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Raina R, Shetty DC, Nasreen N, DAS S, Sethi A, Chikara A, Rai G, Kumar A, Tulsyan S, Sisodiya S, Hussain S. Mitochondrial DNA content as a biomarker for oral carcinogenesis: correlation with clinicopathologic parameters. Minerva Dent Oral Sci 2023; 72:211-220. [PMID: 37066891 DOI: 10.23736/s2724-6329.23.04756-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
BACKGROUND Mitochondrial genome (mtDNA) exhibits greater vulnerability to mutations and/or copy number variations than nuclear counterpart (nDNA) in both normal and cancer cells due to oxidative stress generated by inflammation, viral infections, physical, mechanical, and chemical load. The study was designed to evaluate the mtDNA content in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC). Various parameters were analyzed including its variation with human papillomavirus (HPV) during oral carcinogenesis. METHODS The present cross-sectional study comprised of two hundred patients (100 OPMDs and 100 OSCCs) and 100 healthy controls. PCR amplifications were done for mtDNA content and HPV in OPMDs and OSCC using real-time and conventional PCR respectively. RESULTS The relative mtDNA content was assessed quantitatively and it was observed that mtDNA was greater in OSCC (7.60±0.94) followed by OPMDs (5.93±0.92) and controls (5.37±0.95). It showed a positive linear correlation with habits and increasing histopathological grades. Total HPV-positive study groups showed higher mtDNA content (7.06±1.64) than HPV-negative counterparts (6.21±1.29). CONCLUSIONS An elevated mutant mtDNA may be attributed to increased free radicals and selective cell clonal proliferation in test groups. Moreover, sustained HPV infection enhances tumorigenesis through mitochondria mediated apoptosis. Since, mtDNA content is directly linked to oxidative DNA damage, these quantifications might serve as a surrogate measure for invasiveness in dysplastic lesions and typify their malignant potential.
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Affiliation(s)
- Reema Raina
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Indian Council of Medical Research, Noida, India
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Centre for Dental Studies and Research, Muradnagar, India
| | - Devi C Shetty
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Centre for Dental Studies and Research, Muradnagar, India
| | - Nighat Nasreen
- Department of Oral Pathology and Microbiology, Divya Jyoti College of Dental Sciences and Research, Modinagar, India
| | - Shukla DAS
- Department of Microbiology, University College of Medical Sciences and GTB Hospital, Dilshad Garden, New Delhi, India
| | - Aashka Sethi
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Centre for Dental Studies and Research, Muradnagar, India
| | - Atul Chikara
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Indian Council of Medical Research, Noida, India
| | - Gargi Rai
- Department of Microbiology, University College of Medical Sciences and GTB Hospital, Dilshad Garden, New Delhi, India
| | - Anshuman Kumar
- Department of Surgical Oncology, Dharamshila Narayana Superspeciality Hospital, Vasundhara Enclave, New Delhi, India
| | - Sonam Tulsyan
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Indian Council of Medical Research, Noida, India
| | - Sandeep Sisodiya
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Indian Council of Medical Research, Noida, India
| | - Showket Hussain
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Indian Council of Medical Research, Noida, India -
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Diwan P, Nirwan M, Bahuguna M, Kumari SP, Wahlang J, Gupta RK. Evaluating Alterations of the Oral Microbiome and Its Link to Oral Cancer among Betel Quid Chewers: Prospecting Reversal through Probiotic Intervention. Pathogens 2023; 12:996. [PMID: 37623956 PMCID: PMC10459687 DOI: 10.3390/pathogens12080996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 08/26/2023] Open
Abstract
Areca nut and slaked lime, with or without tobacco wrapped in Piper betle leaf, prepared as betel quid, is extensively consumed as a masticatory product in many countries across the world. Betel Quid can promote the malignant transformation of oral lesions as well as trigger benign cellular and molecular changes. In the oral cavity, it causes changes at the compositional level in oral microbiota called dysbiosis. This dysbiosis may play an important role in Oral Cancer in betel quid chewers. The abnormal presence and increase of bacteria Fusobacterium nucleatum, Capnocytophaga gingivalis, Prevotella melaninogenica, Peptostreptococcus sp., Porphyromonas gingivalis, and Streptococcus mitis in saliva and/or other oral sites of the cancer patients has attracted frequent attention for its association with oral cancer development. In the present review, the authors have analysed the literature reports to revisit the oncogenic potential of betel quid and oral microbiome alterations, evaluating the potential of oral microbiota both as a driver and biomarker of oral cancer. The authors have also shared a perspective that the restoration of local microbiota can become a potentially therapeutic or prophylactic strategy for the delay or reversal of lip and oral cavity cancers, especially in high-risk population groups.
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Affiliation(s)
- Prerna Diwan
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi 110021, India; (M.N.); (M.B.); (S.P.K.); (R.K.G.)
| | - Mohit Nirwan
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi 110021, India; (M.N.); (M.B.); (S.P.K.); (R.K.G.)
| | - Mayank Bahuguna
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi 110021, India; (M.N.); (M.B.); (S.P.K.); (R.K.G.)
| | - Shashi Prabha Kumari
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi 110021, India; (M.N.); (M.B.); (S.P.K.); (R.K.G.)
| | - James Wahlang
- Department of Biochemistry, St. Edmund’s College, Shillong 793003, India;
| | - Rakesh Kumar Gupta
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi 110021, India; (M.N.); (M.B.); (S.P.K.); (R.K.G.)
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Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14:230-246. [PMID: 37583950 PMCID: PMC10424089 DOI: 10.5306/wjco.v14.i7.230] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/21/2023] [Indexed: 07/19/2023] Open
Abstract
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Perth 6009, Crawley NA, Australia
- Department of Medical Oncology, Sir Charles Gardner Hospital, Nedlands 6009, Australia
| | - Angela Felicia Sunjaya
- Institute of Cardiovascular Science, University College London, London WC1E 6DD, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland 6056, WA, Australia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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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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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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Wuda granule, a traditional Chinese herbal medicine, ameliorates postoperative ileus by anti-inflammatory action. Pathol Res Pract 2020; 216:152605. [PMID: 31974003 DOI: 10.1016/j.prp.2019.152605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 08/04/2019] [Accepted: 08/18/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Postoperative ileus (POI) is a temporary disturbance in gastrointestinal motility following surgery, and intestinal inflammatory response plays a critical role in the pathogenesis of POI. Wuda granule (WDG), a gastrointestinal prokinetic Chinese herbal medicine, is prescribed to promote recovery of gastrointestinal function after abdominal surgery. However, it has remained unclear whether WDG shows anti-inflammatory effects in POI. In the present study, we investigated the effects of WDG in a rat POI model and attempted to clarify the detailed mechanisms of action. METHOD Experimental POI was induced in adult male SD rats by intestinal manipulation (IM). WDG were orally administered after surgery at the same points (6 h, 12 h, 18 h, 24 h). Histological changes of mesenterium, levels of cytokines, and CD68 and iNOS expression were determined in rats treated or not with WDG. We also investigated the transcriptome profile of rats treated with WDG in a POI model. RESULTS Experimental POI in rats was characterized by a marked intestinal and systemic inflammatory response. WDG significantly inhibited the infiltration of neutrophils and macrophages, reduced the levels of IL-6, and CRP, and inhibited protein expressions of CD68 and iNOS in mesentery. Comparison analysis showed that there are 1432 differentially expressed genes (DEGs) between the POI and CON sample, whereas 331 DEGs between the WDG -treated sample and the POI group. And 16 DEGs were shared by the POI vs CON and WDG vs POI groups, among which 6 hub genes associated with immune system processes were identified and verified. CONCLUSIONS WDG treatment ameliorates the impaired gastrointestinal motility in the rat model of POI through inhibiting the inflammatory response of mesentery.
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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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Elamir A, ElRefai SM, Ghazy SE. Molecular alterations of mitochondrial D-loop in oral leukoplakia. J Cell Biochem 2019; 120:13944-13951. [PMID: 30945332 DOI: 10.1002/jcb.28668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 02/01/2019] [Accepted: 02/14/2019] [Indexed: 11/07/2022]
Abstract
BACKGROUND Over the years, numerous studies proposed a crucial role of mutations of nuclear DNA in the carcinogenesis process. Of late, many researchers suppose that alterations of mitochondrial DNA should not be excepted from this analysis. Mutational analysis of mitochondrial DNA displayed that mitochondrial D-loop is assessed as a hotspot for molecular alterations in various types of malignant tumors encompassing oral squamous cell carcinoma. Squamous cell carcinoma is believed to emerge through precancerous stages, which might be merely morphologic aspects of cumulative genetic variations. METHODS In keeping with this model of molecular tumor progression, this study aimed to investigate the qualitative and quantitative alterations that might occur in mitochondrial D-loop in oral leukoplakia whether dysplastic or not by semiquantitation of a product of the polymerase chain reaction and sequence analyses of mitochondrial D-loop gene. RESULTS Statistically significant increases in the mean values of D-loop concentrations were observed across the dysplasia gradient of oral leukoplakia. Sequence analyses revealed the presence of point mutations in both dysplastic and nondysplastic oral leukoplakia but not in normal mucosa. CONCLUSION The results of this study suggested that quantitative and qualitative alterations in mitochondrial D-loop could be a promising molecular marker for early detection and progression of the malignancy.
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Affiliation(s)
- Azza Elamir
- Department of Medical Biochemistry, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Sahar M ElRefai
- Department of Oral Pathology, Faculty of Dentistry, Princess Nourah University, Riyadh, Kingdom of Saudi Arabia
| | - Shaimaa E Ghazy
- Department of Oral Pathology, Faculty of Dentistry, Ain Shams University, Cairo, Egypt
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Huang KJ, Kuo CH, Chen SH, Lin CY, Lee YR. Honokiol inhibits in vitro and in vivo growth of oral squamous cell carcinoma through induction of apoptosis, cell cycle arrest and autophagy. J Cell Mol Med 2018; 22:1894-1908. [PMID: 29363886 PMCID: PMC5824386 DOI: 10.1111/jcmm.13474] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 10/30/2017] [Indexed: 01/22/2023] Open
Abstract
Honokiol, an active natural product derived from Magnolia officinalis, exerted anticancer effects through a variety of mechanisms on multiple types of cancers. In this study, the molecular mechanisms of honokiol in suppressing the human oral squamous cell carcinoma (OSCC) cells were evaluated. Treatment of two OSCC cell lines with honokiol resulted in reducing the cell proliferation and arresting the cell cycle at G1 stage which was correlated with the down‐regulation of Cdk2 and Cdk4 and the up‐regulation of cell cycle suppressors, p21 and p27. In addition, the caspase‐dependent programmed cell death was substantially detected, and the autophagy was induced as the autophagosome formation and autophagic flux proceeded. Modulation of autophagy by autophagic inducer, rapamycin or inhibitors, 3‐MA or bafilomycin, potentiated the honokiol‐mediated anti‐OSCC effects where honokiol exerted multiple actions in suppression of MAPK pathway and regulation of Akt/mTOR or AMPK pathways. As compared to clinical therapeutic agent, 5‐FU, honokiol exhibited more potent activity against OSCC cells and synergistically enhanced the cytotoxic effect of 5‐FU. Furthermore, orally administrated honokiol exerted effective antitumour activity in vivo in OSCC‐xenografted mice. Thus, this study revealed that honokiol could be a promising candidate in preventing human OSCCs.
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Affiliation(s)
- Kao-Jean Huang
- Development Center for Biotechnology, Institute of Biologics, New Taipei City, Taiwan
| | - Chin-Ho Kuo
- Division of Hematology-Oncology and Blood Bank, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Shu-Hsin Chen
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Ching-Yen Lin
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Ying-Ray Lee
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.,Department of Nursing, Min-Hwei College of Health Care Management, Tainan, Taiwan
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Salehi Z, Haghighi A, Haghighi S, Aminian K, Asl SF, Mashayekhi F. Mitochondrial DNA deletion Δ4977 in peptic ulcer disease. Mol Biol 2017. [DOI: 10.1134/s0026893317010162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Chen SY, Liu GH, Chao WY, Shi CS, Lin CY, Lim YP, Lu CH, Lai PY, Chen HR, Lee YR. Piperlongumine Suppresses Proliferation of Human Oral Squamous Cell Carcinoma through Cell Cycle Arrest, Apoptosis and Senescence. Int J Mol Sci 2016; 17:E616. [PMID: 27120594 PMCID: PMC4849064 DOI: 10.3390/ijms17040616] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 04/19/2016] [Accepted: 04/20/2016] [Indexed: 11/17/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells.
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Affiliation(s)
- San-Yuan Chen
- Department of Chinese Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan.
- Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan.
| | - Geng-Hung Liu
- Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan.
| | - Wen-Ying Chao
- Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan City 736, Taiwan.
| | - Chung-Sheng Shi
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Chiayi 613, Taiwan.
| | - Ching-Yen Lin
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan.
| | - Yun-Ping Lim
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan.
| | - Chieh-Hsiang Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan.
| | - Peng-Yeh Lai
- Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan.
| | - Hau-Ren Chen
- Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan.
| | - Ying-Ray Lee
- Department of Nursing, Min-Hwei Junior College of Health Care Management, Tainan City 736, Taiwan.
- Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan.
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Yang CH, Lin YD, Yen CY, Chuang LY, Chang HW. A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2016; 19:238-47. [PMID: 25831063 DOI: 10.1089/omi.2014.0121] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Oral cancer is the sixth most common cancer worldwide with a high mortality rate. Biomarkers that anticipate susceptibility, prognosis, or response to treatments are much needed. Oral cancer is a polygenic disease involving complex interactions among genetic and environmental factors, which require multifaceted analyses. Here, we examined in a dataset of 103 oral cancer cases and 98 controls from Taiwan the association between oral cancer risk and the DNA repair genes X-ray repair cross-complementing group (XRCCs) 1-4, and the environmental factors of smoking, alcohol drinking, and betel quid (BQ) chewing. We employed logistic regression, multifactor dimensionality reduction (MDR), and hierarchical interaction graphs for analyzing gene-gene (G×G) and gene-environment (G×E) interactions. We identified a significantly elevated risk of the XRCC2 rs2040639 heterozygous variant among smokers [adjusted odds ratio (OR) 3.7, 95% confidence interval (CI)=1.1-12.1] and alcohol drinkers [adjusted OR=5.7, 95% CI=1.4-23.2]. The best two-factor based G×G interaction of oral cancer included the XRCC1 rs1799782 and XRCC2 rs2040639 [OR=3.13, 95% CI=1.66-6.13]. For the G×E interaction, the estimated OR of oral cancer for two (drinking-BQ chewing), three (XRCC1-XRCC2-BQ chewing), four (XRCC1-XRCC2-age-BQ chewing), and five factors (XRCC1-XRCC2-age-drinking-BQ chewing) were 32.9 [95% CI=14.1-76.9], 31.0 [95% CI=14.0-64.7], 49.8 [95% CI=21.0-117.7] and 82.9 [95% CI=31.0-221.5], respectively. Taken together, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes appear to be significantly associated with oral cancer. These were enhanced by exposure to certain environmental factors. The observations presented here warrant further research in larger study samples to examine their relevance for routine clinical care in oncology.
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Affiliation(s)
- Cheng-Hong Yang
- 1 Department of Electronic Engineering, National Kaohsiung University of Applied Sciences , Kaohsiung, Taiwan
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Li PT, Tsai YJ, Lee MJ, Chen CT. Increased Histone Deacetylase Activity Involved in the Suppressed Invasion of Cancer Cells Survived from ALA-Mediated Photodynamic Treatment. Int J Mol Sci 2015; 16:23994-4010. [PMID: 26473836 PMCID: PMC4632734 DOI: 10.3390/ijms161023994] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 09/25/2015] [Indexed: 02/06/2023] Open
Abstract
Previously, we have found that cancer cells survived from 5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) have abnormal mitochondrial function and suppressed cellular invasiveness. Here we report that both the mRNA expression level and enzymatic activity of histone deacetylase (HDAC) were elevated in the PDT-derived variants with dysfunctional mitochondria. The activated HDAC deacetylated histone H3 and further resulted in the reduced migration and invasion, which correlated with the reduced expression of the invasion-related genes, matrix metalloproteinase 9 (MMP9), paternally expressed gene 1 (PEG1), and miR-355, the intronic miRNA. Using chromatin immunoprecipitation, we further demonstrate the reduced amount of acetylated histone H3 on the promoter regions of MMP9 and PEG1, supporting the down-regulation of these two genes in PDT-derived variants. These results indicate that HDAC activation induced by mitochondrial dysfunction could modulate the cellular invasiveness and its related gene expression. This argument was further verified in the 51-10 cybrid cells with the 4977 bp mtDNA deletion and A375 ρ⁰ cells with depleted mitochondria. These results indicate that mitochondrial dysfunction might suppress tumor invasion through modulating histone acetylation.
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Affiliation(s)
- Pei-Tzu Li
- Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan.
| | - Yi-Jane Tsai
- Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan.
| | - Ming-Jen Lee
- Department of Neurology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 100, Taiwan.
| | - Chin-Tin Chen
- Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan.
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Impact of somatic mutations in the D-loop of mitochondrial DNA on the survival of oral squamous cell carcinoma patients. PLoS One 2015; 10:e0124322. [PMID: 25906372 PMCID: PMC4408030 DOI: 10.1371/journal.pone.0124322] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 02/28/2015] [Indexed: 01/12/2023] Open
Abstract
Objectives The aim of this study was to investigate somatic mutations in the D-loop of mitochondrial DNA (mtDNA) and their impact on survival in oral squamous cell carcinoma patients. Materials and Methods Surgical specimen confirmed by pathological examination and corresponding non-cancerous tissues were collected from 120 oral squamous cell carcinoma patients. The sequence in the D-loop of mtDNA from non-cancerous tissues was compared with that from paired cancer samples and any sequence differences were recognized as somatic mutations. Results Somatic mutations in the D-loop of mtDNA were identified in 75 (62.5%) oral squamous cell carcinoma patients and most of them occurred in the poly-C tract. Although there were no significant differences in demographic and tumor-related features between participants with and without somatic mutation, the mutation group had a better survival rate (5 year disease-specific survival rate: 64.0% vs. 43.0%, P = 0.0266). Conclusion Somatic mutation in D-loop of mtDNA was associated with a better survival in oral squamous cell carcinoma patients.
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15
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Abstract
Oral submucous fibrosis (OSF) is a premalignant condition caused by betel chewing. It is very common in Southeast Asia but has started to spread to Europe and North America. OSF can lead to squamous cell carcinoma, a risk that is further increased by concomitant tobacco consumption. OSF is a diagnosis based on clinical symptoms and confirmation by histopathology. Hypovascularity leading to blanching of the oral mucosa, staining of teeth and gingiva, and trismus are major symptoms. Major constituents of betel quid are arecoline from betel nuts and copper, which are responsible for fibroblast dysfunction and fibrosis. A variety of extracellular and intracellular signaling pathways might be involved. Treatment of OSF is difficult, as not many large, randomized controlled trials have been conducted. The principal actions of drug therapy include antifibrotic, anti-inflammatory, and antioxygen radical mechanisms. Potential new drugs are on the horizon. Surgery may be necessary in advanced cases of trismus. Prevention is most important, as no healing can be achieved with available treatments.
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Affiliation(s)
- Uwe Wollina
- Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany
| | | | - Fareedi Mukram Ali
- Departments of Oral and Maxillofacial Surgery, SMBT Dental College, Sangamner, Maharashtra, India
| | - Kishor Patil
- Departments of Oral Pathology and Microbiology, SMBT Dental College, Sangamner, Maharashtra, India
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Datta S, Chattopadhyay E, Ray JG, Majumder M, Roy PD, Roy B. D-loop somatic mutations and ∼5 kb "common" deletion in mitochondrial DNA: important molecular markers to distinguish oral precancer and cancer. Tumour Biol 2014; 36:3025-33. [PMID: 25527154 DOI: 10.1007/s13277-014-2937-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 12/03/2014] [Indexed: 11/27/2022] Open
Abstract
Apart from genomic DNA, mutations at mitochondrial DNA (mtDNA) have been hypothesized to play vital roles in cancer development. In this study, ∼5 kb deletion and D-loop mutations in mtDNA and alteration in mtDNA content were investigated in buccal smears from 104 healthy controls and 74 leukoplakia and 117 cancer tissue samples using Taqman-based quantitative assay and re-sequencing. The ∼5 kb deletion in mtDNA was significantly less (9.8 and 10.5 folds, P < 0.0001) in cancer tissues compared to control and leukoplakia tissues, respectively. On the other hand, somatic mutations in D-loop, investigated in 54 controls, 50 leukoplakias and 56 cancer patients, were found to be significantly more in cancer tissues, but not in leukoplakia tissues, compared to control (Z-score = 5.4). MtDNA contents were observed to be significantly more in leukoplakia (2.1 folds, P = 0.004) and cancer (1.6 folds, P = 0.03) tissues compared to control tissues. So, D-loop somatic mutations and ∼5 kb deletion patterns could be used as distinguishing markers between precancer and cancer tissues. This observation further suggests that somatic mutations in D-loop may facilitate carcinogenesis and cancer cells with less ∼5 kb deletion, i.e., intact mtDNA, may become resistant to apoptosis.
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Affiliation(s)
- Sayantan Datta
- Human Genetics Unit, Indian Statistical Institute, 203 B.T. Road, Kolkata, 700108, India
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17
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Liu SA, Jiang RS, Wang WY, Lin JC. Somatic mutations in the D-loop of mitochondrial DNA in head and neck squamous cell carcinoma. Head Neck 2014; 37:878-83. [DOI: 10.1002/hed.23680] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/14/2014] [Accepted: 03/07/2014] [Indexed: 11/06/2022] Open
Affiliation(s)
- Shih-An Liu
- Department of Otolaryngology; Taichung Veterans General Hospital; Taichung Taiwan
- Faculty of Medicine, School of Medicine; National Yang-Ming University; Taipei Taiwan
| | - Rong-San Jiang
- Department of Otolaryngology; Taichung Veterans General Hospital; Taichung Taiwan
| | - Wen-Yi Wang
- Department of Nursing; Hung-Kuang University; Taichung Taiwan
| | - Jin-Ching Lin
- Department of Radiation Oncology; Taichung Veterans General Hospital; Taichung Taiwan
- Faculty of Medicine, School of Medicine; National Yang-Ming University; Taipei Taiwan
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18
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Dysfunction of mitochondria due to environmental carcinogens in nasopharyngeal carcinoma in the ethnic group of Northeast Indian population. Tumour Biol 2014; 35:6715-24. [PMID: 24711137 DOI: 10.1007/s13277-014-1897-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 03/26/2014] [Indexed: 10/25/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a rare cancer worldwide, but in India, NPC is uncommon in its subcontinent except in the north-eastern part of the country. NPC is thought to be caused by the combined effects of environmental carcinogens, genetic susceptibility and Epstein-Barr virus (EBV). This is the first study that aimed to examine the selected risk factors, mostly dietary, viral environmental, metabolic gene polymorphisms, mitochondrial DNA (mtDNA) copy number variation and their risk, in subjects who are highly prone to NPC in the ethnic groups of Northeast India, which has included cases, first-degree relatives and controls. The cases and controls were selected from three ethnic groups (Manipuri, Naga and Mizo) of Northeast India with high prevalence of NPC. This case-control family study includes 64 NPC patients, 88 first-degree relatives and 100 controls having no history of cancer. PCR-based detection was done for EBV-latent membrane protein 1 (LMP1) gene and glutathione S-transferase Mu 1 (GSTM1)-glutathione S-transferase theta 1 (GSTT1) polymorphism. A comparative ΔCt method was used for the determination of mtDNA content. An increased risk of 2.00-6.06-folds to NPC was observed with those who intake smoked meat and fish, salted fish and fermented fish; betel nut chewers; tobacco smokers; alcohol drinkers; and those who have kitchen inside the living room, glutathione S-transferase null genotype and EBV infection. The risk of NPC increased in cases with decreased mtDNA copy number (P trend = 0.007). A significant difference between GST null genotypes and EBV infection with mtDNA content was found in the cases (P < 0.0001). The understandings of environment-genetic risk factors and their role in the etiology of NPC are helpful as preventive measures and screening.
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Pandey R, Mehrotra D, Mahdi AA, Sarin R, Kowtal P. Additional cytosine inside mitochondrial C-tract D-loop as a progression risk factor in oral precancer cases. J Oral Biol Craniofac Res 2014; 4:3-7. [PMID: 25737911 DOI: 10.1016/j.jobcr.2014.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 02/11/2014] [Indexed: 10/25/2022] Open
Abstract
INTRODUCTION Alterations inside Polycytosine tract (C-tract) of mitochondrial DNA (mtDNA) have been described in many different tumor types. The Poly-Cytosine region is located within the mtDNA D-loop region which acts as point of mitochondrial replication origin. A suggested pathogenesis is that it interferes with the replication process of mtDNA which in turn affects the mitochondrial functioning and generates disease. METHODOLOGY 100 premalignant cases (50 leukoplakia & 50 oral submucous fibrosis) were selected and the mitochondrial DNA were isolated from the lesion tissues and from the blood samples. Polycytosine tract in mtDNA was sequenced by direct capillary sequencing. RESULTS 40 (25 leukoplakia & 15 oral submucous fibrosis) patients harbored lesions that displayed one additional cytosine after nucleotide thymidine (7CT6C) at nt position 316 in C-tract of mtDNA which were absent in corresponding mtDNA derived from blood samples. CONCLUSION Our results show an additional cytosine in the mtDNA at polycytosine site in oral precancer cases. It is postulated that any increase/decrease in the number of cytosine residues in the Poly-Cytosine region may affect the rate of mtDNA replication by impairing the binding of polymerase and other transacting factors. By promoting mitochondrial genomic instability, it may have a central role in the dysregulation of mtDNA functioning, for example alterations in energy metabolism that may promote tumor development. We, therefore, report and propose that this alteration may represent the early development of oral cancer. Further studies with large number of samples are needed in to confirm the role of such mutation in carcinogenesis.
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Affiliation(s)
- Rahul Pandey
- Department of Oral & Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Divya Mehrotra
- Department of Oral & Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Rajiv Sarin
- ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharastra, India
| | - Pradnya Kowtal
- ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharastra, India
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Mitochondrial common deletion, a potential biomarker for cancer occurrence, is selected against in cancer background: a meta-analysis of 38 studies. PLoS One 2013; 8:e67953. [PMID: 23861839 PMCID: PMC3701633 DOI: 10.1371/journal.pone.0067953] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 05/23/2013] [Indexed: 12/24/2022] Open
Abstract
Mitochondrial dysfunction has been long proposed to play a major role in tumorigenesis. Mitochondrial DNA (mtDNA) mutations, especially the mtDNA 4,977 bp deletion has been found in patients of various types of cancer. In order to comprehend the mtDNA 4,977 bp deletion status in various cancer types, we performed a meta-analysis composed of 33 publications, in which a total of 1613 cancer cases, 1516 adjacent normals and 638 healthy controls were included. When all studies were pooled, we found that cancerous tissue carried a lower mtDNA 4,977 bp deletion frequency than adjacent non-cancerous tissue (OR = 0.43, 95% CI = 0.20-0.92, P = 0.03 for heterogeneity test, I(2) = 91.5%) among various types of cancer. In the stratified analysis by cancer type the deletion frequency was even lower in tumor tissue than in adjacent normal tissue of breast cancer (OR = 0.19, 95% CI = 0.06-0.61, P = 0.005 for heterogeneity test, I(2)= 82.7%). Interestingly, this observation became more significant in the stratified studies with larger sample sizes (OR = 0.70, 95% CI = 0.58-0.86, P = 0.0005 for heterogeneity test, I(2) = 95.1%). Furthermore, when compared with the normal tissue from the matched healthy controls, increased deletion frequencies were observed in both adjacent non-cancerous tissue (OR = 3.02, 95% CI = 2.13-4.28, P<0.00001 for heterogeneity test, I(2)= 53.7%), and cancerous tissue (OR = 1.36, 95% CI = 1.04-1.77, P = 0.02 for heterogeneity test, I(2)= 83.5%). This meta-analysis suggests that the mtDNA 4,977 bp deletion is often found in cancerous tissue and thus has the potential to be a biomarker for cancer occurrence in the tissue, but at the same time being selected against in various types of carcinoma tissues. Larger and better-designed studies are still warranted to confirm these findings.
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Pandey R, Mehrotra D, Mahdi AA, Sarin R, Kowtal P, Maurya SS, Parmar D. Association between mitochondrial C-tract alteration and tobacco exposure in oral precancer cases. Natl J Maxillofac Surg 2013; 4:219-24. [PMID: 24665180 PMCID: PMC3961899 DOI: 10.4103/0975-5950.127655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Tobacco exposure is a known risk factor for oral cancer. India is home to oral cancer epidemic chiefly due to the prevalent use of both smoke and smokeless tobacco. To reduce the related morbidity early detection is required. The key to this is detailing molecular events during early precancer stage. Mitochondrion is an important cellular organelle involved in cell metabolism and apoptosis. Mitochondrial dysfunction is thought to be the key event in oncogenesis. Last decade has seen a spurt of reports implicating mitochondrial mutations in oral carcinogenesis. However, there are few reports that study mitochondrial deoxyribonucleic acid (mtDNA) changes in oral precancer. This study aims to understand and link effect of tobacco exposure on mtDNA in oral precancer cases. SUBJECTS AND METHODS A total of 100 oral precancer cases of which 50 oral leukoplakia and 50 oral submucous fibrosis were recruited in the study and a detailed questionnaire were filled about the tobacco habits. Their tissue and blood samples were collected. Total genomic DNA was isolated from both sources. Mitochondrial C-tract was amplified and bidirectional sequencing was carried out. Mutations were scored over matched blood DNA. RESULTS There was a significant association between the presence of mitochondrial C-tract alteration and duration of tobacco exposure. The probability increased with increasing duration of tobacco consumption. The risk of having this alteration was more in chewers than in smokers. CONCLUSIONS Tobacco in both form, chewable and smoke, is oncogenic and causes early changes in mitochondrial genome and chances increases with increasing duration of tobacco consumption.
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Affiliation(s)
- Rahul Pandey
- Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Divya Mehrotra
- Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Rajiv Sarin
- Cancer Research Institute, ACTREC, Tata Memorail Centre, Mumbai, Maharashtra, India
| | - Pradnya Kowtal
- Cancer Research Institute, ACTREC, Tata Memorail Centre, Mumbai, Maharashtra, India
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Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, Laskar RS, Rabha B, Dey P, Ganguli S, NathChoudhury M, Talukdar FR, Chaudhuri B, Dhar B. Mitochondrial DNA copy number and risk of oral cancer: a report from Northeast India. PLoS One 2013; 8:e57771. [PMID: 23469236 PMCID: PMC3587625 DOI: 10.1371/journal.pone.0057771] [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: 11/19/2012] [Accepted: 01/24/2013] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is the sixth most common cancer globally. Tobacco consumption and HPV infection, both are the major risk factor for the development of oral cancer and causes mitochondrial dysfunction. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contributing to the individual susceptibility to cancer. Here, we have investigated the association of tobacco - betel quid chewing, HPV infection, GSTM1-GSTT1 null genotypes, and tumour stages with mitochondrial DNA (mtDNA) content variation in oral cancer patients. METHODOLOGY/PRINCIPAL FINDINGS The study comprised of 124 cases of OSCC and 140 control subjects to PCR based detection was done for high-risk HPV using a consensus primer and multiplex PCR was done for detection of GSTM1-GSTT1 polymorphism. A comparative ΔCt method was used for determination of mtDNA content. The risk of OSCC increased with the ceased mtDNA copy number (Ptrend = 0.003). The association between mtDNA copy number and OSCC risk was evident among tobacco - betel quid chewers rather than tobacco - betel quid non chewers; the interaction between mtDNA copy number and tobacco - betel quid was significant (P = 0.0005). Significant difference was observed between GSTM1 - GSTT1 null genotypes (P = 0.04, P = 0.001 respectively) and HPV infection (P<0.001) with mtDNA content variation in cases and controls. Positive correlation was found with decrease in mtDNA content with the increase in tumour stages (P<0.001). We are reporting for the first time the association of HPV infection and GSTM1-GSTT1 null genotypes with mtDNA content in OSCC. CONCLUSION Our results indicate that the mtDNA content in tumour tissues changes with tumour stage and tobacco-betel quid chewing habits while low levels of mtDNA content suggests invasive thereby serving as a biomarker in detection of OSCC.
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Affiliation(s)
- Rosy Mondal
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Sankar Kumar Ghosh
- Department of Biotechnology, Assam University, Silchar, Assam, India
- * E-mail:
| | | | - Anil Seram
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Kavita Sinha
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Marine Hussain
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Bijuli Rabha
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Pradip Dey
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Sabitri Ganguli
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | | | | | - Bishal Dhar
- Department of Biotechnology, Assam University, Silchar, Assam, India
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Tung CL, Lin ST, Chou HC, Chen YW, Lin HC, Tung CL, Huang KJ, Chen YJ, Lee YR, Chan HL. Proteomics-based identification of plasma biomarkers in oral squamous cell carcinoma. J Pharm Biomed Anal 2012; 75:7-17. [PMID: 23312379 DOI: 10.1016/j.jpba.2012.11.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 11/09/2012] [Accepted: 11/10/2012] [Indexed: 12/20/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive cancer and its occurrence is closely related to betel nut chewing in Taiwan. However, there are few prognostic and diagnostic biomarkers for this disease especially for its association with betel nut chewing. Recent progresses in quantitative proteomics have offered opportunities to discover plasma proteins as biomarkers for tracking the progression and for understanding the molecular mechanisms of OSCC. In present study, plasma samples from OSCC patients with at least 5-year history of betel nut chewing and healthy donors were analyzed by fluorescence 2D-DIGE-based proteomic analysis. Totally, 38 proteins have been firmly identified representing 13 unique gene products. These proteins mainly function in inflammatory responses (such as fibrinogen gamma chain) and transport (Apolipoprotein A-I). Additionally, the current quantitative proteomic approach has identified numerous OSCC biomarkers including fibrinogen (alpha/beta/gamma) chain, haptoglobin, leucine-rich alpha-2-glycoprotein and ribosomal protein S6 kinase alpha-3 (RSK2) which have not been reported and may be associated with the progression and development of the disease. In summary, this study reports a comprehensive patient-based proteomic approach for the identification of potential plasma biomarkers in OSCC. The potential of utilizing these markers for screening and treating OSCC warrants further investigations.
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Affiliation(s)
- Chun-Liang Tung
- Department of Pathology, Chiayi Christian Hospital, Chiayi, Taiwan
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Sharan RN, Mehrotra R, Choudhury Y, Asotra K. Association of betel nut with carcinogenesis: revisit with a clinical perspective. PLoS One 2012; 7:e42759. [PMID: 22912735 PMCID: PMC3418282 DOI: 10.1371/journal.pone.0042759] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 07/11/2012] [Indexed: 01/04/2023] Open
Abstract
Betel nut (BN), betel quid (BQ) and products derived from them are widely used as a socially endorsed masticatory product. The addictive nature of BN/BQ has resulted in its widespread usage making it the fourth most abused substance by humans. Progressively, several additives, including chewing tobacco, got added to simple BN preparations. This addictive practice has been shown to have strong etiological correlation with human susceptibility to cancer, particularly oral and oropharyngeal cancers. The PUBMED database was searched to retrieve all relevant published studies in English on BN and BQ, and its association with oral and oropharyngeal cancers. Only complete studies directly dealing with BN/BQ induced carcinogenesis using statistically valid and acceptable sample size were analyzed. Additional relevant information available from other sources was also considered. This systematic review attempts to put in perspective the consequences of this widespread habit of BN/BQ mastication, practiced by approximately 10% of the world population, on oral cancer with a clinical perspective. BN/BQ mastication seems to be significantly associated with susceptibility to oral and oropharyngeal cancers. Addition of tobacco to BN has been found to only marginally increase the cancer risk. Despite the widespread usage of BN/BQ and its strong association with human susceptibility to cancer, no serious strategy seems to exist to control this habit. The review, therefore, also looks at various preventive efforts being made by governments and highlights the multifaceted intervention strategies required to mitigate and/or control the habit of BN/BQ mastication.
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Affiliation(s)
- Rajeshwar N Sharan
- Radiation and Molecular Biology Unit, Department of Biochemistry, North-Eastern Hill University, Shillong, Meghalaya, India.
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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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Lee HC, Wei YH. Mitochondria and Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 942:311-27. [DOI: 10.1007/978-94-007-2869-1_14] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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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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Abstract
Oral cancer is a fatal disease, accounting for the fourth highest incidence of malignancy in males and the seventh in females in Taiwan. The relatively high prevalence of oral cancer in Taiwan is mainly because there is a high-risk group of 2.5 million people with the habit of smoking and betel nut chewing. Unfortunately, 50% of new cases in our medical center who present with TNM stage III or IV lesions have a shorter than 5-year survival after treatment. This highlights the need for: (1) early treatment of fresh oral cancer cases; (2) screening of the high-risk population to detect new lesions; (3) careful follow-up of cases after treatment; and (4) detection of occult early neck nodal adenopathy in surgical cases. It is generally accepted that prevention and screening of oral cancer are equally important to treatment due to its location. In this review article, we describe the nature of oral cancer and highlight the various conventional and novel methods of screening for this disease and ongoing important related research. Related literature is reviewed and future work that needs to be done is detailed.
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Affiliation(s)
- Shou-Yen Kao
- Department of Stomatology, Taipei Veterans General Hospital, Taiwan, R.O.C.
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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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Partridge MA, Huang SXL, Kibriya MG, Ahsan H, Davidson MM, Hei TK. Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2009; 72:301-4. [PMID: 19184745 DOI: 10.1080/15287390802526381] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
One of the long-term objectives of the research in our laboratory was to determine whether mitochondrial DNA (mtDNA) mutations were generated in cell lines exposed to a variety of known mutagens. Many of these mutagens are known to increase oxidative stress in the cell, and one potential outcome of this would be an increased incidence of point mutations in mtDNA. Recently, there has been some controversy regarding the validity of point mutations in the regulatory region of mtDNA as a predictive or causative marker for carcinogenesis. Studies were undertaken to assess whether nuclear mutagens such as arsenic (As), asbestos, and ultraviolet (UV) and gamma-radiation, induced both heteroplasmic and homoplasmic point mutations in mtDNA. A direct sequencing approach was used to reduce the occurrence of experimental errors and cross-checked all base changes with databases of known polymorphisms. Our results showed that, while base changes did occur, there was no marked difference between the number of changes in treated and untreated cells. Furthermore, in human lymphocyte samples from subjects exposed to As, most of these base changes were previously reported. Interestingly, there was an increase in the number of transversions (purine ( pyrimidine) in smokers from a human population study, but as with the findings in cell culture samples, there was no difference in the total number of base changes. Data suggest that only a change in the number of rare transversions would be indicative of an increase in point mutations in mtDNA after exposure to mutagens.
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Affiliation(s)
- Michael A Partridge
- Center for Radiological Research, Columbia University, New York, NY 10032, USA
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Chen YJ, Chang JTC, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF, Cheng AJ. Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 2008; 99:1507-14. [PMID: 18754860 PMCID: PMC11159516 DOI: 10.1111/j.1349-7006.2008.00863.x] [Citation(s) in RCA: 221] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Head and neck cancer (HNC) is one of the 10 most frequent cancers worldwide, with an estimated over 500,000 new cases being diagnosed annually. The overall 5-year survival rate in patients with HNC is one of the lowest among common malignant neoplasms and has not significantly changed during the last two decades. Oral cavity squamous cell carcinoma (OSCC) shares part of HNC and has been reported to be increasing in the betel quid chewing area in recent years. During 2006, OSCC has become the sixth most common type of cancer in Taiwan, and it is also the fourth most common type of cancer among men. It follows that this type of cancer wreaks a high social and personal cost. Environmental carcinogens such as betel quid chewing, tobacco smoking and alcohol drinking have been identified as major risk factors for head and neck cancer. There is growing interest in understanding the relationship between genetic susceptibility and the prevalent environmental carcinogens for HNC prevention. Within this review, we discuss the molecular and cellular aspects of HNC carcinogenesis in Taiwan, an endemic betel quid chewing area. Knowledge of molecular carcinogenesis of HNC may provide critical clues for diagnosis, prognosis, individualization of therapy and molecular therapeutics.
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Affiliation(s)
- Yin-Ju Chen
- Graduate Institute of Biomedical Science, Chang Gung University, 259 Wen-Hwa 1 Road, Taoyuan 333, Taiwan
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Cohen EEW. A disturbance in the force--mitochondrial mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res 2007; 13:4317-9. [PMID: 17671110 DOI: 10.1158/1078-0432.ccr-07-1015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Ezra E W Cohen
- Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA.
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Partridge MA, Huang SXL, Hernandez-Rosa E, Davidson MM, Hei TK. Arsenic induced mitochondrial DNA damage and altered mitochondrial oxidative function: implications for genotoxic mechanisms in mammalian cells. Cancer Res 2007; 67:5239-47. [PMID: 17545603 DOI: 10.1158/0008-5472.can-07-0074] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A(L) cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells.
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Affiliation(s)
- Michael A Partridge
- Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
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Ye C, Shu XO, Wen W, Pierce L, Courtney R, Gao YT, Zheng W, Cai Q. Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases. Breast Cancer Res Treat 2007; 108:427-34. [PMID: 17541740 PMCID: PMC3836503 DOI: 10.1007/s10549-007-9613-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 05/03/2007] [Indexed: 10/23/2022]
Abstract
The mitochondrial DNA (mtDNA) 4977-bp deletion (DeltamtDNA(4977) mutation) is one of the most frequently observed mtDNA mutations in human tissues and may play a role in carcinogenesis. Only a few studies have evaluated DeltamtDNA(4977) mutation in breast cancer tissue, and the findings have been inconsistent, which may be due to methodological differences. In this study, we developed a quantitative real-time PCR assay to assess the level of the DeltamtDNA(4977) mutation in tumor tissue samples from 55 primary breast cancer patients and 21 patients with benign breast disease (BBD). The DeltamtDNA(4977) mutation was detected in all of the samples with levels varying from 0.000149% to 7.0%. The DeltamtDNA(4977) mutation levels were lower in tumor tissues than in adjacent normal tissues in both breast cancer and BBD subjects. The differences, however, were not statistically significant. No significant difference between breast cancer and BBD patients was found in the DeltamtDNA(4977) mutation levels of tumor tissues and adjacent normal tissues. The DeltamtDNA(4977) mutation levels were not significantly associated with clinicopathological characteristics (age, histology, tumor stage, and ER/PR status) in breast cancer or BBD patients. These results do not support the notion that the mitochondrial DNA 4977-bp deletion plays a major role in breast carcinogenesis.
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Affiliation(s)
- Chuanzhong Ye
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Xiao-Ou Shu
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Wanqing Wen
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Larry Pierce
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Regina Courtney
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Wei Zheng
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Qiuyin Cai
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram-Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
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Lee HC, Hsu LS, Yin PH, Lee LM, Chi CW. Heteroplasmic mutation of mitochondrial DNA D-loop and 4977-bp deletion in human cancer cells during mitochondrial DNA depletion. Mitochondrion 2007; 7:157-63. [PMID: 17280876 DOI: 10.1016/j.mito.2006.11.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2006] [Accepted: 10/06/2006] [Indexed: 11/19/2022]
Abstract
Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various human cancers. Many cancers have high frequently of mtDNA with homoplasmic point mutations, and carry less frequently of mtDNA with large-scale deletions as compared with corresponding non-cancerous tissue. Moreover, most cancers harbor a decreased copy number of mtDNA than their corresponding non-cancerous tissue. However, it is unclear whether the process of decreasing in mtDNA content would be involved in an increase in the heteroplasmic level of somatic mtDNA point mutation, and/or involved in a decrease in the proportion of mtDNA with large-scale deletion in cancer cells. In this study, we provided evidence that the heteroplasmic levels of variations in cytidine number in np 303-309 poly C tract of mtDNA in three colon cancer cells were not changed during an ethidium bromide-induced mtDNA depleting process. In the mtDNA depleting process, the proportions of mtDNA with 4977-bp deletion in cybrid cells were not significantly altered. These results suggest that the decreasing process of mtDNA copy number per se may neither contribute to the shift of homoplasmic/heteroplasmic state of point mutation in mtDNA nor to the decrease in proportion of mtDNA with large-scale deletions in cancer cells. Mitochondrial genome instability and reduced mtDNA copy number may independently occur in human cancer.
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Affiliation(s)
- Hsin-Chen Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112, Republic of China.
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Datta S, Majumder M, Biswas NK, Sikdar N, Roy B. Increased risk of oral cancer in relation to common Indian mitochondrial polymorphisms and AutosomalGSTP1 locus. Cancer 2007; 110:1991-9. [PMID: 17886251 DOI: 10.1002/cncr.23016] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Polymorphisms at mitochondrial (mt) loci could modulate the risk of diseases including cancers. Here the mtDNA polymorphisms at 12,308 nucleotide pairs (np), 11,467 np, 10,400 np, and 10,398 np were studied to examine the association with the risk of oral cancer and leukoplakia, alone and in combination with polymorphisms at the GST loci. METHODS Polymorphisms at mt loci were screened in 310 cancer, 224 leukoplakia, and 389 control individuals by polymerase chain reaction (PCR) restriction length polymorphism (RFLP) and most of the GST genotype data were taken from previously published reports. Data were analyzed to determine the risk of the diseases. RESULTS The major allele, A, at 12,308 np on tRNA(Leu) (CUN), increased the risk of cancer (odd ratio [OR] of 1.7; 95% confidence interval [95% CI], 1.1-2.6) but not that of leukoplakia. The same allele also appeared to increase the risk of cancer in smokers (OR of 4.0; 95% CI, 1.1-14.4), who are mostly males (OR of 1.8; 95% CI, 1.1-3-2), but not in smokeless tobacco users, who are mostly females. The major allele A at 11467 np demonstrated identical results as the major allele, A, at 12,308 np. The major alleles G at 10,398 np and T at 10,400 np (ie, M-haplogroup) increased the risk of cancer significantly in smokers (OR of 2.6; 95% CI, 1.2-5.7 and OR of 2.4; 95% CI, 1.1-5.1, respectively). The risk-risk genotype-allele combination at GSTP1 and mt12308 np loci increased the risk of cancer (OR of 2.6; 95% CI, 1.4-4.9) when compared with the nonrisk-nonrisk combination in leukoplakia patients. CONCLUSIONS Polymorphisms at the mt loci alone and in combination with the risk genotype at GSTP1 increased the risk of oral cancer. Thus, risk genotypes from 2 different organelles may work in combination to increase the risk of oral cancer.
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Affiliation(s)
- Sayantan Datta
- Human Genetics Unit, Indian Statistical Institute, Kolkata, India
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Shieh DB, Chen CC, Shih TS, Tai HM, Wei YH, Chang HY. Mitochondrial DNA alterations in blood of the humans exposed to N,N-dimethylformamide. Chem Biol Interact 2006; 165:211-9. [PMID: 17254560 DOI: 10.1016/j.cbi.2006.12.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2006] [Revised: 11/28/2006] [Accepted: 12/09/2006] [Indexed: 11/24/2022]
Abstract
N,N-Dimethylformamide (DMF) has been widely used in industries because of its extensive miscibility with water and solvents. Its health effects include hepatotoxicity and male reproductoxicity, possibly linked with mitochondrial DNA (mtDNA) alterations including mtDNA common deletion (DeltamtDNA(4977)) and mtDNA copy number. The relationship between DMF exposure and mtDNA alterations, however, has not been postulated yet. The purposes of this study were to investigate whether the DMF exposure is associated with DeltamtDNA(4977) and mtDNA copy number and to evaluate the DMF-derived mtDNA alterations are more associated with exposure to the airborne DMF concentrations or to the levels of two urinary DMF biomarkers of N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoryl) cysteine(AMCC). Thirteen DMF-exposed workers and 13 age and seniority-matched control workers in a synthetic leather factory were monitored on their airborne DMF, NMF and AMCC in the urine as well as DeltamtDNA(4977) and mtDNA copy number in blood cells. We found that the frequencies of relative DeltamtDNA(4977) in DMF-exposed group were significantly higher than those in the control group. Moreover, elevation in the proportion of DeltamtDNA(4977) of individuals with high urine AMCC (U-AMCC) and airborne DMF levels were significantly higher than those without. We conclude that long-term exposure to DMF is highly associated with the alterations of mtDNA in urine and blood cells. The DeltamtDNA(4977) was more significantly related to repeated exposure to DMF and mtDNA copy number was more closely related to short-term DMF exposure. We also confirmed that U-AMCC is more appropriate to serve as a toxicity biomarker for DMF exposure than U-NMF. Further study with a larger number of subjects is warranted.
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Affiliation(s)
- Dar-Bin Shieh
- Institute of Oral Medicine, National Cheng Kung University Medical College, Tainan, Taiwan
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Kamalidehghan B, Houshmand M, Panahi MSS, Abbaszadegan MR, Ismail P, Shiroudi MB. Tumoral Cell mtDNA ∼8.9 kb Deletion Is More Common than Other Deletions in Gastric Cancer. Arch Med Res 2006; 37:848-53. [PMID: 16971224 DOI: 10.1016/j.arcmed.2006.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2005] [Accepted: 03/03/2006] [Indexed: 12/19/2022]
Abstract
BACKGROUND The aim of the study was to clarify the role of deletion of mitochondrial DNA (mtDNA) in gastric carcinogenesis and to determine prevalence of mitochondrial deletions in different regions of tumoral tissue in comparison with adjacent non-tumoral tissue in gastric cancer. METHODS In order to investigate whether a high incidence of mutations exists in mtDNA of gastric cancer tissues, we screened five regions of the mitochondrial genome by PCR amplification, Southern blot and DNA sequence analysis. RESULTS Of 71 cancer patients, the approximately 8.9 kb deletion was detected among different deletions in 9 cases (12.67%) of the tumoral tissues and 1 case (1.40%) in non-tumoral tissues that were adjacent to the tumors. Level of the 8.9 kb deletion has been found to be more than other deletions in tumoral tissues. CONCLUSIONS The approximately 8.9 kb deletion has an obvious correlation with age and histological type. These data suggest that the approximately 8.9 kb deletion in mtDNA may play an important role in gastric carcinogenesis.
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Affiliation(s)
- Behnam Kamalidehghan
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Tseng LM, Yin PH, Chi CW, Hsu CY, Wu CW, Lee LM, Wei YH, Lee HC. Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer. Genes Chromosomes Cancer 2006; 45:629-38. [PMID: 16568452 DOI: 10.1002/gcc.20326] [Citation(s) in RCA: 203] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various tumors, including breast cancer. However, it still remains unclear whether the alterations in mtDNA are related to the clinicopathological features and/or the prognosis in the breast cancer. We analyzed somatic mutations in the D-loop region, the common 4,977-bp deletion, and the copy number of mtDNA in breast cancer and paired nontumorous breast tissues from 60 Taiwanese patients. We found that 18 of the 60 (30%) breast cancers displayed somatic mutations in mtDNA D-loop region. The incidence of the 4,977-bp deletion in nontumorous breast tissues (47%) was much higher than that in breast cancers (5%). The copy number of mtDNA was significantly decreased in 38 of the 60 (63%) breast cancers as compared to their corresponding nontumorous breast tissues (P = 0.0008). The occurrence of D-loop mutations was associated with an older onset age (>or=50 years old, P = 0.042), and tumors that lacked expressions of estrogen receptor and progesterone receptor (P = 0.024). Patients with mtDNA D-loop mutation and breast cancer had significantly poorer disease-free survival than those without mutation, when assessed by Kaplan-Meier curves and log-rank test (P = 0.005). Multivariate Cox regression analysis indicated that a D-loop mutation is a significant marker that is independent of other clinical variables and that it can be used to assess the prognosis of patients. Our findings suggest that somatic mutations in mtDNA D-loop can be used as a new molecular prognostic indicator in breast cancer.
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Affiliation(s)
- Ling-Ming Tseng
- Department of Surgery, Taipei Veterans General Hospital, and National Yang-Ming University, Taiwan, Republic of China
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Thajeb P, Ma YS, Tzen CY, Chuang CK, Wu TY, Chen SC, Wei YH. Oculopharyngeal somatic myopathy in a patient with a novel large-scale 3,399 bp deletion and a homoplasmic T5814C transition of the mitochondrial DNA. Clin Neurol Neurosurg 2006; 108:407-10. [PMID: 16644408 DOI: 10.1016/j.clineuro.2005.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2004] [Revised: 12/29/2004] [Accepted: 01/04/2005] [Indexed: 11/25/2022]
Abstract
We report a 65-year-old woman with a sporadic form of progressive oculopharyngeal somatic myopathy due to a novel large-scale 3,399 base pair (bp) deletion of the mitochondrial DNA (mtDNA) and co-occurrence of a homoplasmic T5814C transition. The onset of myopathy began from chronic progressive external ophthalmoplegia (CPEO) at age of 20 years. Bulbar weakness, neck and proximal limb paralysis, slowly progressed to eventual respiratory failure. The plasma levels of pyruvate (1.5 mg/dL) and lactate (20.2 mg/dL) were elevated. Muscle biopsy showed decreased enzymatic activity of cytochrome c oxidase, but no ragged-red fibers. Electron microscopy showed "parking-lot" paracrystalline inclusions in the enlarged mitochondria suggestive for mitochondrial myopathy. Sequencing of the whole mitochondrial genome of the patient's muscle and leukocytes showed 3,399 bp deletion of the mtDNA from nucleotide position 8,024 to 11,423 and a homoplasmic thymidine to cytosine transition at nucleotide position 5,814 of the tRNA(Cys) gene of mtDNA (T5814C). T5814C was absent in the white blood cells of the patient's daughter and in 205 normal controls. We conclude that a large-scale deletion may coexist with T5814C transition in patients with sporadic form of mitochondrial cytopathy manifested by slowly progressive oculopharyngeal somatic myopathy.
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Affiliation(s)
- Peterus Thajeb
- Department of Neurology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.
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Yamada S, Nomoto S, Fujii T, Kaneko T, Takeda S, Inoue S, Kanazumi N, Nakao A. Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma. Eur J Surg Oncol 2006; 32:303-7. [PMID: 16478656 DOI: 10.1016/j.ejso.2006.01.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Accepted: 01/11/2006] [Indexed: 12/15/2022] Open
Abstract
AIMS In the current study, we investigated possible correlations of the mtDNA copy number in hepatocellular carcinoma (HCC) with the pathological findings and prognosis. METHODS We studied 31 HCC specimens using quantitative real-time polymerase chain reaction analysis, and the correlation between the mtDNA copy number and the clinicopathologic parameters and mutations in the D-loop region of the mitochondrial genome. RESULTS The mtDNA copy number was reduced in HCCs compared with the corresponding non-cancerous liver tissues (p=0.002), and significantly correlated with tumour size (p=0.014) and cirrhosis (p=0.048). Patients with a low mtDNA copy number tended to show shorter 5-year survival rates than patients with a high mtDNA copy number when assessed by Kaplan-Meier curves, but not a significant (overall survival rate, 63 vs 83%; p=0.19). The copy number of HCC with mtDNA D-loop mutation or deletion was lower, but not significantly so (p=0.656, p=0.590, respectively). CONCLUSIONS Our results indicated that a reduced copy number of mtDNA is correlated with HCC and associated with malignant potential.
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Affiliation(s)
- S Yamada
- Department of Surgery II, Graduate School and Faculty of Medicine, University of Nagoya, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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Chang MC, Hung SC, Chen WYK, Chen TL, Lee CF, Lee HC, Wang KL, Chiou CC, Wei YH. Accumulation of mitochondrial DNA with 4977-bp deletion in knee cartilage--an association with idiopathic osteoarthritis. Osteoarthritis Cartilage 2005; 13:1004-11. [PMID: 16165375 DOI: 10.1016/j.joca.2005.06.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2004] [Accepted: 06/21/2005] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Since mitochondrial DNA (mtDNA) mutations have been established to associate with the aging process and some degenerative diseases, we investigated the correlation between idiopathic osteoarthritis (OA) and the 4977-bp mtDNA deletion. DESIGN Cartilage were collected from six sites in knee joints removed from 18 aged patients with idiopathic OA, 10 aged non-OA cadavers, 3 young cadavers (YC), and lateral femoral condyle of 9 young patients. Histopathologic changes were examined and the common 4977-bp mtDNA deletions were analyzed in young and elderly cartilages obtained from different sites in the knee joint. The association of the 4977-bp deletion of mtDNA with idiopathic OA and aging was evaluated. RESULTS The 4977-bp mtDNA deletion was detected in 17 of the 18 OA patients, 9 of the 10 aged non-OA cadavers, and 1 of the 3 YC. None of the nine specimens collected from the lateral femoral condyle of young patients had a detectable deletion of mtDNA. The 4977-bp mtDNA deletion was not significantly correlated with the severity of OA graded by the Mankin score. The frequencies of occurrence of the 4977-bp mtDNA deletion were significantly different between the OA group and the aged non-OA control group (P=0.004) and between the aged non-OA group and the young control group (P=0.002). CONCLUSIONS The results suggest that accumulation of the 4977-bp deletion of mtDNA in knee cartilage increases with age and may play a role in the development of idiopathic OA in the knee joint.
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Affiliation(s)
- Ming-Chau Chang
- Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, and Department of Surgery, National Yang-Ming University, Taipei, Taiwan 112, Republic of China.
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Wu CW, Yin PH, Hung WY, Li AFY, Li SH, Chi CW, Wei YH, Lee HC. Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 2005; 44:19-28. [PMID: 15892105 DOI: 10.1002/gcc.20213] [Citation(s) in RCA: 187] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Gastric carcinoma is one of the most common types of cancer in Taiwan. Somatic mitochondrial DNA (mtDNA) alteration in gastric carcinoma and its association with clinicopathologic features remain unclear. When we used polymerase chain reaction (PCR) and direct sequencing, 15 of the 31 (48%) gastric carcinomas displayed somatic mutations in the D-loop region, a hot spot for mutations in mtDNA of human cancers. Ten (67%) cancers with the somatic mutations in the D-loop had insertion or deletion mutations in nucleotide position (np) 303-309 in the mononucleotide repeat region. One carcinoma carried tandem duplication and triplication flanked by mononucleotide repeats starting at np 311 and 568, respectively, in the D-loop. We also detected the common 4,977-bp deletion in 17 (55%) of the noncancerous tissue samples, but only in three (9%) carcinomas. Moreover, we quantified the mtDNA content using a competitive PCR technique and found that mtDNA depletion occurred in 17 (55%) of the gastric carcinomas. Although no significant association was found between clinicopathologic features and the mtDNA mutations in the D-loop, mtDNA depletion was observed significantly in the ulcerated, infiltrating (Borrmann's type III) and diffusely thick (Borrmann's type IV) types of gastric carcinomas (P = 0.018). Our results suggest that somatic mtDNA mutations and mtDNA depletion occur in gastric cancer and that mtDNA depletion is involved in carcinogenesis and/or cancer progression of gastric carcinoma.
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Affiliation(s)
- Chew-Wun Wu
- Department of Surgery, Taipei Veterans General Hospital, Taiwan, Republic of China
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Murray EB, Edwards JW. Differential induction of micronuclei in peripheral lymphocytes and exfoliated urothelial cells of workers exposed to 4,4'-methylenebis-(2-chloroaniline) (MOCA) and bitumen fumes. REVIEWS ON ENVIRONMENTAL HEALTH 2005; 20:163-76. [PMID: 16335575 DOI: 10.1515/reveh.2005.20.3.163] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Cytogenetic end-points used to estimate risk of genotoxic events in workers include the measurement of micronuclei (MN) in exfoliated cells, lymphocytes, and other tissues. Micronuclei are chromatin-containing bodies outside the cell nucleus resulting from contaminant-induced DNA damage. A review of 71 reports of human genotoxic responses to chemical or physical agents published between 1999 and 2001 revealed that 14% of such studies measured genotoxicity endpoints in specific target tissues relevant to the site of disease for the agent examined; 18% used endpoints in surrogate or non-target tissues but considered the relations between endpoints in surrogate and disease target tissues, and 68% measured genotoxicity endpoints in accessible tissues without reference to specific targets for disease. Methylenebis-(2-chloroaniline) (MOCA), used in polyurethane manufacture, is a suspected bladder carcinogen. Bitumen, used in road surfacing, contains skin and lung carcinogens. In this study, we aimed to compare genotoxicity in urothelial cells and in lymphocytes of workers exposed to these materials. Twelve men employed in polyurethane manufacture, twelve bitumen road layers, and eighteen hospital stores personnel (controls) were recruited and all provided blood and urine samples on the same day. Blood cultures were prepared using a cytochalasin B-block method. Exfoliated urothelial cells were collected from urine and stained for light microscopy. The number of MN in urothelial cells was higher in MOCA-exposed (14.27 +/- 0.56 MN/1000, 9.69 +/- 0.32 MN cells/1000) than in bitumen exposed workers (11.99 +/- 0.65 MN/1000, 8.66 +/- 0.46 MN cells/1000) or in control subjects (6.88 +/- 0.18 MN/1000, 5.17 +/- 0.11 MN cells/1000). Conversely, in lymphocytes, MN were higher in bitumen-exposed (16.24 +/- 0.63 MN/1000, 10.65 +/- 0.24 MN cells/1000) than in MOCA-exposed workers (13.25 +/- 0.48 MN/1000, 8.54 +/- 0.14 MN cells/1000) or in control subjects (9.24 +/- 0.29 MN/ 1000, 5.93 +/- 0.13 MN cells/1000). The results of this study suggest that genotoxins can cause different rates of micronuclei formation in different tissues. Thus, the sensitivity and relevance to cancer risk may be greater if the tissues selected for genotoxicity studies reflect the target tissue for the chemicals concerned.
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Affiliation(s)
- E B Murray
- Department of Environmental Health, School of Medicine Flinders University, Adelaide, Australia
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Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 2005; 37:822-34. [PMID: 15694841 DOI: 10.1016/j.biocel.2004.09.010] [Citation(s) in RCA: 485] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2004] [Revised: 09/15/2004] [Accepted: 09/23/2004] [Indexed: 10/26/2022]
Abstract
Mitochondrial biogenesis and mitochondrial DNA (mtDNA) maintenance depend on coordinated expression of genes in the nucleus and mitochondria. A variety of intracellular and extracellular signals transmitted by hormones and second messengers have to be integrated to provide mammalian cells with a suitable abundance of mitochondria and mtDNA to meet their energy demand. It has been proposed that reactive oxygen species (ROS) and free radicals generated from respiratory chain are involved in the signaling from mitochondria to the nucleus. Increased oxidative stress may contribute to alterations in the abundance of mitochondria as well as the copy number and integrity of mtDNA in human cells in pathological conditions and in aging process. Within a certain level, ROS may induce stress responses by altering expression of specific nuclear genes to uphold the energy metabolism to rescue the cell. Once beyond the threshold, ROS may cause oxidative damage to mtDNA and other components of the affected cells and to elicit apoptosis by induction of mitochondrial membrane permeability transition and release of pro-apoptotic proteins such as cytochrome c. On the basis of recent findings gathered from this and other laboratories, we review the alterations in the abundance of mitochondria and mtDNA copy number of mammalian cells in response to oxidative stress and the signaling pathways that are involved.
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Affiliation(s)
- Hsin-Chen Lee
- Department of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, Republic of China
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Akimoto M, Niikura M, Ichikawa M, Yonekawa H, Nakada K, Honma Y, Hayashi JI. Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells. Biochem Biophys Res Commun 2005; 327:1028-35. [PMID: 15652499 DOI: 10.1016/j.bbrc.2004.12.105] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2004] [Indexed: 12/12/2022]
Abstract
Recent studies showed high frequencies of homoplasmic mtDNA mutations in various human tumor types, suggesting that the mutated mtDNA haplotypes somehow contribute to expression of tumor phenotypes. We directly addressed this issue by isolating mouse mtDNA-less (rho(0)) cells for complete mtDNA replacement between normal cells and their carcinogen-induced transformants, and examined the effect of the mtDNA replacement on expression of tumorigenicity, a phenotype forming tumors in nude mice. The results showed that genome chimera cells carrying nuclear DNA from tumor cells and mtDNA from normal cells expressed tumorigenicity, whereas those carrying nuclear DNA from normal cells and mtDNA from tumor cells did not. These observations provided direct evidence that nuclear DNA, but not mtDNA, is responsible for carcinogen-induced malignant transformation, although it remains possible that mtDNA mutations and resultant respiration defects may influence the degree of malignancy, such as invasive or metastatic properties.
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Affiliation(s)
- Miho Akimoto
- Institute of Biological Sciences, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
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Dai JG, Lei X, Min JX, Zhang GQ, Wei H. Mitochondrial DNA sequence analysis of two mouse hepatocarcinoma cell lines. World J Gastroenterol 2005; 11:264-7. [PMID: 15633228 PMCID: PMC4205414 DOI: 10.3748/wjg.v11.i2.264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study genetic difference of mitochondrial DNA (mtDNA) between two hepatocarcinoma cell lines (Hca-F and Hca-P) with diverse metastatic characteristics and the relationship between mtDNA changes in cancer cells and their oncogenic phenotype.
METHODS: Mitochondrial DNA D-loop, tRNAMet+Glu+Ile and ND3 gene fragments from the hepatocarcinoma cell lines with 1100, 1126 and 534 bp in length respectively were analysed by PCR amplification and restriction fragment length polymorphism techniques. The D-loop 3’ end sequence of the hepatocarcinoma cell lines was determined by sequencing.
RESULTS: No amplification fragment length polymorphism and restriction fragment length polymorphism were observed in tRNAMet+Glu+Ile, ND3 and D-loop of mitochondrial DNA of the hepatocarcinoma cells. Sequence differences between Hca-F and Hca-P were found in mtDNA D-loop.
CONCLUSION: Deletion mutations of mitochondrial DNA restriction fragment may not play a significant role in carcinogenesis. Genetic difference of mtDNA D-loop between Hca-F and Hca-P, which may reflect the environmental and genetic influences during tumor progression, could be linked to their tumorigenic phenotypes.
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MESH Headings
- Animals
- Base Sequence
- Carcinoma, Hepatocellular/genetics
- Cell Line, Tumor
- DNA Primers
- DNA, Mitochondrial/genetics
- Liver Neoplasms/genetics
- Mice
- Mutation
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- RNA, Transfer, Glu/genetics
- RNA, Transfer, Ile/genetics
- RNA, Transfer, Met/genetics
- Restriction Mapping
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Affiliation(s)
- Ji-Gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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Lee JJ, Jeng JH, Wang HM, Chang HH, Chiang CP, Kuo YS, Lan WH, Kok SH. Univariate and multivariate analysis of prognostic significance of betel quid chewing in squamous cell carcinoma of buccal mucosa in Taiwan. J Surg Oncol 2005; 91:41-7. [PMID: 15999357 DOI: 10.1002/jso.20276] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND AND OBJECTIVES While betel quid (BQ) chewing is clearly the most avoidable risk factor of squamous cell carcinoma of buccal mucosa (BMSCC), little is known about the influence of this habit on the prognosis of BMSCC. METHODS We surveyed 280 patients with BMSCC who were treated during an 8-year period in a cohort study to assess the independent predictive value of pretreatment BQ chewing habit on the prognosis by univariate and multivariate analysis. RESULTS We found by univariate analysis that sex, age, clinical stage, smoking, and BQ chewing significantly affected the patients' prognosis and only age, clinical stage, and BQ chewing had significant influence on prognosis by multivariate analysis (P < 0.05). Further analysis revealed that the prognostic effect of BQ chewing changed in a dose- and time-dependent manner. The risk of death was 31.4-fold higher in heavy user (duration >30 years, daily consumption >30 quids, age of start <20 years old) when compared to those who chewed BQ to a milder degree (duration <10 years, daily consumption <15 quids, age of start > or =20 years old ) (P < 0.001). CONCLUSIONS Pretreatment BQ chewing habit worsens the prognosis of BMSCC in Taiwan. BQ chewing is a prognostic indicator that can be used in conjunction with clinical staging to help plan the treatment for the patients.
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Affiliation(s)
- Jang-Jaer Lee
- School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
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Poetsch M, Dittberner T, Petersmann A, Woenckhaus C. Mitochondrial DNA instability in malignant melanoma of the skin is mostly restricted to nodular and metastatic stages. Melanoma Res 2004; 14:501-8. [PMID: 15577321 DOI: 10.1097/00008390-200412000-00010] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Ultraviolet (UV) radiation is thought to be a major contributor to the development of sporadic malignant melanoma of the skin. It may induce alterations in genomic or mitochondrial DNA (mtDNA), especially C to T or CC to TT changes. Mutations or other alterations in mtDNA have been reported in a variety of human cancers and may be due to different mechanisms. In this study, we have attempted to elucidate whether aberrations in the mtDNA of melanoma are due to UV radiation or other factors by investigating two parts of the mitochondrial D-loop and two mitochondrial genes, as well as looking for the delta4977 mtDNA deletion and mtDNA duplications, in 61 primary malignant melanomas and neighbouring normal skin tissue (in 70% of primary tumours; otherwise, corresponding blood samples). Point mutations were a rare feature, occurring in only seven tumour samples and never as a C to T change, whereas mtDNA instability in the D-loop (mtMSI) was found in 13% of primary nodular tumours and 20% of metastases. A de novo delta4977 mtDNA deletion was demonstrated in 10% of melanomas; in 20% of patients, mtDNA duplications and/or the delta4977 mtDNA deletion was detectable. Our data indicate that mtDNA alterations in malignant melanoma are not induced by UV radiation. In addition, point mutations and mtMSI were mostly a feature of nodular and metastatic melanoma samples.
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Affiliation(s)
- Micaela Poetsch
- Institute of Forensic Medicine, University of Greifswald, Germany.
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Poetsch M, Petersmann A, Lignitz E, Kleist B. Relationship between mitochondrial DNA instability, mitochondrial DNA large deletions, and nuclear microsatellite instability in head and neck squamous cell carcinomas. ACTA ACUST UNITED AC 2004; 13:26-32. [PMID: 15163006 DOI: 10.1097/00019606-200403000-00005] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Mitochondrial DNA (mtDNA) mutations in coding and noncoding regions have been reported in a variety of human cancers. Despite a greater number of studies, the relationship between such alterations and nuclear microsatellite instability (nMSI) of the tumor cells remains controversial. To contribute new data to this discussion, we investigated head and neck squamous cell carcinomas (HNSCC) for mutations and mitochondrial microsatellite instability (mtMSI) in 2 parts of the mitochondrial D-loop as well as mutations in 2 mitochondrial genes and for the delta4977 mtDNA deletion. These results were compared with data of an analysis for microsatellite instability at IGFIIR, hMSH3, hMSH6, and 5 dinucleotide repeats. We found mtMSI, low nMSI, and high nMSI in 42%, 36%, and 13% of HNSCC primary tumors, respectively. A de novo delta4977 mtDNA deletion could be demonstrated in 25% of HNSCCs. A correlation between mtMSI and nMSI or between a de novo occurrence of the delta4977 mtDNA deletion and nMSI could not be detected in our HNSCC samples (P values 0.527 and 0.078, respectively). Nevertheless, the high rate of mtMSI suggests an involvement of mtDNA alterations in the tumorigenesis of this head and neck cancer and supports the proposal that this aberration may be a new tumor marker.
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Affiliation(s)
- Micaela Poetsch
- Institute of Forensic Medicine, University of Greifswald, Germany.
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