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1
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Myeong J, Lee M, Lee B, Kim JH, Nam Y, Choi Y, Kim J, Jeon SY, Shim H, Jung DR, Shin Y, Jeong M, Oh B, Jung J, Kim CS, Han HS, Shin JH, Lee YH, Park NJY, Chong GO, Jeong Y. Microbial metabolites control self-renewal and precancerous progression of human cervical stem cells. Nat Commun 2025; 16:2327. [PMID: 40057497 PMCID: PMC11890575 DOI: 10.1038/s41467-025-57323-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 02/18/2025] [Indexed: 05/13/2025] Open
Abstract
Cervical cancer is the fourth most common female cancer, with the uterine ectocervix being the most commonly affected site. However, cervical stem cells, their differentiation, and their regulation remain poorly understood. Here, we report the isolation of a population enriched for human cervical stem cells and their regulatory mechanisms. Using single-cell RNA sequencing, we characterize the cellular heterogeneity of the human ectocervix and identify cluster-specific cell surface markers. By establishing normal and precancerous cervical organoids and an intralingual transplantation system, we show that ITGB4 and CD24 enable enrichment of human and murine ectocervical stem cells. We discover that Lactobacilli-derived lactic acid regulates cervical stem cells' self-renewal and early tumorigenesis through the PI3K-AKT pathway and YAP1. Finally, we show that D-lactic acid suppresses growth of normal and precancerous organoids, while L-lactic acid does not. Our findings reveal roles of human cervical stem cells and microbial metabolites in cervical health and diseases.
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Affiliation(s)
| | - Minho Lee
- Department of Life Science, Dongguk University, Gyeonggi-do, Korea
| | - Bawool Lee
- Department of New Biology, DGIST, Daegu, Korea
- New Biology Research Center, DGIST, Daegu, Korea
| | - Joon Hyung Kim
- Department of Life Science, Dongguk University, Gyeonggi-do, Korea
| | - Yeji Nam
- School of Undergraduate Studies, DGIST, Daegu, Korea
| | - Yeseul Choi
- Graduate Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea
- BK21 Four Program, Kyungpook National University School of Medicine, Daegu, Korea
| | | | - Se Young Jeon
- Department of Obstetrics and Gynecology, Kyungpook National University Chilgok Hospital, Daegu, Korea
- Clinical Omics Institute, Kyungpook National University, Daegu, Korea
| | - Haewon Shim
- Department of Life Science, Dongguk University, Gyeonggi-do, Korea
| | - Da-Ryung Jung
- Department of Applied Biosciences, Kyungpook National University, Daegu, Korea
| | - Youngjin Shin
- Department of Life Science, Dongguk University, Gyeonggi-do, Korea
| | - Minsoo Jeong
- Department of Applied Biosciences, Kyungpook National University, Daegu, Korea
| | - Byungmoo Oh
- Department of New Biology, DGIST, Daegu, Korea
- New Biology Research Center, DGIST, Daegu, Korea
| | - Jaehun Jung
- Department of Life Science, Dongguk University, Gyeonggi-do, Korea
| | - Christine S Kim
- Department of New Biology, DGIST, Daegu, Korea
- New Biology Research Center, DGIST, Daegu, Korea
| | - Hyung Soo Han
- Graduate Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea
- BK21 Four Program, Kyungpook National University School of Medicine, Daegu, Korea
- Clinical Omics Institute, Kyungpook National University, Daegu, Korea
- Department of Physiology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jae-Ho Shin
- Department of Applied Biosciences, Kyungpook National University, Daegu, Korea
| | - Yoon Hee Lee
- Department of Obstetrics and Gynecology, Kyungpook National University Chilgok Hospital, Daegu, Korea
- Clinical Omics Institute, Kyungpook National University, Daegu, Korea
- Department of Obstetrics and Gynecology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Nora Jee-Young Park
- Clinical Omics Institute, Kyungpook National University, Daegu, Korea
- Department of Pathology, Kyungpook National University Chilgok Hospital, Daegu, Korea
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Gun Oh Chong
- Department of Obstetrics and Gynecology, Kyungpook National University Chilgok Hospital, Daegu, Korea.
- Clinical Omics Institute, Kyungpook National University, Daegu, Korea.
- Department of Obstetrics and Gynecology, Kyungpook National University School of Medicine, Daegu, Korea.
| | - Youngtae Jeong
- Department of New Biology, DGIST, Daegu, Korea.
- New Biology Research Center, DGIST, Daegu, Korea.
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2
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Branda F, Pavia G, Ciccozzi A, Quirino A, Marascio N, Gigliotti S, Matera G, Romano C, Locci C, Azzena I, Pascale N, Sanna D, Casu M, Ceccarelli G, Ciccozzi M, Scarpa F. Human Papillomavirus (HPV) Vaccination: Progress, Challenges, and Future Directions in Global Immunization Strategies. Vaccines (Basel) 2024; 12:1293. [PMID: 39591195 PMCID: PMC11598998 DOI: 10.3390/vaccines12111293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
Human papillomavirus (HPV) is a widespread viral pathogen, responsible for a significant burden of cervical and other cancers worldwide. Over the past decades, the development and widespread adoption of prophylactic HPV vaccines have dramatically reduced the incidence of HPV-related diseases. However, despite the efficacy of these vaccines, global immunization efforts still face several obstacles, including low vaccination coverage in low- and middle-income countries, vaccine hesitancy, and disparities in access to healthcare. This review aims to provide a comprehensive overview of the current state of HPV vaccines, including their mechanisms of action, safety profiles, and real-world efficacy. We will explore the impact of HPV vaccines on cancer prevention, examine the challenges related to vaccine distribution and uptake, and assess the role of public health policies in improving global vaccination rates. Additionally, the review will highlight the latest advancements in therapeutic HPV vaccines, ongoing research into next-generation vaccines, and the potential of HPV vaccination strategies in the context of personalized medicine. By examining these factors, we aim to provide insights into the future directions of HPV vaccination and its role in global public health.
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Affiliation(s)
- Francesco Branda
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Grazia Pavia
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro-“Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (G.P.); (A.Q.); (N.M.); (S.G.); (G.M.)
| | - Alessandra Ciccozzi
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.)
| | - Angela Quirino
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro-“Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (G.P.); (A.Q.); (N.M.); (S.G.); (G.M.)
| | - Nadia Marascio
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro-“Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (G.P.); (A.Q.); (N.M.); (S.G.); (G.M.)
| | - Simona Gigliotti
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro-“Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (G.P.); (A.Q.); (N.M.); (S.G.); (G.M.)
| | - Giovanni Matera
- Unit of Clinical Microbiology, Department of Health Sciences, “Magna Græcia” University of Catanzaro-“Renato Dulbecco” Teaching Hospital, 88100 Catanzaro, Italy; (G.P.); (A.Q.); (N.M.); (S.G.); (G.M.)
| | - Chiara Romano
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Chiara Locci
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.)
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Ilenia Azzena
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Noemi Pascale
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
- Department of Chemical Physical Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy
| | - Daria Sanna
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.)
| | - Marco Casu
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy; (I.A.); (N.P.); (M.C.)
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy; (C.R.); (M.C.)
| | - Fabio Scarpa
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (A.C.); (C.L.); (D.S.)
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3
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Liu Y, Niu M, Luo Y, Pan M, Hong S. DNA damage response and inflammatory response: Two traffic lights for HPVs on the road to transformation. J Med Virol 2024; 96:e29815. [PMID: 39073137 DOI: 10.1002/jmv.29815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/17/2024] [Accepted: 07/08/2024] [Indexed: 07/30/2024]
Abstract
Human papillomaviruses (HPVs) are non-enveloped double-stranded DNA viruses. When HPV infection persists, infected tissues can develop many HPV-related diseases such as cervical cancer and head and neck squamous cell carcinoma. To establish their persistent infection, HPVs have evolved mechanisms to manipulate the host cellular processes such as DNA damage response (DDR), which includes homologous recombination, nonhomologous end joining, and microhomology-mediated end joining. Additionally, HPVs utilize host inflammatory processes to facilitate their life cycles. Here, we bridge the concepts of DDR and inflammatory response, and discuss how HPV proteins orchestrate a sophisticated manipulation of DDR and inflammation to promote their viral replication, ultimately fostering the progression of infected cells towards oncogenic transformation to malignancy.
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Affiliation(s)
- Yanfei Liu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Mengda Niu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Ying Luo
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Min Pan
- Department of Otorhinolaryngology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shiyuan Hong
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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4
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Kushwah AS, Masood S, Mishra R, Banerjee M. Genetic and epigenetic alterations in DNA repair genes and treatment outcome of chemoradiotherapy in cervical cancer. Crit Rev Oncol Hematol 2024; 194:104240. [PMID: 38122918 DOI: 10.1016/j.critrevonc.2023.104240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/06/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Cervical cancer (CaCx) is the deadliest malignancy among women which is caused by human papillomavirus (HPV) and anthro-demographical/clinicopathological factors. HPV oncoproteins E6 and E7 target p53 and RB (retinoblastoma) protein degradation, Ataxia telangiectasia mutated (ATM), ATM-RAD3-related (ATR) inactivation and subsequent impairment of non-homologous end joining (NHEJ), homologous recombination, and base excision repair pathways. There is also an accumulation of genetic and epigenetic alterations in Tumor Growth Suppressors (TGS), oncogenes, and DNA repair genes leading to increased genome instability and CaCx development. These alterations might be responsible for differential clinical response to Cisplatin-based chemoradiotherapy (CRT) in patients. This review explores HPV-mediated DNA damage as a risk factor in CaCx development, the mechanistic role of genetic and epigenetic alterations in DNA repair genes and their association with CRT and outcome, It also explores new possibilities for the development of genetic and epigenetic-based biomarkers for diagnostic, prognostic, and molecular therapeutic interventions.
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Affiliation(s)
- Atar Singh Kushwah
- Department of Urology and Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York 10029, NY, USA; Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India; Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Shireen Masood
- Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Rajnikant Mishra
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India.
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5
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Abbasi SF, Mahjabeen I, Parveen N, Qamar I, Haq MFU, Shafique R, Saeed N, Ashraf NS, Kayani MA. Exploring homologous recombination repair and base excision repair pathway genes for possible diagnostic markers in hematologic malignancies. Mol Genet Genomics 2023; 298:1527-1543. [PMID: 37861816 DOI: 10.1007/s00438-023-02078-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 10/04/2023] [Indexed: 10/21/2023]
Abstract
Hematologic malignancies (HMs) are a collection of malignant transformations, originating from the cells in the bone marrow and lymphoid organs. HMs comprise three main types; leukemia, lymphoma, and multiple myeloma. Globally, HMS accounts for approximately 10% of newly diagnosed cancer. DNA repair pathways defend the cells from recurrent DNA damage. Defective DNA repair mechanisms such as homologous recombination repair (HRR), nucleotide excision repair (NER), and base excision repair (BER) pathways may lead to genomic instability, which initiates HM progression and carcinogenesis. Expression deregulation of HRR, NER, and BER has been investigated in various malignancies. However, no studies have been reported to assess the differential expression of selected DNA repair genes combinedly in HMs. The present study was designed to assess the differential expression of HRR and BER pathway genes including RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 in blood cancer patients to highlight their significance as diagnostic/ prognostic marker in hematological malignancies. The study cohort comprised of 210 blood cancer patients along with an equal number of controls. For expression analysis, q-RT PCR was performed. DNA damage was measured in blood cancer patients and controls using the comet assay and LORD Q-assay. Data analysis showed significant downregulation of selected genes in blood cancer patients compared to healthy controls. To check the diagnostic value of selected genes, the Area under curve (AUC) was calculated and 0.879 AUC was observed for RAD51 (p < 0.0001) and 0.830 (p < 0.0001) for APEX1. Kaplan-Meier analysis showed that downregulation of RAD51 (p < 0.0001), XRCC3 (p < 0.02), and APEX1 (p < 0.0001) was found to be associated with a significant decrease in survival of blood cancer patients. Cox regression analysis showed that deregulation of RAD51 (p < 0.0001), XRCC2 (p < 0.02), XRCC3 (p < 0.003), and APEX1 (p < 0.00001) was found to be associated with the poor prognosis of blood cancer patients. Comet assay showed an increased number of comets in blood cancer patients compared to controls. These results are confirmed by performing the LORD q-assay and an increased frequency of lesions/Kb was observed in selected genes in cancer patients compared to controls. Our results showed significant downregulation of RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 genes with increased DNA damage in blood cancer patients. The findings of the current research suggested that deregulated expression of HRR and BER pathway genes can act as a diagnostic/prognostic marker in hematologic malignancies.
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Affiliation(s)
- Sumaira Fida Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan.
| | - Neelam Parveen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Imama Qamar
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Maria Fazal Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Rabia Shafique
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Nida Sarosh Ashraf
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
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6
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Zuo N, Ma L, Liu T, Hu W, Luo Y, Meng H, Ren Q, Deng Y, Wei L, Liu Q. Human papillomavirus associated XPF deficiency increases alternative end joining and cisplatin sensitivity in head and neck squamous cell carcinoma. Oral Oncol 2023; 140:106367. [PMID: 36996606 DOI: 10.1016/j.oraloncology.2023.106367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/02/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023]
Abstract
OBJECTIVES Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) showed a considerably better prognosis with greater cisplatin sensitivity compared to their HPV-negative counterparts. Deciphering the underlying molecular mechanisms for HPV-induced cisplatin sensitivity is imperative to improve the prognosis of HPV-negative HNSCC. MATERIALS AND METHODS The Fanconi anemia (FA) pathway status in HNSCC cells was analysed by detecting the cell cycle and chromosomal aberrations. XPF expression was validated using PCR, western blot, and immunohistochemistry. Droplet digital PCR and GFP expressing reporter assay were used to analyse the changes in alternative end-joining (alt-EJ) levels. The cisplatin sensitization was verified by cell proliferation assay, clonogenic cell survival assay, and TUNEL. RESULTS HPV-positive HNSCC cells showed significant prolonged G2-M cell cycle arrest and aberrant chromosome formation under interstrand crosslinker treatment. Both mRNA and protein expression of XPF were considerably decreased in HPV-positive HNSCC, according to the analysis of cellular and clinical data. XPF inhibition upregulated the activity of the alt-EJ pathway in HPV-negative HNSCC cells by 32.02% (P < 0.001) but had little effect on HPV-positive HNSCC. Consistent with this, simultaneous suppression of XPF and alt-EJ enhanced cisplatin sensitivity of HPV-negative HNSCC in vitro and in vivo. CONCLUSION HPV-positive HNSCC cells exhibit a profound FA pathway deficiency associated with reduced XPF expression. HNSCC cells with compromised XPF function are more reliant on the alt-EJ pathway for genomic stability. Combining FA and alt-EJ inhibition may be used to cope with the hard-to-treat HPV-negative HNSCC.
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7
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Du P, Li G, Wu L, Huang M. Perspectives of ERCC1 in early-stage and advanced cervical cancer: From experiments to clinical applications. Front Immunol 2023; 13:1065379. [PMID: 36713431 PMCID: PMC9875293 DOI: 10.3389/fimmu.2022.1065379] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023] Open
Abstract
Cervical cancer is a public health problem of extensive clinical importance. Excision repair cross-complementation group 1 (ERCC1) was found to be a promising biomarker of cervical cancer over the years. At present, there is no relevant review article that summarizes such evidence. In this review, nineteen eligible studies were included for evaluation and data extraction. Based on the data from clinical and experimental studies, ERCC1 plays a key role in the progression of carcinoma of the uterine cervix and the therapeutic response of chemoradiotherapy. The majority of the included studies (13/19, 68%) suggested that ERCC1 played a pro-oncogenic role in both early-stage and advanced cervical cancer. High expression of ERCC1 was found to be associated with the poor survival rates of the patients. ERCC1 polymorphism analyses demonstrated that ERCC1 might be a useful tool for predicting the risk of cervical cancer and the treatment-related toxicities. Experimental studies indicated that the biological effects exerted by ERCC1 in cervical cancer might be mediated by its associated genes and affected signaling pathways (i.e., XPF, TUBB3, and. To move towards clinical applications by targeting ERCC1 in cervical cancer, more clinical, in-vitro, and in-vivo investigations are still warranted in the future.
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8
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Association of ERCC1 rs11615 Polymorphism with the Risk of Cervical Cancer Especially in Chinese Populations: A Meta-Analysis. JOURNAL OF ONCOLOGY 2022; 2022:1790993. [PMID: 36245993 PMCID: PMC9568358 DOI: 10.1155/2022/1790993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 09/07/2022] [Accepted: 09/16/2022] [Indexed: 11/18/2022]
Abstract
Abnormalities of the ERCC1 gene can affect DNA repair pathways, thereby having a vital effect on genomic stability. A growing amount of case-control studies have focused on making an investigation of the association between ERCC1 rs11615 polymorphism and cervical cancer susceptibility. However, the controversial results have raised concerns. To draw a more accurate conclusion, six studies were elaborately selected from the electronic databases for this meta-analysis, with 753 cervical cancer cases and 851 healthy controls. We applied pooled ORs combined with 95% CIs to test the potential associations. Significant associations were revealed in Chinese populations (T vs C:
and
; TT vs CC:
and
; TT/CT vs CC:
and
; and TT vs CT/CC:
and
). Even when the studies deviating from HWE were excluded, an increased cervical cancer susceptibility was observed in Chinese. These results disclose that there is an obvious correlation between the risk of cervical cancer and ERCC1 rs11615 polymorphism, especially in Chinese populations, and the T variant is the risky one. Also, our findings need further studies to validate.
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9
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Pasqui A, Boddi A, Campanacci DA, Scoccianti G, Bernini A, Grasso D, Gambale E, Scolari F, Palchetti I, Palomba A, Fancelli S, Caliman E, Antonuzzo L, Pillozzi S. Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma. Int J Mol Sci 2022; 23:ijms23158360. [PMID: 35955506 PMCID: PMC9369086 DOI: 10.3390/ijms23158360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 02/02/2023] Open
Abstract
Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.
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Affiliation(s)
- Adriano Pasqui
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.P.); (L.A.); (S.P.)
| | - Anna Boddi
- Orthopaedic Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.B.); (D.A.C.); (G.S.); (F.S.)
| | - Domenico Andrea Campanacci
- Orthopaedic Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.B.); (D.A.C.); (G.S.); (F.S.)
- Orthopaedic Oncology Unit, Careggi University Hospital, Department of Health Sciences, University of Florence, 50134 Florence, Italy
| | - Guido Scoccianti
- Orthopaedic Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.B.); (D.A.C.); (G.S.); (F.S.)
| | - Andrea Bernini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
- Correspondence:
| | - Daniela Grasso
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Elisabetta Gambale
- Clinical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Federico Scolari
- Orthopaedic Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.B.); (D.A.C.); (G.S.); (F.S.)
| | - Ilaria Palchetti
- Department of Chemistry Ugo Schiff, University of Florence, 50019 Sesto Fiorentino, Italy;
| | - Annarita Palomba
- Histopathology and Molecular Diagnostic Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Sara Fancelli
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.F.); (E.C.)
| | - Enrico Caliman
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.F.); (E.C.)
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.P.); (L.A.); (S.P.)
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.F.); (E.C.)
| | - Serena Pillozzi
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (A.P.); (L.A.); (S.P.)
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (S.F.); (E.C.)
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10
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Sahaba SA, Rashid MA, Islam MS, Nahid NA, Apu MNH, Sultana TN, Chaity NI, Hasan MM, Islam MS. The link of ERCC2 rs13181 and ERCC4 rs2276466 polymorphisms with breast cancer in the Bangladeshi population. Mol Biol Rep 2021; 49:1847-1856. [PMID: 34837148 DOI: 10.1007/s11033-021-06994-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/19/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Breast cancer (BC) is the most common disease in women and the leading cause of death from cancer globally. Epidemiological studies examined that nucleotide excision repair genes ERCC2 (rs13181) and ERCC4 (rs2276466) SNPs might increase cancer risk. Based on the previous investigation, this study was conducted to explore the correlation between these polymorphisms and BC susceptibility in Bangladeshi women. METHODS AND RESULTS Between January 2019 and January 2020, 140 blood samples were collected from female patients histologically diagnosed with BC, and 111 female controls were recruited from non-cancer subjects. Genotyping was performed applying the PCR-RFLP method, and all statistical analyzes were conducted using SPSS, version 25.0. Comparison of characteristics and clinicopathological features between ERCC2 rs13181 and ERCC4 rs2276466 carriers and non-carriers showed no significant link with BC. Analysis of ERCC2 rs13181 with the risk of BC showed that the GG genotype and G allele carriers showed a fourfold and 1.78-fold higher risk (OR 4.00, P = 0.001 and OR 1.78, P = 0.002) that are statistically significant. In addition, the patients with combined TG+GG genotype revealed a 2.09-fold increased chance (OR 2.09, P = 0.020) BC development. Analysis of recessive model (GG vs. TT+TG) also depicted 2.74-times significantly higher risk (OR 2.74, P = 0.002). On the other hand, ERCC4 rs2276466 polymorphism did not show any significant association with BC (P > 0.05). CONCLUSIONS Our findings show that ERCC2 rs13181 is linked to an elevated risk of BC. Our study also shows that ERCC4 rs2276466 polymorphism has no substantial risk of BC in the Bangladeshi population.
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Affiliation(s)
- Shaid All Sahaba
- Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh
| | | | - Md Saiful Islam
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Noor Ahmed Nahid
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Mohd Nazmul Hasan Apu
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Taposhi Nahid Sultana
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Nusrat Islam Chaity
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Md Mehedi Hasan
- Department of Clinical Pharmacy and Pharmacology, University of Dhaka, Dhaka, Bangladesh
| | - Mohammad Safiqul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali, 3814, Bangladesh.
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Cristini A, Géraud M, Sordet O. Transcription-associated DNA breaks and cancer: A matter of DNA topology. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 364:195-240. [PMID: 34507784 DOI: 10.1016/bs.ircmb.2021.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Transcription is an essential cellular process but also a major threat to genome integrity. Transcription-associated DNA breaks are particularly detrimental as their defective repair can induce gene mutations and oncogenic chromosomal translocations, which are hallmarks of cancer. The past few years have revealed that transcriptional breaks mainly originate from DNA topological problems generated by the transcribing RNA polymerases. Defective removal of transcription-induced DNA torsional stress impacts on transcription itself and promotes secondary DNA structures, such as R-loops, which can induce DNA breaks and genome instability. Paradoxically, as they relax DNA during transcription, topoisomerase enzymes introduce DNA breaks that can also endanger genome integrity. Stabilization of topoisomerases on chromatin by various anticancer drugs or by DNA alterations, can interfere with transcription machinery and cause permanent DNA breaks and R-loops. Here, we review the role of transcription in mediating DNA breaks, and discuss how deregulation of topoisomerase activity can impact on transcription and DNA break formation, and its connection with cancer.
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Affiliation(s)
- Agnese Cristini
- Cancer Research Center of Toulouse, INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, Toulouse, France.
| | - Mathéa Géraud
- Cancer Research Center of Toulouse, INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, Toulouse, France
| | - Olivier Sordet
- Cancer Research Center of Toulouse, INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, Toulouse, France.
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12
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Moreira DGL, Morais EFD, Santos HBDP, Freitas RDA. Immunohistochemical expression of DNA repair proteins in oral tongue and lower lip squamous cell carcinoma. Braz Oral Res 2020; 34:e101. [PMID: 32901726 DOI: 10.1590/1807-3107bor-2020.vol34.0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 06/15/2020] [Indexed: 04/27/2025] Open
Abstract
The DNA repair system involves genes and proteins that are essential for the maintenance of genome integrity and the consequent control of various cellular processes. Alterations in these genes and proteins play a role in tumor development and progression and might be associated with prognosis. The aims of this study were to analyze the immunoexpression of two DNA repair proteins, XPF and XRCC1, in lower lip squamous cell carcinoma (LLSCC) and oral tongue squamous cell carcinoma (OTSCC), and to investigate possible associations with clinical and histopathological parameters. The immunohistochemical expression of XPF and XRCC1 was analyzed semi-quantitatively in 40 cases each of LLSCC and OTSCC. The chi-squared test or Fisher's exact test, when appropriate, was used to investigate the association between expression of the proteins and clinicopathological characteristics. The cytoplasmic immunoexpression of XPF was high in OTSCC (95% of the cases analyzed) but low in LLSCC (52.5%). Among the clinicopathological parameters evaluated, a statistically significant association was observed between high nuclear expression of XRCC1 and the absence of regional lymph node metastasis in patients diagnosed with OTSCC (p=0.006). The high protein expression of XPF and XRCC1 in OTSCC and LLSCC suggests an important role in the development and progression of these tumors. Our study found an association between high nuclear expression of XRCC1 and the absence of loco-regional metastasis in cases diagnosed as OTSCC, suggesting a role of this protein in tumor progression.
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Affiliation(s)
- Deborah Gondim Lambert Moreira
- Universidade Federal do Rio Grande do Norte - UFRN, Centro de Ciênicas da Saúde, Department of Oral Pathology, Natal, RN, Brazil
| | - Everton Freitas de Morais
- Universidade Federal do Rio Grande do Norte - UFRN, Centro de Ciênicas da Saúde, Department of Oral Pathology, Natal, RN, Brazil
| | - Hellen Bandeira de Pontes Santos
- Universidade Federal do Rio Grande do Norte - UFRN, Centro de Ciênicas da Saúde, Department of Oral Pathology, Natal, RN, Brazil
| | - Roseana de Almeida Freitas
- Universidade Federal do Rio Grande do Norte - UFRN, Centro de Ciênicas da Saúde, Department of Oral Pathology, Natal, RN, Brazil
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13
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Expression of DNA repair genes in oral squamous cell carcinoma using reverse transcription-quantitative polymerase chain reaction. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 130:298-305. [PMID: 32682592 DOI: 10.1016/j.oooo.2020.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/14/2020] [Accepted: 06/01/2020] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the expression of DNA repair genes in cases of oral squamous cell carcinoma (OSCC). STUDY DESIGN Expression of the MLH1, MSH2, MLH3, ATM, MRE11A, XRCC1, and PMS2 genes was evaluated by reverse transcription-quantitative polymerase chain reaction in the OSCC group (32 patients) and the control group (15 patients). The groups were compared by using the Mann-Whitney test, with Bonferroni correction. Associations between gene expression levels and clinical data were explored by using Pearson's and Spearman's correlation coefficients, with P value less than .05 indicating a significant difference. RESULTS The MLH1, MSH2, MLH3, ATM, MRE11A, XRCC1, and PMS2 genes were downregulated in the OSCC group compared with the control group, with significant values for MLH1 (P < .0001); MSH2 (P = .038); MLH3 (P < .0001); ATM (P < .0001); MRE11A (P < .0001); XRCC1 (P = .0004); and PMS2 (P = .008). Analysis of the correlation between gene expression and clinical data only revealed a significant negative correlation between age and expression of the PMS2 gene. CONCLUSIONS Expression of the DNA repair genes MLH1, MSH2, MLH3, ATM, MRE11 AMRE11A, XRCC1, and PMS2 was reduced in OSCC.
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Kulkarni S, Solomon M, Pankaj D, Carnelio S, Chandrashekar C, Shetty N. Elucidating the role of excision repair cross-complement group 1 in oral epithelial dysplasia and early invasive squamous cell carcinoma: An immunohistochemical study. J Oral Maxillofac Pathol 2020; 24:20-25. [PMID: 32508443 PMCID: PMC7269280 DOI: 10.4103/jomfp.jomfp_60_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/09/2019] [Accepted: 07/26/2019] [Indexed: 11/17/2022] Open
Abstract
Objectives: Oral epithelial dysplasia (OED) is characterized by cellular alterations which have the proclivity of progressing to squamous cell carcinoma. Excision repair cross-complement group 1 (ERCC1) is one of the key proteins involved in nucleotide excision repair (NER) pathway. The expression of ERCC1 has been studied in colorectal, esophageal, ovarian and oral squamous cell carcinoma; but, very few studies have been done to apprehend the expression of ERCC1 in OED and early invasive squamous cell carcinoma (EISCC). The goal of this study is to evaluate the role of ERCC1 in OED and EISCC. Materials and Methods: Histopathologically diagnosed cases of moderate dysplasia (n = 10), severe dysplasia (n = 10) and EISCC (n = 10) were retrieved. 4 μ thick sections were cut from the formalin-fixed paraffin-embedded tissue blocks. The sections were immunohistochemically stained for ERCC1 following standard protocols. The expression of ERCC1 was evaluated semiquantitatively. Statistical analysis was carried out using Fischer's exact t-test. Results: The expression of ERCC1 was found to be strong (+3) in EISCC, moderate (+2) in severe dysplasia and mild (+1) in moderate dysplasia. Thus, the results were statistically significant between the three groups (P < 0.001). Conclusion: Disruption in the mechanisms that regulate cell cycle checkpoints and DNA repair mechanism results in genomic instability; these alterations might contribute to carcinoma. ERCC1 is essential to repair the DNA damage induced by various carcinogens. The present study shows significant difference in the expression of ERCC1 between EISCC and OED, which suggests ERCC1 could be used as one of the predictive markers.
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Affiliation(s)
- Spoorti Kulkarni
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Monica Solomon
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Deepthi Pankaj
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sunitha Carnelio
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Chetana Chandrashekar
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Nisha Shetty
- Department of Oral Pathology and Microbiology, Manipal College of Dental Science's, Manipal Academy of Higher Education, Manipal, Karnataka, India
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15
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Clementi E, Inglin L, Beebe E, Gsell C, Garajova Z, Markkanen E. Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient restriction. BMC Biol 2020; 18:36. [PMID: 32228693 PMCID: PMC7106853 DOI: 10.1186/s12915-020-00771-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/16/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Hence, tight adaptation of BER capacity is essential for DNA stability. However, counterintuitive to this, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Based on our previous findings that XRCC1 downregulation causes wide-ranging anabolic changes, we hypothesised that BER depletion could enhance cellular survival under stress, such as nutrient restriction. RESULTS Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. Furthermore, we demonstrate that SSBs, induced either through depletion of the transcription factor Sp1, responsible for XRCC1 levels, or through prolonged oxidative stress, trigger ISR-mediated cell survival under nutrient restriction as well. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks. CONCLUSIONS Our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.
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Affiliation(s)
- Elena Clementi
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland
| | - Larissa Inglin
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland
| | - Erin Beebe
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland
| | - Corina Gsell
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland
| | - Zuzana Garajova
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland
| | - Enni Markkanen
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, 8057, Zürich, Switzerland.
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16
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Sá MC, Conceição TS, de Moura Santos E, de Morais EF, Galvão HC, de Almeida Freitas R. Immunohistochemical expression of TFIIH and XPF in oral tongue squamous cell carcinoma. Eur Arch Otorhinolaryngol 2019; 277:893-902. [PMID: 31828418 DOI: 10.1007/s00405-019-05757-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE The query for biomarkers that indicate tumor aggressiveness and the host's response to treatment is still one of the leading aims of cancer research. To investigate a possible role for DNA nucleotide repair proteins in oral cancer behavior, this study evaluated the immunoexpression of the proteins TFIIH and XPF and its association with clinical, histological, and survival parameters in oral tongue squamous-cell carcinoma (OTSCC). METHODS TFIIH and XPF immunoexpressions were evaluated in 82 cases of oral tongue squamous-cell carcinoma. Tumor budding and depth of invasion were assessed for histopathological grading (BD model). RESULTS Tumor cells exhibited high expression of TFIIH and XPF, which was associated to nodal status; both proteins were not associated with other clinical parameters, histopathological grading or survival. Tumor size, nodal status, tumor staging, and depth of invasion > 4 mm were significantly associated to disease-specific survival. CONCLUSIONS We have demonstrated that the overexpression of TFIIH correlates positively with node metastasis, while XPF correlates negatively with node metastasis; therefore, the expression of XPF and TFIIH had a potential value for predicting the progression of OTSCC patients.
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Affiliation(s)
- Melka Coêlho Sá
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil
| | - Thalita Santana Conceição
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil
| | - Edilmar de Moura Santos
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil
| | - Everton Freitas de Morais
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil
| | - Hébel Cavalcanti Galvão
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil
| | - Roseana de Almeida Freitas
- Oral Pathology Postgraduate Program, Department of Dentistry, Federal University of Rio Grande Do Norte, Av. Salgado Filho, 1787, Natal, RN, Brazil. .,Department of Oral Pathology, Federal University of Rio Grande of Norte, Av. Salgado Filho, 1787, Lagoa Nova, Natal, RN, 59056-000, Brazil.
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17
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Birkett N, Al-Zoughool M, Bird M, Baan RA, Zielinski J, Krewski D. Overview of biological mechanisms of human carcinogens. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2019; 22:288-359. [PMID: 31631808 DOI: 10.1080/10937404.2019.1643539] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
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Affiliation(s)
- Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mustafa Al-Zoughool
- Department of Community and Environmental Health, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Michael Bird
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Robert A Baan
- International Agency for Research on Cancer, Lyon, France
| | - Jan Zielinski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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18
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Expression deregulation of DNA repair pathway genes in gastric cancer. Cancer Genet 2019; 237:39-50. [DOI: 10.1016/j.cancergen.2019.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 05/08/2019] [Accepted: 06/06/2019] [Indexed: 12/28/2022]
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19
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Singh N, Kazim SN, Sultana R, Tiwari D, Borkotoky R, Kakati S, Nath Das N, Kumar Saikia A, Bose S. Oxidative stress and deregulations in base excision repair pathway as contributors to gallbladder anomalies and carcinoma - a study involving North-East Indian population. Free Radic Res 2019; 53:473-485. [PMID: 31117842 DOI: 10.1080/10715762.2019.1606423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of XRCC1 and hOGG1 was significantly associated with both susceptibility and severity of GBC. The XRCC1 codon280 polymorphism was associated with disease susceptibility; and significantly higher oxidative stress was observed in hOGG1 genotypic variants. The genomes of GBC patients were found to be more hypermethylated compared to controls, with the promoters of XRCC1 and hOGG1 being hypermethylated and, therefore, being silenced. This study underlined the prognostic significance of the oxidative stress marker 8-OH-dG and BER pathway genes, especially hOGG1 and XRCC1, in gallbladder anomalies and GBC, as well as stated their potential for therapeutic targeting.
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Affiliation(s)
- Nidhi Singh
- a Department of Biotechnology , Gauhati University , Guwahati , India
| | - Syed Naqui Kazim
- b Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi , India
| | - Rizwana Sultana
- c Bioengineering and Technology , Gauhati University , Guwahati , India
| | - Diptika Tiwari
- c Bioengineering and Technology , Gauhati University , Guwahati , India
| | - Raktim Borkotoky
- a Department of Biotechnology , Gauhati University , Guwahati , India
| | | | | | - Anjan Kumar Saikia
- e Central Railway Hospital , Guwahati , India.,f GNRC Hospital , Guwahati , India
| | - Sujoy Bose
- a Department of Biotechnology , Gauhati University , Guwahati , India
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20
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Anoushirvani AA, Aghabozorgi R, Ahmadi A, Arjomandzadegan M, Khalili S, Sahraei M, Fereydouni T, Khademi Z. The Relationship Between rs3212986C>A Polymorphism and Tumor Stage in Lung Cancer Patients. Cureus 2019; 11:e4423. [PMID: 31245210 PMCID: PMC6559387 DOI: 10.7759/cureus.4423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Background The nucleotide excision repair (NER) system is one of the most important deoxyribonucleic acid (DNA) repair mechanisms and is critical for chemotherapy resistance. We conducted the present study to investigate the association between two polymorphisms of excision of repair cross-complementing group 1 (ERCC1), the key component of the NER pathway, and the clinicopathological features of patients with non-small cell lung cancer (NSCLC). Methods A total of 38 patients with confirmed NSCLC were included in our study. DNA was extracted from peripheral blood. ERCC1 rs3212986 (8092) and rs11615 (118) were genotyped using molecular assays including polymerase chain reaction (PCR) with restriction fragment length polymorphism (by MboII and HpyCH4 enzymes) and sequencing. Results The PCR results indicated the correct performance of the genomics extraction and molecular protocols. The distribution of C/C, C/A and A/A genotypes at position 8092 was 42.10%, 47.36%, and 10.52% respectively (P=0.03). Multivariate regression analysis showed that there was a significant correlation between C8092A (rs3212986) polymorphism and metastasis, grade of the tumor, and response to treatment. Individuals carrying the rs3212986 CA genotype and A allele had a significantly worse response to the treatment. Also, the correlation between alteration at this genomics location and patients with NSCLC who used to smoke cigarettes was positive. However, no significant association was detected between rs11615 C118>T polymorphism and demographic characteristics of patients with NSCLC. Conclusion We concluded that in lung cancer patients there is a relationship between tumor stage and rs3212986C>A polymorphism.
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Affiliation(s)
| | - Reza Aghabozorgi
- Internal Medicine, Arak University of Medical Sciences, Arak, IRN
| | - Azam Ahmadi
- Genetics, Arak University of Medical Sciences, Arak, IRN
| | | | - Sara Khalili
- Microbiology, Arak University of Medical Sciences, Arak, IRN
| | - Maryam Sahraei
- Genetics, Arak University of Medical Sciences, Arak, IRN
| | - Taha Fereydouni
- Internal Medicine, Arak University of Medical Sciences, Arak, IRN
| | - Zoha Khademi
- Internal Medicine, Arak University of Medical Sciences, Arak, IRN
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Prati B, da Silva Abjaude W, Termini L, Morale M, Herbster S, Longatto-Filho A, Nunes RAL, Córdoba Camacho LC, Rabelo-Santos SH, Zeferino LC, Aguayo F, Boccardo E. Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo. Sci Rep 2019; 9:351. [PMID: 30674977 PMCID: PMC6344518 DOI: 10.1038/s41598-018-37064-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 10/17/2018] [Indexed: 12/17/2022] Open
Abstract
Alterations in specific DNA damage repair mechanisms in the presence of human papillomavirus (HPV) infection have been described in different experimental models. However, the global effect of HPV on the expression of genes involved in these pathways has not been analyzed in detail. In the present study, we compared the expression profile of 135 genes involved in DNA damage repair among primary human keratinocytes (PHK), HPV-positive (SiHa and HeLa) and HPV-negative (C33A) cervical cancer derived cell lines. We identified 9 genes which expression pattern distinguishes HPV-positive tumor cell lines from C33A. Moreover, we observed that Three Prime Repair Exonuclease 1 (TREX1) expression is upregulated exclusively in HPV-transformed cell lines and PHK expressing HPV16 E6 and E7 oncogenes. We demonstrated that TREX1 silencing greatly affects tumor cells clonogenic and anchorage independent growth potential. We showed that this effect is associated with p53 upregulation, accumulation of subG1 cells, and requires the expression of E7 from high-risk HPV types. Finally, we observed an increase in TREX1 levels in precancerous lesions, squamous carcinomas and adenocarcinomas clinical samples. Altogether, our results indicate that TREX1 upregulation is important for cervical tumor cells growth and may contribute with tumor establishment and progression.
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Affiliation(s)
- Bruna Prati
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil
| | - Walason da Silva Abjaude
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil
| | - Lara Termini
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
| | - Mirian Morale
- Department of Biochemistry, Institute of Chemistry, USP, São Paulo, Brazil
| | - Suellen Herbster
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil
| | - Adhemar Longatto-Filho
- Laboratory of Medical Investigation (LIM 14), Department of Pathology, School of Medicine, USP, Av. Dr. Arnaldo 455, São Paulo, 01246-903, Brazil.,Life and Health Sciences Research Institute, School of Health Sciences, ICVS/3B's - PT Government Associate Laboratory, University of Minho, Braga, Guimarães, Portugal.,Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Barretos, Rua Antenor Duarte Villela, 1331, Barretos, 14784-400, Brazil
| | - Rafaella Almeida Lima Nunes
- Centro de Investigação Translacional em Oncologia (LIM24), Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
| | - Lizeth Carolina Córdoba Camacho
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil.,Laboratório de Oncologia Experimental, Departamento de Radiologia, Faculdade de Medicina, USP, São Paulo, SP, Brazil.,Centro de Investigação Translacional em Oncologia, ICESP, São Paulo, SP, Brazil
| | | | - Luiz Carlos Zeferino
- School of Medical Sciences, State University of Campinas (UNICAMP), Rua Alexander Fleming 101, 13083-881, Campinas, SP, Brazil
| | - Francisco Aguayo
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Enrique Boccardo
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo (USP), Av. Prof. Lineu Prestes 1374, 05508-900, São Paulo, SP, Brazil.
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22
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Prati B, Marangoni B, Boccardo E. Human papillomavirus and genome instability: from productive infection to cancer. Clinics (Sao Paulo) 2018; 73:e539s. [PMID: 30208168 PMCID: PMC6113919 DOI: 10.6061/clinics/2018/e539s] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 05/16/2018] [Indexed: 12/29/2022] Open
Abstract
Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.
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Affiliation(s)
- Bruna Prati
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Bruna Marangoni
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Enrique Boccardo
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
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23
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Legrand AJ, Poletto M, Pankova D, Clementi E, Moore J, Castro-Giner F, Ryan AJ, O’Neill E, Markkanen E, Dianov GL. Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts. Oncotarget 2018; 9:13666-13681. [PMID: 29568385 PMCID: PMC5862606 DOI: 10.18632/oncotarget.24446] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/30/2018] [Indexed: 02/03/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence suggesting that a pro-inflammatory microenvironment (e.g. ROS and cytokines) promotes CAF formation during tumorigenesis, although the exact mechanisms involved remain unclear. In this study, we reveal that a prolonged pro-inflammatory stimulation causes a de facto deficiency in base excision repair, generating unrepaired DNA strand breaks and thereby triggering an ATF4-dependent reprogramming of normal fibroblasts into CAF-like cells. Based on the phenotype of in vitro-generated CAFs, we demonstrate that midostaurin, a clinically relevant compound, selectively eliminates CAF-like cells deficient in base excision repair and prevents their stimulatory role in cancer cell growth and migration.
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Affiliation(s)
- Arnaud J. Legrand
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | - Mattia Poletto
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | - Daniela Pankova
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | - Elena Clementi
- Institute of Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Zürich 8057, Switzerland
| | - John Moore
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | | | - Anderson J. Ryan
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | - Eric O’Neill
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
| | - Enni Markkanen
- Institute of Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Zürich 8057, Switzerland
| | - Grigory L. Dianov
- CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK
- Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk 630090, Russian Federation
- Novosibirsk State University, Novosibirsk 630090, Russian Federation
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24
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Markkanen E. Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair (Amst) 2017; 59:82-105. [PMID: 28963982 DOI: 10.1016/j.dnarep.2017.09.007] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 09/20/2017] [Indexed: 02/07/2023]
Abstract
Oxidative DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to C:G→A:T transversion mutations. Cells have evolved a variety of pathways to mitigate the mutational potential of 8-oxo-G that include i) mechanisms to avoid incorporation of oxidized nucleotides into DNA through nucleotide pool sanitisation enzymes (by MTH1, MTH2, MTH3 and NUDT5), ii) base excision repair (BER) of 8-oxo-G in DNA (involving MUTYH, OGG1, Pol λ, and other components of the BER machinery), and iii) faithful bypass of 8-oxo-G lesions during replication (using a switch between replicative Pols and Pol λ). In the following, the fate of 8-oxo-G in mammalian cells is reviewed in detail. The differential origins of 8-oxo-G in DNA and its consequences for genetic stability will be covered. This will be followed by a thorough discussion of the different mechanisms in place to cope with 8-oxo-G with an emphasis on Pol λ-mediated correct bypass of 8-oxo-G during MUTYH-initiated BER as well as replication across 8-oxo-G. Furthermore, the multitude of mechanisms in place to regulate key proteins involved in 8-oxo-G repair will be reviewed. Novel functions of 8-oxo-G as an epigenetic-like regulator and insights into the repair of 8-oxo-G within the cellular context will be touched upon. Finally, a discussion will outline the relevance of 8-oxo-G and the proteins involved in dealing with 8-oxo-G to human diseases with a special emphasis on cancer.
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Affiliation(s)
- Enni Markkanen
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Winterthurerstr. 260, 8057 Zürich, Switzerland.
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25
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Fang S, Zhang Y, Xu M, Xue C, He L, Cai L, Xing X. Identification of Damaging nsSNVs in HumanERCC2 Gene. Chem Biol Drug Des 2016; 88:441-50. [PMID: 27085493 DOI: 10.1111/cbdd.12772] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 01/05/2023]
Abstract
The hERCC2 gene is an important DNA repair molecule for initiating Cutaneous melanoma (CM). Therefore, it is advisable to study the possible functional SNVs in hERCC2. To achieve this goal, we collected total 2, 253 SNVs in hERCC2from the EMBL website, of which 303 are non-synonymous single nucleotide variants (nsSNVs). Then, SIFT and PolyPhen were used to predict the damaging nsSNVs, and four nsSNVs (rs368866996, rs377739017, rs370819591, and rs121913022) were suggested to be damaging mutations. Since I-Mutant2.0 showed a decrease in stability for the mutants containing each of the four nsSNVs, a 3D protein structure was modeled. Based on the comparison of the energy after minimization, RMSD and stabilizing residues between the native and mutant proteins' structure, rs121913022 was proposed to be the most damaging variant among the nsSNVs in hERCC2 gene by decreasing the stability of protein. The mutant G713R of hERCC2 protein caused by rs121913022 was found to have less expression level than native hERCC2 protein in melanoma cells. These results suggest that rs121913022 may have potentially important clinical and drug target implications.
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Affiliation(s)
- Shuo Fang
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China.,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Yuntong Zhang
- Department of Orthopedics, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
| | - Miao Xu
- Department of Plastic and Reconstruction Surgery, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Chunyu Xue
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
| | - Lin He
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Lei Cai
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Bio-X Institutes, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Xin Xing
- Department of Plastic and Reconstruction, Shanghai Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China
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26
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Cheng YW, Lin FCF, Chen CY, Hsu NY. Environmental exposure and HPV infection may act synergistically to induce lung tumorigenesis in nonsmokers. Oncotarget 2016; 7:19850-62. [PMID: 26918347 PMCID: PMC4991423 DOI: 10.18632/oncotarget.7628] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/16/2016] [Indexed: 11/25/2022] Open
Abstract
Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers.
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Affiliation(s)
- Ya-Wen Cheng
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Frank Cheau-Feng Lin
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yi Chen
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Nan-Yung Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
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27
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HERD OLIVIA, FRANCIES FLAVIA, KOTZEN JEFFREY, SMITH TRUDY, NXUMALO ZWIDE, MULLER XANTHENE, SLABBERT JACOBUS, VRAL ANNE, BAEYENS ANS. Chromosomal radiosensitivity of human immunodeficiency virus positive/negative cervical cancer patients in South Africa. Mol Med Rep 2016; 13:130-6. [PMID: 26549042 PMCID: PMC4686097 DOI: 10.3892/mmr.2015.4504] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 07/28/2015] [Indexed: 12/01/2022] Open
Abstract
Cervical cancer is the second most common cancer amongst South African women and is the leading cause of cancer-associated mortality in this region. Several international studies on radiation‑induced DNA damage in lymphocytes of cervical cancer patients have remained inconclusive. Despite the high incidence of cervical cancer in South Africa, and the extensive use of radiotherapy to treat it, the chromosomal radiosensitivity of South African cervical cancer patients has not been studied to date. Since a high number of these patients are human immunodeficiency virus (HIV)‑positive, the effect of HIV infection on chromosomal radiosensitivity was also investigated. Blood samples from 35 cervical cancer patients (20 HIV‑negative and 15 HIV‑positive) and 20 healthy controls were exposed to X‑rays at doses of 6 MV of 2 and 4 Gy in vitro. Chromosomal radiosensitivity was assessed using the micronucleus (MN) assay. MN scores were obtained using the Metafer 4 platform, an automated microscopic system. Three scoring methods of the MNScore module of Metafer were applied and compared. Cervical cancer patients had higher MN values than healthy controls, with HIV‑positive patients having the highest MN values. Differences between groups were significant when using a scoring method that corrects for false positive and false negative MN. The present study suggested increased chromosomal radiosensitivity in HIV-positive South African cervical cancer patients.
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Affiliation(s)
- OLIVIA HERD
- Department of Radiation Biophysics, NRF-iThemba LABS, Somerset West 7129, South Africa
- Department of Radiation Sciences, University of Witwatersrand, Johannesburg 2193, South Africa
| | - FLAVIA FRANCIES
- Department of Radiation Biophysics, NRF-iThemba LABS, Somerset West 7129, South Africa
- Department of Radiation Sciences, University of Witwatersrand, Johannesburg 2193, South Africa
| | - JEFFREY KOTZEN
- Department of Radiation Oncology, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg 2193, South Africa
| | - TRUDY SMITH
- Department of Obstetrics and Gynaecology, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg 2193, South Africa
| | - ZWIDE NXUMALO
- Department of Obstetrics and Gynaecology, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg 2193, South Africa
| | - XANTHENE MULLER
- Department of Radiation Biophysics, NRF-iThemba LABS, Somerset West 7129, South Africa
| | - JACOBUS SLABBERT
- Department of Radiation Biophysics, NRF-iThemba LABS, Somerset West 7129, South Africa
| | - ANNE VRAL
- Department of Basic Medical Sciences, Ghent University, Ghent B-9000, Belgium
| | - ANS BAEYENS
- Department of Radiation Biophysics, NRF-iThemba LABS, Somerset West 7129, South Africa
- Department of Radiation Sciences, University of Witwatersrand, Johannesburg 2193, South Africa
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28
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Gupta RK, Bajpai D, Singh N. Influence of Morinda citrifolia (Noni) on Expression of DNA Repair Genes in Cervical Cancer Cells. Asian Pac J Cancer Prev 2015; 16:3457-61. [PMID: 25921162 DOI: 10.7314/apjcp.2015.16.8.3457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies have suggested that Morinda citrifolia (Noni) has potential to reduce cancer risk. OBJECTIVE The purpose of this study was to investigate the effect of Noni, cisplatin, and their combination on DNA repair genes in the SiHa cervical cancer cell line. MATERIALS AND METHODS SiHa cells were cultured and treated with 10% Noni, 10 μg/dl cisplatin or their combination for 24 hours. Post culturing, the cells were pelleted, RNA extracted, and processed for investigating DNA repair genes by real time PCR. RESULTS The expression of nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and base excision repair gene XRCC1 was increased 4 fold, 8.9 fold, 4 fold, and 5.5 fold, respectively, on treatment with Noni as compared to untreated controls (p<0.05). In contrast, expression was found to be decreased 22 fold, 13 fold, 16 fold, and 23 fold on treatment with cisplatin (p<0.05). However, the combination of Noni and cisplatin led to an increase of 2 fold, 1.6 fold, 3 fold, 1.2 fold, respectively (p<0.05). CONCLUSIONS Noni enhanced the expression of DNA repair genes by itself and in combination with cisplatin. However, high expression of DNA repair genes at mRNA level only signifies efficient DNA transcription of the above mentioned genes; further investigations are needed to evaluate the DNA repair protein expression.
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Affiliation(s)
- Rakesh Kumar Gupta
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India E-mail :
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29
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Markkanen E, Fischer R, Ledentcova M, Kessler BM, Dianov GL. Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability. Nucleic Acids Res 2015; 43:3667-79. [PMID: 25800737 PMCID: PMC4402536 DOI: 10.1093/nar/gkv222] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 03/04/2015] [Indexed: 12/27/2022] Open
Abstract
Genetic instability, provoked by exogenous mutagens, is well linked to initiation of cancer. However, even in unstressed cells, DNA undergoes a plethora of spontaneous alterations provoked by its inherent chemical instability and the intracellular milieu. Base excision repair (BER) is the major cellular pathway responsible for repair of these lesions, and as deficiency in BER activity results in DNA damage it has been proposed that it may trigger the development of sporadic cancers. Nevertheless, experimental evidence for this model remains inconsistent and elusive. Here, we performed a proteomic analysis of BER deficient human cells using stable isotope labelling with amino acids in cell culture (SILAC), and demonstrate that BER deficiency, which induces genetic instability, results in dramatic changes in gene expression, resembling changes found in many cancers. We observed profound alterations in tissue homeostasis, serine biosynthesis, and one-carbon- and amino acid metabolism, all of which have been identified as cancer cell ‘hallmarks’. For the first time, this study describes gene expression changes characteristic for cells deficient in repair of endogenous DNA lesions by BER. These expression changes resemble those observed in cancer cells, suggesting that genetically unstable BER deficient cells may be a source of pre-cancerous cells.
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Affiliation(s)
- Enni Markkanen
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
| | - Roman Fischer
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom
| | - Marina Ledentcova
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia
| | - Benedikt M Kessler
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom
| | - Grigory L Dianov
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia
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30
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Pathak S, Bajpai D, Banerjee A, Bhatla N, Jain SK, Jayaram HN, Singh N. Serum one-carbon metabolites and risk of cervical cancer. Nutr Cancer 2014; 66:818-24. [PMID: 24848140 DOI: 10.1080/01635581.2014.916318] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Most cases of cervical cancer are associated with human papilloma virus (HPV) infection of high risk types. In folate deficiency, heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) interferes with HPV16 viral capsid protein synthesis. We aimed to study the importance of 1-carbon metabolism in cervical carcinogenesis by examining serum vitamin B12 (cobalamin), homocysteine, folate levels, and the RNA and protein expression of HPV16 L1, L2, E6, E7, and to correlate them with hnRNP-E1 expression and HPV infection in normals, squamous intraepithelial lesions (SILs), and cervical cancer subjects. Serum cobalamin, folate, and homocysteine were estimated using kits, RNA by real time PCR and proteins by Western blotting. We observed that lower folate and vitamin B12 levels were associated with HPV infection. hnRNP-E1 progressively decreased from normals (100%) to SILs (75%) to cervical cancer (52.6%). The findings show that HPV16 E6 and E7 are overexpresed whereas HPV16 L1 and L2 are downregulated at mRNA and protein levels in cervical cancer as compared to normals and SILs. The results indicate that perhaps the reduced expression of hnRNP-E1 might be involved with the cervical cancer pathogenesis, with folate playing a role in the natural history of HPV infection.
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Affiliation(s)
- Sujata Pathak
- a Department of Biochemistry , All India Institute of Medical Sciences , New Delhi , India
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31
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Bhandaru M, Martinka M, Li G, Rotte A. Loss of XRCC1 confers a metastatic phenotype to melanoma cells and is associated with poor survival in patients with melanoma. Pigment Cell Melanoma Res 2014; 27:366-75. [DOI: 10.1111/pcmr.12212] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 01/07/2014] [Indexed: 11/30/2022]
Affiliation(s)
- Madhuri Bhandaru
- Department of Dermatology and Skin Science; University of British Columbia; Vancouver BC Canada
| | - Magdalena Martinka
- Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver BC Canada
| | - Gang Li
- Department of Dermatology and Skin Science; University of British Columbia; Vancouver BC Canada
| | - Anand Rotte
- Department of Dermatology and Skin Science; University of British Columbia; Vancouver BC Canada
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