damage and decreased repair activities, (2) induction of mutations in the mitochondrial DNA, and (3) generation of a transient mutator phenotype that induces mutations in the nuclear genome.
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Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res 2009; 19:802-15. [PMID: 19532122 DOI: 10.1038/cr.2009.69] [Citation(s) in RCA: 204] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Alterations in oxidative phosphorylation resulting from mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA (mtDNA) mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.
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Hung WY, Wu CW, Yin PH, Chang CJ, Li AFY, Chi CW, Wei YH, Lee HC. Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim Biophys Acta Gen Subj 2009; 1800:264-70. [PMID: 19527772 DOI: 10.1016/j.bbagen.2009.06.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Accepted: 06/06/2009] [Indexed: 01/02/2023]
Abstract
BACKGROUND Somatic mutation in mitochondrial DNA (mtDNA) has been proposed to contribute to initiation and progression of human cancer. In our previous study, high frequency of somatic mutations was found in the D-loop region of mtDNA of gastric cancers. However, it is unclear whether somatic mutations occur in the coding region of mtDNA of gastric cancers. METHODS Using DNA sequencing, we studied 31 gastric cancer specimens and corresponding non-cancerous stomach tissues. Moreover, a human gastric cancer SC-M1 cell line was treated with oligomycin to induce mitochondrial dysfunction. Cisplatin sensitivity and cell migration were analyzed. RESULTS We identified eight somatic mutations in the coding region of mtDNAs of seven gastric cancer samples (7/31, 22.6%). Patients with somatic mutations in the entire mtDNA of gastric cancers did not show significant association with their clinicopathologic features. Among the eight somatic mutations, five point mutations (G3697A, G4996A, G9986A, C12405T and T13015C) are homoplasmic and three mutations (5895delC, 7472insC and 12418insA) are heteroplasmic. Four (4/8, 50%) of these somatic mutations result in amino acid substitutions in the highly conserved regions of mtDNA, which potentially lead to mitochondrial dysfunction. In addition, in vitro experiments in SC-M1 cells revealed that oligomycin-induced mitochondrial dysfunction promoted resistance to cisplatin and enhanced cell migration. N-acetyl cysteine was effective in the prevention of the oligomycin-enhanced migration, which suggests that reactive oxygen species generated by defective mitochondria may be involved in the enhanced migration of SC-M1 cells. GENERAL SIGNIFICANCE Our results suggest that somatic mtDNA mutations and mitochondrial dysfunction may play an important role in the malignant progression of gastric cancer.
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Affiliation(s)
- Wen-Yi Hung
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112, ROC
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Machado AMD, Figueiredo C, Touati E, Máximo V, Sousa S, Michel V, Carneiro F, Nielsen FC, Seruca R, Rasmussen LJ. Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res 2009; 15:2995-3002. [PMID: 19383819 DOI: 10.1158/1078-0432.ccr-08-2686] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Helicobacter pylori is a major cause of gastric carcinoma. To investigate a possible link between bacterial infection and genetic instability of the host genome, we examined the effect of H. pylori infection on known cellular repair pathways in vitro and in vivo. Moreover, various types of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. EXPERIMENTAL DESIGN We observed the effects of H. pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of H. pylori infection on base excision repair and mismatch repair (MMR) was analyzed by reverse transcription-PCR, Western blot, and activity assays. In mice, MMR expression was analyzed by reverse transcription-PCR and the CA repeat instabilities were examined by Mutation Detection Enhancement gel electrophoresis. Mutation spectra in AGS cells and chronic gastritis tissue were determined by PCR, single-stranded conformation polymorphism, and sequencing. H. pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization. RESULTS Following H. pylori infection, the activity and expression of base excision repair and MMR are down-regulated both in vitro and in vivo. Moreover, H. pylori induces genomic instability in nuclear CA repeats in mice and in mtDNA of AGS cells and chronic gastritis tissue, and this effect in mtDNA is associated with bacterial virulence. CONCLUSIONS Our results suggest that H. pylori impairs central DNA repair mechanisms, inducing a transient mutator phenotype, rendering gastric epithelial cells vulnerable to the accumulation of genetic instability and thus contributing to gastric carcinogenesis in infected individuals.
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Máximo V, Lima J, Soares P, Sobrinho-Simões M. Mitochondria and cancer. Virchows Arch 2009; 454:481-95. [PMID: 19343360 DOI: 10.1007/s00428-009-0766-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Revised: 03/06/2009] [Accepted: 03/17/2009] [Indexed: 12/23/2022]
Abstract
The authors review the role played by mutations in mitochondrial DNA and in nuclear genes encoding mitochondrial proteins in cancer development, with an emphasis on the alterations of the oxidative phosphorylation system and glycolysis.
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Affiliation(s)
- Valdemar Máximo
- Department of Pathology, Medical Faculty, University of Porto, Porto, Portugal
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Shi H, Pan L, Song T. Impact of Platinum on the Whole Mitochondrial Genome of Ovarian Carcinomas Both In Vivo and In Vitro. Int J Gynecol Cancer 2009; 19:423-30. [DOI: 10.1111/igc.0b013e3181a19ff0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Objectives:To investigate somatic mitochondrial DNA mutation in primary and recurrent ovarian carcinoma tissues as well as that in drug-resistant cell lines to illuminate the impact of chemotherapeutic drugs on mitochondrial DNA (mtDNA).Methods:Complete mtDNA genomes of 20 pairs of ovarian carcinomas and their matched normal tissues together with 2 ovarian carcinoma cell lines and their 4 platinum-resistant cell lines were sequenced. Mitochondrial DNA alterations, consequent amino acid alterations were compared between the 2 groups of patients and the 2 types of cell lines.Results:A large number of mtDNA new polymorphisms (55) and mutations (18) were identified in 20 ovarian carcinoma samples. Platinum-based chemotherapy did not increase the number of new polymorphisms (P = 0.094), mutations (P = 0.688), and consequent amino acid alterations (P = 0.202 and 0.795). Data gained from the cell lines also indicated that platinum had some effect on the mitochondrial genome but not specific to particular positions.Conclusions:What we found suggested that mtDNA damage could be made by chemotherapeutic drugs but not as much as imagined in ovarian carcinomas. Some of the mtDNA defects might be part of the disease processes and cell properties as well as a consequence of treatment.
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Lee HC, Wei YH. Mitochondrial DNA instability and metabolic shift in human cancers. Int J Mol Sci 2009; 10:674-701. [PMID: 19333428 PMCID: PMC2660656 DOI: 10.3390/ijms10020674] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2009] [Revised: 02/20/2009] [Accepted: 02/23/2009] [Indexed: 12/16/2022] Open
Abstract
A shift in glucose metabolism from oxidative phosphorylation to glycolysis is one of the biochemical hallmarks of tumor cells. Mitochondrial defects have been proposed to play an important role in the initiation and/or progression of various types of cancer. In the past decade, a wide spectrum of mutations and depletion of mtDNA have been identified in human cancers. Moreover, it has been demonstrated that activation of oncogenes or mutation of tumor suppressor genes, such as p53, can lead to the upregulation of glycolytic enzymes or inhibition of the biogenesis or assembly of respiratory enzyme complexes such as cytochrome c oxidase. These findings may explain, at least in part, the well documented phenomena of elevated glucose uptake and mitochondrial defects in cancers. In this article, we review the somatic mtDNA alterations with clinicopathological correlations in human cancers, and their potential roles in tumorigenesis, cancer progression, and metastasis. The signaling pathways involved in the shift from aerobic metabolism to glycolysis in human cancers are also discussed.
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Affiliation(s)
- Hsin-Chen Lee
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan 112; E-Mail:
| | - Yau-Huei Wei
- Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 112
- Author to whom correspondence should be addressed; E-mail:
; Tel. 02-2826-7118; Fax: 02-28264843
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Bragoszewski P, Kupryjanczyk J, Bartnik E, Rachinger A, Ostrowski J. Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer. BMC Cancer 2008; 8:292. [PMID: 18842121 PMCID: PMC2571110 DOI: 10.1186/1471-2407-8-292] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2008] [Accepted: 10/08/2008] [Indexed: 12/19/2022] Open
Abstract
Background In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas. Methods We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1) were quantified in 62 cancer tissues by real-time RT-PCR. Results Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy. Conclusion In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.
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Affiliation(s)
- Piotr Bragoszewski
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw, Poland.
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Rigoli L, Di Bella C, Verginelli F, Falchetti M, Bersiga A, Rocco A, Nardone G, Mariani-Costantini R, Caruso RA. Histological heterogeneity and somatic mtDNA mutations in gastric intraepithelial neoplasia. Mod Pathol 2008; 21:733-41. [PMID: 18425082 DOI: 10.1038/modpathol.2008.58] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Somatic mutations of mitochondrial DNA (mtDNA) are associated with various types of human cancer. To elucidate their role in gastric carcinogenesis, we analyzed mutations in the displacement loop region of mtDNA in 24 paraffin-embedded gastric intraepithelial neoplasias (formerly dysplasia) from a high gastric cancer risk area in northern Italy. Helicobacter pylori infection was assessed by histological examination (Giemsa staining). Gastritis was classified according to the guidelines of the Updated Sydney System. The mtDNA displacement loop region was amplified and sequenced from gastric intraepithelial neoplasia samples and adjacent non-neoplastic gastric mucosa. The gastric intraepithelial neoplasias were divided into two groups by their association with H. pylori gastritis. Group A with lesions arising on a background of H. pylori-positive gastritis contained 7 patients, and group B with lesions associated with H. pylori-negative gastritis contained 17 patients. Group A had a larger proportion of high-grade lesions than group B and showed a foveolar phenotype (type II dysplasia). Group B had a larger proportion of cases with mtDNA displacement loop region mutations than group A (P=0.004, Fisher's exact test) and exhibited an intestinal phenotype. No evidence of heteroplasmic variants in the mtDNA displacement loop, suggestive of mutations, was detected in gastric biopsies from 25 H. pylori-negative subjects and 60 cancer-unaffected H. pylori-positive patients. These results provide further evidence for the morphologic and mtDNA biomolecular differences of gastric intraepithelial neoplasias, and suggest the existence of two distinct pathways to gastric cancer--corpus-dominant H. pylori gastritis and the atrophy-metaplasia pathway.
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Affiliation(s)
- Luciana Rigoli
- Department of Pediatrics, University Hospital, Messina, Italy
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Mithani SK, Smith IM, Zhou S, Gray A, Koch WM, Maitra A, Califano JA. Mitochondrial resequencing arrays detect tumor-specific mutations in salivary rinses of patients with head and neck cancer. Clin Cancer Res 2008; 13:7335-40. [PMID: 18094415 DOI: 10.1158/1078-0432.ccr-07-0220] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alterations of the mitochondrial genome have been identified in multiple solid tumors and in many head and neck squamous cell carcinomas (HNSCC). Identification of mitochondrial mutations in the salivary rinses of patients with HNSCC has potential application in disease detection. In this study, we used the MitoChip v2.0 mitochondrial genome resequencing array to detect minor populations of mitochondrial DNA in salivary rinses of patients with HNSCC. EXPERIMENTAL DESIGN Salivary rinses from 13 patients with HNSCC, whose tumors carried mitochondrial mutations, were collected before surgical resection. DNA isolated from salivary rinses and serial dilutions of DNA derived from HNSCC-derived cell lines with known mitochondrial mutations were sequenced using the MitoChip, and analyzed using a quantitative algorithm which we developed to detect minor populations of mitochondrial DNA from MitoChip probe intensity data. RESULTS We detected heteroplasmic populations of mitochondrial DNA up to a 1:200 dilution using MitoChip v2.0 and our analysis algorithm. A logarithmic relationship between the magnitude of assay intensity and concentration of minor mitochondrial populations was shown. This technique was able to identify tumor-specific mitochondrial mutations in salivary rinses from 10 of 13 (76.9%) patients with head and neck cancer. CONCLUSIONS Minor populations of mitochondrial DNA and disease-specific mitochondrial mutations in salivary rinses of patients with HNSCC can be successfully identified using the MitoChip resequencing array and the algorithm which we have developed. This technique has potential application in the surveillance of patients after resection and may have applicability in the surveillance of body fluids in other tumor types.
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Affiliation(s)
- Suhail K Mithani
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
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Yu M, Shi Y, Zhang F, Zhou Y, Yang Y, Wei X, Zhang L, Niu R. Sequence variations of mitochondrial DNA D-loop region are highly frequent events in familial breast cancer. J Biomed Sci 2007; 15:535-43. [PMID: 18157618 DOI: 10.1007/s11373-007-9229-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2007] [Accepted: 12/11/2007] [Indexed: 01/13/2023] Open
Abstract
Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations. The non-coding displacement (D)-loop, especially a mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310), has been recently identified as a frequent hotspot of mutations in human neoplasia, including breast cancer. To further explore the sequence variations of mitochondrial D-loop region in familial breast cancer and their possible associations with breast cancer risk, PCR-SSCP and direct DNA sequencing methods were used to detect the variants of the mtDNA D-Loop in 23 familial breast cancer patients as well as three high-risk cancer families. Compared to that in sporadic breast tumors (53.3%, 16/30) and healthy blood donors (6.7%, 2/30), we identified a total of 126 sequence alterations in 23/23 (100%) of familial breast cancer patients, including eight novel nucleotide variants. Among these changes, A to G at nt.263, T to C at nt.489, T to C at nt.310, TC insertion at nt.311, CA deletion at nt.522, and C to G at nt.527 were highly frequent ones. In addition, among three high-risk cancer families, we found that individuals affected with breast cancer harbored more mtDNA sequence variants in mtDNA D310 area than other affected family members. Together, our data indicate that sequence variants within the mtDNA D-Loop region are frequent events in Chinese familial breast cancer patients. Some of these nucleotide abnormalities, particularly those in D310 segment, might be involved in the breast carcinogenesis and could be included in a panel of molecular biomarkers for cancer susceptibility early-detection strategy.
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Affiliation(s)
- Man Yu
- State Key Laboratory of Breast Cancer Prevention and Treatment, Cancer Hospital and Institute, Tianjin Medical University, Tianjin 300060, PR China
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Gargano G, Calcara D, Corsale S, Agnese V, Intrivici C, Fulfaro F, Pantuso G, Cajozzo M, Morello V, Tomasino RM, Ottini L, Colucci G, Bazan V, Russo A. Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study. Ann Oncol 2007; 18 Suppl 6:vi103-9. [PMID: 17591800 DOI: 10.1093/annonc/mdm236] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC. PATIENTS AND METHODS nMSI and mtMSI were evaluated in a consecutive series of 100 GC patients. For the analysis of the nMSI, we followed the National Cancer Institute guidelines. mtMSI was assessed by analyzing a portion of the displacement-loop region. The aberrant methylation of RUNX3 was analyzed in 40 GC patients by methylation-specific PCR. RESULTS Overall, 55% of GC demonstrated methylation of the RUNX3 promoter; 82% of GC was classified as stable microsatellite instability, 5% as low-level microsatellite instability and 13% as high-level microsatellite instability (MSI-H); mtMSI was detected in 11% of GC. A significant association was found between mtMSI and tumor-node-metastasis staging, furthermore an interesting association between MSI-H status, mtMSI and RUNX3 methylation. CONCLUSION These data suggest that RUNX3 is an important target of methylation in the evolution of mtMSI and nMSI-H GC.
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Affiliation(s)
- G Gargano
- Section of Medical Oncology, Department of Oncology, Università di Palermo, Italy
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