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Maurya N, Meena A, Luqman S. Role of microRNAs in lung oncogenesis: Diagnostic implications, resistance mechanisms, and therapeutic strategies. Int J Biol Macromol 2025:144261. [PMID: 40381781 DOI: 10.1016/j.ijbiomac.2025.144261] [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: 07/28/2024] [Revised: 04/16/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Lung cancer continues to pose a significant global health concern, presenting a formidable challenge on a worldwide scale, necessitating a deeper understanding of molecular mechanisms underlying its pathogenesis and treatment responses. microRNA (miRNA) modulation in the context of lung cancer therapeutics aims to unravel the complexities of miRNA-mediated regulatory networks. This comprehensive review elucidates microRNA's diverse roles in lung cancer, encompassing their involvement in key signaling pathways, cellular processes, the regulation of oncogenic or tumor-suppressive targets, and drug sensitivity. Moreover, this review critically examines the potential of miRNAs as diagnostic and prognostic biomarkers and their implications in therapeutic interventions for lung cancer. microRNAs are effective in making lung cancer therapy more efficient. They can make tumor cells more responsive to chemotherapy, radiation, and targeted therapies. microRNAs can target the drug efflux mechanism, increasing the effectiveness of chemotherapy agents and decreasing resistance. Furthermore, microRNAs play a crucial role in developing and inhibiting the resistance mechanisms against conventional treatments; improving the dysregulated expression of microRNAs enhances the therapeutic efficacy of existing therapies. By compiling knowledge on miRNA-mediated processes related to lung cancer, this review offers a comprehensive resource for researchers to understand and address the complexities of oncogenesis, diagnostics, resistance mechanisms, and therapeutic strategies.
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Affiliation(s)
- Nidhi Maurya
- CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226 015, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 001, Uttar Pradesh, India
| | - Abha Meena
- CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226 015, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 001, Uttar Pradesh, India
| | - Suaib Luqman
- CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226 015, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 001, Uttar Pradesh, India.
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2
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Guo M, Zhu X, Ma T, Xu C, Zhangsun D, Yu J, Kaas Q, Harvey PJ, McIntosh JM, Craik DJ, Luo S. Selective Inhibition of Rat α7 Nicotinic Acetylcholine Receptors by LvID, a Newly Characterized α4/7-Conotoxin from Conus lividus. J Med Chem 2025; 68:8163-8173. [PMID: 40205658 DOI: 10.1021/acs.jmedchem.4c02810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
The α7 nicotinic acetylcholine receptors (nAChRs), identified in peripheral and central nervous systems, are crucial for cognitive function, memory, inflammation, and are linked to disorders like Alzheimer's disease (AD), lung cancer, myasthenia gravis, and atherosclerosis. Here we report that a novel α4/7-conotoxin (CTx) LvID, from Conus lividus, potently inhibits rat α7 nAChRs expressed in Xenopus oocytes with an IC50 of 13.8 nM, showing little activity against other rat nAChR subtypes. The structure of LvID was elucidated using nuclear magnetic resonance (NMR) spectroscopy and comprises a short helix braced by disulfide bonds. The key residues of LvID that bind to the α7 nAChRs were determined from a series of alanine mutants. Molecular simulation provided a possible explanation for the activity and specificity of LvID binding to α7 nAChRs. This finding offers a vital pharmacological tool for investigating the structural features and functional mechanisms of α7 nAChRs.
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Affiliation(s)
- Man Guo
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311113, China
- Key Laboratory of Tropical Biological Resources, Ministry of Education, Hainan University, Haikou 570228, China
| | - Xiaopeng Zhu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
| | - Tao Ma
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
| | - Chenxing Xu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
| | - Dongting Zhangsun
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
- Key Laboratory of Tropical Biological Resources, Ministry of Education, Hainan University, Haikou 570228, China
| | - Jinpeng Yu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
| | - Quentin Kaas
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Peta J Harvey
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - J Michael McIntosh
- Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112, United States
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah 84108, United States
| | - David J Craik
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Sulan Luo
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
- Key Laboratory of Tropical Biological Resources, Ministry of Education, Hainan University, Haikou 570228, China
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Korde A, Ramaswamy A, Anderson S, Jin L, Zhang JG, Hu B, Velasco WV, Diao L, Wang J, Pisani MA, Sauler M, Boffa DJ, Puchalski JT, Yan X, Moghaddam SJ, Takyar SS. Cigarette smoke induces angiogenic activation in the cancer field through dysregulation of an endothelial microRNA. Commun Biol 2025; 8:511. [PMID: 40155749 PMCID: PMC11953391 DOI: 10.1038/s42003-025-07710-y] [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: 08/23/2024] [Accepted: 02/10/2025] [Indexed: 04/01/2025] Open
Abstract
Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial growth factor-driven pathway. Applying a multi-step molecular screen, we identified angiogenic genes regulated by miR-1 in the lungs of smokers. Knockdown of one of these genes, Notch homolog protein 3, simulates the anti-angiogenic effects of miR-1. These findings suggest that miR-1 can be used as an indicator of malignant transformation.
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Affiliation(s)
- Asawari Korde
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Anuradha Ramaswamy
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Seth Anderson
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Lei Jin
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jian-Ge Zhang
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Buqu Hu
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Walter V Velasco
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lixia Diao
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Wang
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Margaret A Pisani
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Maor Sauler
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Daniel J Boffa
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
| | - Jonathan T Puchalski
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Xiting Yan
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Seyed Javad Moghaddam
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shervin S Takyar
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.
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Kim M, Han KD, Ko SH, Woo Y, Han JH. Effect of smoking on the risk of gastrointestinal cancer after cholecystectomy: A national population-based cohort study. World J Gastrointest Surg 2024; 16:2796-2807. [PMID: 39351570 PMCID: PMC11438817 DOI: 10.4240/wjgs.v16.i9.2796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/04/2024] [Accepted: 07/31/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND The role of smoking in the incidence of colorectal cancer (CRC) or gastric cancer (GC) in populations undergoing cholecystectomy has not been investigated. AIM To evaluate the effect of smoking on CRC or GC development in cholecystectomy patients. METHODS A total of 174874 patients who underwent cholecystectomy between January 1, 2010 and December 31, 2017 were identified using the Korean National Health Insurance Service claims database. These patients were matched 1:1 with members of a healthy population according to age and sex. CRC or GC risk after cholecystectomy and the association between smoking and CRC or GC risk in cholecystectomy patients were evaluated using adjusted hazard ratios (HRs) and 95%CIs. RESULTS The risks of CRC (adjusted HR: 1.15; 95%CI: 1.06-1.25; P = 0.0013) and GC (adjusted HR: 1.11; 95%CI: 1.01-1.22; P = 0.0027) were significantly higher in cholecystectomy patients. In the population who underwent cholecystectomy, both CRC and GC risk were higher in those who had smoked compared to those who had never smoked. For both cancers, the risk tended to increase in the order of non-smokers, ex-smokers, and current smokers. In addition, a positive correlation was observed between the amount of smoking and the risks of both CRC and GC. CONCLUSION Careful follow-up and screening should be performed, focusing on the increased risk of gastrointestinal cancer in the cholecystectomy group, particularly considering the individual smoking habits.
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Affiliation(s)
- Minseob Kim
- Department of Surgery, Graduate School of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Kyung-Do Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul 06978, South Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea
| | - Yoonkyung Woo
- Division of Hepatobiliary-Pancreas Surgery and Liver Transplantation, Department of Surgery, St Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea
| | - Jae Hyun Han
- Division of Hepatobiliary-Pancreas Surgery and Liver Transplantation, Department of Surgery, St Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, South Korea
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Jang HJ, Min HY, Kang YP, Boo HJ, Kim J, Ahn JH, Oh SH, Jung JH, Park CS, Park JS, Kim SY, Lee HY. Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression. Nat Commun 2024; 15:4909. [PMID: 38851766 PMCID: PMC11162468 DOI: 10.1038/s41467-024-49199-9] [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: 07/15/2022] [Accepted: 05/23/2024] [Indexed: 06/10/2024] Open
Abstract
Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.
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Affiliation(s)
- Hyun-Ji Jang
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hye-Young Min
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yun Pyo Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hye-Jin Boo
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- Department of Histology, College of Medicine, Jeju National University, Jeju, 63243, Republic of Korea
| | - Jisung Kim
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jee Hwan Ahn
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seung Ho Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jin Hwa Jung
- PET core, Convergence Medicine Research Center, Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Choon-Sik Park
- Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea
| | - Jong-Sook Park
- Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea
| | - Seog-Young Kim
- PET core, Convergence Medicine Research Center, Asan Medical Center, Seoul, 05505, Republic of Korea
- Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Ho-Young Lee
- Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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Di Fusco SA, Spinelli A, Castello L, Marino G, Maraschi I, Gulizia MM, Gabrielli D, Colivicchi F. Do Pathophysiologic Mechanisms Linking Unhealthy Lifestyle to Cardiovascular Disease and Cancer Imply Shared Preventive Measures? - A Critical Narrative Review. Circ J 2024; 88:189-197. [PMID: 34544961 DOI: 10.1253/circj.cj-21-0459] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Growing evidence has shown a bidirectional link between the cardiologic and oncologic fields. Several investigations support the role of unhealthy behaviors as pathogenic factors of both cardiovascular disease and cancer. We report epidemiological and research findings on the pathophysiological mechanisms linking unhealthy lifestyle to cardiovascular disease and cancer. For each unhealthy behavior, we also discuss the role of preventive measures able to affect both cardiovascular disease and cancer occurrence and progression.
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Affiliation(s)
| | | | - Lorenzo Castello
- Clinical and Rehabilitation Cardiology Unit, San Filippo Neri Hospital
| | - Gaetano Marino
- Clinical and Rehabilitation Cardiology Unit, San Filippo Neri Hospital
| | - Ilaria Maraschi
- Clinical and Rehabilitation Cardiology Unit, San Filippo Neri Hospital
| | | | | | - Furio Colivicchi
- Clinical and Rehabilitation Cardiology Unit, San Filippo Neri Hospital
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Peña-Oyarzún D, Flores T, Torres VA, Quest AFG, Lobos-González L, Kretschmar C, Contreras P, Maturana-Ramírez A, Criollo A, Reyes M. Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis. Clin Cancer Res 2024; 30:209-223. [PMID: 37812478 DOI: 10.1158/1078-0432.ccr-23-0318] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/12/2023] [Accepted: 10/05/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/β-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis. EXPERIMENTAL DESIGN We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59. RESULTS Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear β-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions. CONCLUSIONS The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.
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Affiliation(s)
- Daniel Peña-Oyarzún
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Physiology Department, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
- Interdisciplinary Center for Research in Territorial Health of the Aconcagua Valley (CIISTe Aconcagua), School of Medicine, Faculty of Medicine, San Felipe Campus, Universidad de Valparaiso, Chile
| | - Tania Flores
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Research Centre in Dental Science (CICO), Faculty of Dentistry, Universidad de La Frontera, Temuco, Chile
- Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Vicente A Torres
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, Santiago, Chile
| | - Andrew F G Quest
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Lorena Lobos-González
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Center for Regenerative Medicine, Faculty of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
| | - Catalina Kretschmar
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Pamela Contreras
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Andrea Maturana-Ramírez
- Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Alfredo Criollo
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Montserrat Reyes
- Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
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Zhou L, Jian T, Wan Y, Huang R, Fang H, Wang Y, Liang C, Ding X, Chen J. Luteolin Alleviates Oxidative Stress in Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke via Modulation of the TRPV1 and CYP2A13/NRF2 Signaling Pathways. Int J Mol Sci 2023; 25:369. [PMID: 38203542 PMCID: PMC10779282 DOI: 10.3390/ijms25010369] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
The current study aims to investigate the therapeutic potential of luteolin (Lut), a naturally occurring flavonoid found in various medicinal plants, for treating chronic obstructive pulmonary disease (COPD) through both in vitro and in vivo studies. The results demonstrated that Lut increased body weight, reduced lung tissue swelling and lung damage indices, mitigated systemic oxidative stress levels, and decreased alveolar fusion in cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD mice. Additionally, Lut was observed to downregulate the expression of the TRPV1 and CYP2A13 proteins while upregulating SIRT6 and NRF2 protein expression in CS + LPS-induced COPD mice and cigarette smoke extract (CSE)-treated A549 cells. The concentrations of total reactive oxygen species (ROS) and mitochondrial ROS in A549 cells induced by CSE significantly increased. Moreover, CSE caused a notable elevation of intracellular Ca2+ levels in A549 cells. Importantly, Lut exhibited inhibitory effects on the inward flow of Ca2+ and attenuated the overproduction of mitochondrial and intracellular ROS in A549 cells treated with CSE. In conclusion, Lut demonstrated a protective role in alleviating oxidative stress and inflammation in CS + LPS-induced COPD mice and CSE-treated A549 cells by regulating TRPV1/SIRT6 and CYP2A13/NRF2 signaling pathways.
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Affiliation(s)
- Lina Zhou
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; (L.Z.); (T.J.); (C.L.)
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
| | - Tunyu Jian
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; (L.Z.); (T.J.); (C.L.)
| | - Yan Wan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
| | - Rizhong Huang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
| | - Hailing Fang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
| | - Yiwei Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
| | - Chengyuan Liang
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; (L.Z.); (T.J.); (C.L.)
| | - Xiaoqin Ding
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; (L.Z.); (T.J.); (C.L.)
| | - Jian Chen
- Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; (L.Z.); (T.J.); (C.L.)
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; (Y.W.); (R.H.); (H.F.); (Y.W.)
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9
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Al Khashali H, Darweesh B, Ray R, Haddad B, Wozniak C, Ranzenberger R, Goel S, Khalil J, Guthrie J, Heyl D, Evans HG. Regulation of Vascular Endothelial Growth Factor Signaling by Nicotine in a Manner Dependent on Acetylcholine-and/or β-Adrenergic-Receptors in Human Lung Cancer Cells. Cancers (Basel) 2023; 15:5500. [PMID: 38067204 PMCID: PMC10705358 DOI: 10.3390/cancers15235500] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/05/2023] [Accepted: 11/19/2023] [Indexed: 10/15/2024] Open
Abstract
Simple Summary Nicotine, a highly addictive component in cigarette smoke, facilitates tumorigenesis and the accelerated development of non-small cell lung cancer (NSCLC), which is known to account for ~80% of all lung cancer cases. This study sheds light on how the nicotine treatment of NSCLC cells regulates vascular endothelial growth factor (VEGF) signaling, known to be important in the progression of vascular disease and cancer, by acting through nicotinic acetylcholine receptors and by leading to the activation of β-adrenergic receptors through increased levels of the stress neurotransmitters, norepinephrine/noradrenaline, and epinephrine/adrenaline. Nicotine-induced activation of VEGF promoted the function of proteins involved in increased cell survival and suppressed the function of a crucial tumor suppressor, blocking cell death. This work expands our scientific knowledge of mechanisms employed by nicotine in regulating VEGF signaling in a manner dependent on the acetylcholine and/or β-adrenergic receptors, leading to lung cancer cell survival, and also provides significant insights into novel future therapeutic strategies to combat lung cancer. Abstract In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hedeel Guy Evans
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USA; (H.A.K.); (B.D.); (R.R.); (B.H.); (C.W.); (R.R.); (S.G.); (J.K.); (J.G.); (D.H.)
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10
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Ray R, Goel S, Al Khashali H, Darweesh B, Haddad B, Wozniak C, Ranzenberger R, Khalil J, Guthrie J, Heyl D, Evans HG. Regulation of Soluble E-Cadherin Signaling in Non-Small-Cell Lung Cancer Cells by Nicotine, BDNF, and β-Adrenergic Receptor Ligands. Biomedicines 2023; 11:2555. [PMID: 37760996 PMCID: PMC10526367 DOI: 10.3390/biomedicines11092555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/11/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
The ectodomain of the transmembrane protein E-cadherin can be cleaved and released in a soluble form referred to as soluble E-cadherin, or sE-cad, accounting for decreased E-cadherin levels at the cell surface. Among the proteases implicated in this cleavage are matrix metalloproteases (MMP), including MMP9. Opposite functions have been reported for full-length E-cadherin and sE-cad. In this study, we found increased MMP9 levels in the media of two non-small cell lung cancer (NSCLC) cell lines, A549 and H1299, treated with BDNF, nicotine, or epinephrine that were decreased upon cell treatment with the β-adrenergic receptor blocker propranolol. Increased MMP9 levels correlated with increased sE-cad levels in A549 cell media, and knockdown of MMP9 in A549 cells led to downregulation of sE-cad levels in the media. Previously, we reported that A549 and H1299 cell viability increased with nicotine and/or BDNF treatment and decreased upon treatment with propranolol. In investigating the function of sE-cad, we found that immunodepletion of sE-cad from the media of A549 cells untreated or treated with BDNF, nicotine, or epinephrine reduced activation of EGFR and IGF-1R, decreased PI3K and ERK1/2 activities, increased p53 activation, decreased cell viability, and increased apoptosis, while no effects were found using H1299 cells under all conditions tested.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hedeel Guy Evans
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USA; (R.R.); (S.G.); (H.A.K.); (B.D.); (B.H.); (C.W.); (R.R.); (J.K.); (J.G.); (D.H.)
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11
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Jang HJ, Boo HJ, Min HY, Kang YP, Kwon SW, Lee HY. Effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and benzo[a]pyrene exposure on the development of metabolic syndrome in mice. Life Sci 2023; 329:121925. [PMID: 37423377 DOI: 10.1016/j.lfs.2023.121925] [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: 05/26/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/11/2023]
Abstract
AIM The prevalence of metabolic syndrome (MetS), a cluster of serious medical conditions that raise the risk of lung cancer, has increased worldwide. Tobacco smoking (TS) potentially increases the risk of developing MetS. Despite the potential association of MetS with lung cancer, preclinical models that mimic human diseases, including TS-induced MetS, are limited. Here we evaluated the impact of exposure to tobacco smoke condensate (TSC) and two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNK) and benzo[a]pyrene (BaP), on MetS development in mice. MATERIALS AND METHODS FVB/N or C57BL/6 mice were exposed to vehicle, TSC, or NNK and BaP (NB) twice weekly for 5 months. The serum levels of total cholesterol (TCHO), triglycerides, high-density lipoprotein (HDL), blood glucose, and metabolites, along with glucose tolerance and body weight, were measured. KEY FINDINGS Compared with those of vehicle-treated mice, mice with TSC or NB exposure displayed major phenotypes associated with MetS, including increased serum levels of TCHO, triglycerides, and fasting and basal blood glucose and decreased glucose tolerance, and serum levels of HDL. These MetS-associated changes were found in both FVB/N and C57BL/6 mice that were susceptible or resistant to carcinogen-induced tumorigenesis, respectively, indicating that tumor formation is not involved in the TSC- or NB-mediated MetS. Moreover, oleic acid and palmitoleic acid, which are known to be associated with MetS, were significantly upregulated in the serum of TSC- or NB-treated mice compared with those in vehicle-treated mice. SIGNIFICANCE Both TSC and NB caused detrimental health problems, leading to the development of MetS in experimental mice.
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Affiliation(s)
- Hyun-Ji Jang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Hye-Jin Boo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Hye-Young Min
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yun Pyo Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Won Kwon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Ho-Young Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
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Guo W, Yu JZ, Chan W. Face Mask as a Versatile Sampling Device for the Assessment of Personal Exposure to 54 Toxic Compounds in Environmental Tobacco Smoke. Chem Res Toxicol 2023. [PMID: 37406339 DOI: 10.1021/acs.chemrestox.3c00114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Exposure to environmental tobacco smoke (ETS), which contains hundreds of toxic compounds, significantly increases the risk of developing many human diseases, including lung cancer. The most common method of assessing personal exposure to ETS-borne toxicants is by sampling sidestream smoke generated by a smoking machine through a sorbent tube or filter, followed by solvent extraction and instrumental analysis. However, the ETS sampled may not truly represent the ETS in the ambient environment, due to complicating factors from the smoke released by the burning end of the cigarette and from the absorption of the chemicals in the respiratory tract of the smoker. In this study, we developed and validated an alternative air sampling method involving breathing through a face mask to simultaneously determine personal exposure to 54 ETS-borne compounds, including polycyclic aromatic hydrocarbons, aromatic amines, alkaloids, and phenolic compounds in real smoking scenarios. The newly developed method was used to evaluate the risk associated with exposure to ETS released from conventional cigarettes (CCs) and that from novel tobacco products such as e-cigarettes (ECs) and heated tobacco products (HTPs), with the observation of cancer risk associated with exposure to ETS released from CCs significantly higher than that from ECs and HTPs. It is anticipated that this method offers a convenient and sensitive way to collect samples for assessing the health impacts of ETS exposure.
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Patrad E, Khalighfard S, Amiriani T, Khori V, Alizadeh AM. Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy. Cell Oncol 2022; 45:1073-1117. [PMID: 36149600 DOI: 10.1007/s13402-022-00715-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer imposes a substantial global health burden despite its overall incidence decrease. A broad spectrum of inherited, environmental and infectious factors contributes to the development of gastric cancer. A profound understanding of the molecular underpinnings of gastric cancer has lagged compared to several other tumors with similar incidence and morbidity rates, owing to our limited knowledge of the role of carcinogens in this malignancy. The International Agency for Research on Cancer (IARC) has classified gastric carcinogenic agents into four groups based on scientific evidence from human and experimental animal studies. This review aims to explore the potential comprehensive molecular and biological impacts of carcinogens on gastric cancer development and their interactions and interferences with various cellular signaling pathways. CONCLUSIONS In this review, we highlight recent clinical trial data reported in the literature dealing with different ways to target various carcinogens in gastric cancer. Moreover, we touch upon other multidisciplinary therapeutic approaches such as surgery, adjuvant and neoadjuvant chemotherapy. Rational clinical trials focusing on identifying suitable patient populations are imperative to the success of single-agent therapeutics. Novel insights regarding signaling pathways that regulate gastric cancer can potentially improve treatment responses to targeted therapy alone or in combination with other/conventional treatments. Preventive strategies such as control of H. pylori infection through eradication or immunization as well as dietary habit and lifestyle changes may reduce the incidence of this multifactorial disease, especially in high prevalence areas. Further in-depth understanding of the molecular mechanisms involved in the role of carcinogenic agents in gastric cancer development may offer valuable information and update state-of-the-art resources for physicians and researchers to explore novel ways to combat this disease, from bench to bedside. A schematic outlining of the interaction between gastric carcinogenic agents and intracellular pathways in gastric cancer H. pylori stimulates multiple intracellular pathways, including PI3K/AKT, NF-κB, Wnt, Shh, Ras/Raf, c-MET, and JAK/STAT, leading to epithelial cell proliferation and differentiation, apoptosis, survival, motility, and inflammatory cytokine release. EBV can stimulate intracellular pathways such as the PI3K/Akt, RAS/RAF, JAK/STAT, Notch, TGF-β, and NF-κB, leading to cell survival and motility, proliferation, invasion, metastasis, and the transcription of anti-apoptotic genes and pro-inflammatory cytokines. Nicotine and alcohol can lead to angiogenesis, metastasis, survival, proliferation, pro-inflammatory, migration, and chemotactic by stimulating various intracellular signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, ROS, and JAK/STAT. Processed meat contains numerous carcinogenic compounds that affect multiple intracellular pathways such as sGC/cGMP, p38 MAPK, ERK, and PI3K/AKT, leading to anti-apoptosis, angiogenesis, metastasis, inflammatory responses, proliferation, and invasion. Lead compounds may interact with multiple signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, DNA methylation-dependent, and epigenetic-dependent, leading to tumorigenesis, carcinogenesis, malignancy, angiogenesis, DNA hypermethylation, cell survival, and cell proliferation. Stimulating signaling pathways such as PI3K/Akt, RAS/RAF, JAK/STAT, WNT, TGF-β, EGF, FGFR2, and E-cadherin through UV ionizing radiation leads to cell survival, proliferation, and immortalization in gastric cancer. The consequence of PI3K/AKT, NF-κB, Ras/Raf, ROS, JAK/STAT, and WNT signaling stimulation by the carcinogenic component of Pickled vegetables and salted fish is the Warburg effect, tumorigenesis, angiogenesis, proliferation, inflammatory response, and migration.
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Affiliation(s)
- Elham Patrad
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Khalighfard
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Taghi Amiriani
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Vahid Khori
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Breast Disease Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Daryanto B, Wibowo E, Seputra KP, Yudhanto HS. Effect of Conjugated Linoleic Acid (CLA) Supplementation on Expression of B-Cell Lymphoma-2 (Bcl-2) in the Bladder Epithelium of Wistar (Rattus norvegicus) Rats Exposed to Cigarette Smoke. Med Arch 2022; 76:343-347. [PMID: 36545457 PMCID: PMC9760239 DOI: 10.5455/medarh.2022.76.343-347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/18/2022] [Indexed: 11/07/2022] Open
Abstract
Background Bladder carcinoma is the 10th most common cancer in the world with an incidence about 3% of all cancers. The risk factor for smoking is found in 81% of all cases of bladder carcinoma. One of the protein groups associated with bladder urothelial carcinoma is B-Cell Lymphoma-2 (Bcl-2). Nicotine-derived nitrosamine ketone (NNK) contained in cigarette smoke would increase the proliferation of cancer cells through increased the expression of Bcl-2. The expression of Bcl-2 could be suppressed in the presence of Conjugated Linoleic Acid (CLA), a polyunsaturated fatty acid that has role in reducing the risk of cancer development which is reported in several studies, and then stimulate cell apoptosis. Objective To determine the effect of CLA supplementation on Bcl-2 expression in the bladder of rats which is exposed to cigarette smoke. Methods The study is an experimental study with true experimental posttest only control group design on Wistar rats. Sample was divided into 2 case groups: 0.5% of diet (125 mg) CLA supplementation in group A, 1% of diet (250 mg) CLA in group B; and 2 control groups: group without CLA supplementation (group C) as positive control and without cigarette smoke exposure (group D) as negative control. The study takes 60 days of exposure and then Bcl-2 expression on bladder epithelial was evaluated by immunohistochemistry staining. Results The results descriptively showed that rats in group C has an average Bcl-2 expression of 25.8±7.33%, while rats in group D has an average Bcl-2 expression 14.1±7.73% which means cigarette smoke exposure has been shown to increase the expression of Bcl-2 by 45.35% (p=0.019) in the bladder mucosa of experimental animals. Group B obtained an average Bcl-2 expression was 14.2±9.6% and has a significant difference when compared to group C, it shows that the addition of 1% CLA would reduce the expression of Bcl-2 by 44.96% (p=0.032). However, for group A, group with 0.5% diet of CLA supplementation did not showed decrease of Bcl-2 expression when compared to the group C (p=0.37). Conclusion Conjugated Linoleic Acid (CLA) supplementation 1% of diet can reduce Bcl-2 expression in bladder epithelium of wistar rats (Rattus norvegicus) exposed to cigarette smoke.
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Affiliation(s)
- Besut Daryanto
- Department of Urology, Faculty of Medicine Universitas Brawijaya – Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Edi Wibowo
- Department of Urology, Faculty of Medicine Universitas Brawijaya – Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Kurnia Penta Seputra
- Department of Urology, Faculty of Medicine Universitas Brawijaya – Dr. Saiful Anwar General Hospital, Malang, Indonesia
| | - Hendy Setyo Yudhanto
- Department of Pathology Anatomy, Faculty of Medicine Universitas Brawijaya – Dr. Saiful Anwar General Hospital, Malang, Indonesia
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15
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Jin Y, Lin C, Shi X, He Q, Yan J, Yu X, Chen M. Impact of clinical and molecular features on efficacy and outcome of patients with non-small cell lung cancer receiving second-line osimertinib. BMC Cancer 2022; 22:586. [PMID: 35643428 PMCID: PMC9145492 DOI: 10.1186/s12885-022-09683-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background Although with the impressive efficacy, several patients showed intrinsic resistance or an unsatisfactory response to Osimertinib. We aim to explore the impact of clinical and molecular features on efficacy and outcome of patients with EGFR T790M-mutation non-small cell lung cancer (NSCLC) receiving second-line Osimertinib. Methods Patients with EGFR T790M-mutant NSCLC who had acquired resistance to the first-generation EGFR TKI and then received Osimertinib as second-line treatment were included. Patients’ demographic and clinical information, as well as molecular data were extracted from electronic medical records. The impact of clinical and molecular features on treatment response and patients’ outcome were assessed. Results Among the 99 patients, 60 patients were tissue/pleural effusion T790M positive and 69 patients were plasma positive with a median PFS of 12.1 m and 9.9 m (P = 0.25), respectively. In addition, median PFS were similar between patients of plasma T790M + and patients of plasma T790M- (P = 0.94). The Pearson correlation test showed no significant relationship between plasma T790M abundance and PFS (r = 0.074, P = 0.546). In subgroup analyses, PFS was significantly improved in elder patients (P = 0.009) and patients with longer PFS to the first-generation EGFR TKI (P = 0.0008), while smokers tended to have worse PFS compared with non-smokers (P = 0.064). PARP1 mutant-type patients had a worse PFS compared with wild-type group (P = 0.0003). Patients with MYC amplification also had a worse PFS than MYC wild-type patients (P = 0.016). A significant PFS shrinkage was observed in TMB-High group as 6.77 m, compared with 19.10 m in TMB-Low group. The multivariate Cox analysis revealed that years ≥ 65 was an independent positive feature for PFS, while PARP1 mutation and TMB-H were negative features for PFS. Conclusion In conclusion, our findings in this study demonstrated that clinical and molecular features can be served as predictive biomarkers to stratify patients with EGFR T790M-mutant NSCLC receiving second-line Osimertinib. Supplementary information The online version contains supplementary material available at 10.1186/s12885-022-09683-1.
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Aguayo F, Boccardo E, Corvalán A, Calaf GM, Blanco R. Interplay between Epstein-Barr virus infection and environmental xenobiotic exposure in cancer. Infect Agent Cancer 2021; 16:50. [PMID: 34193233 PMCID: PMC8243497 DOI: 10.1186/s13027-021-00391-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022] Open
Abstract
Epstein-Barr virus (EBV) is a herpesvirus associated with lymphoid and epithelial malignancies. Both B cells and epithelial cells are susceptible and permissive to EBV infection. However, considering that 90% of the human population is persistently EBV-infected, with a minority of them developing cancer, additional factors are necessary for tumor development. Xenobiotics such as tobacco smoke (TS) components, pollutants, pesticides, and food chemicals have been suggested as cofactors involved in EBV-associated cancers. In this review, the suggested mechanisms by which xenobiotics cooperate with EBV for carcinogenesis are discussed. Additionally, a model is proposed in which xenobiotics, which promote oxidative stress (OS) and DNA damage, regulate EBV replication, promoting either the maintenance of viral genomes or lytic activation, ultimately leading to cancer. Interactions between EBV and xenobiotics represent an opportunity to identify mechanisms by which this virus is involved in carcinogenesis and may, in turn, suggest both prevention and control strategies for EBV-associated cancers.
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Affiliation(s)
| | - Enrique Boccardo
- Laboratory of Oncovirology, Department of Microbiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Alejandro Corvalán
- Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gloria M Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, 1000000, Arica, Chile.,Center for Radiological Research, Columbia University Medical Center, New York, NY, 10032, USA
| | - Rancés Blanco
- Laboratorio de Oncovirología, Programa de Virología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
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Caini S, Fiorito G, Palli D, Bendinelli B, Polidoro S, Silvestri V, Ottini L, Ambrogetti D, Zanna I, Saieva C, Masala G. Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort. Breast Cancer Res Treat 2021; 189:435-444. [PMID: 34101077 DOI: 10.1007/s10549-021-06273-w] [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: 02/16/2021] [Accepted: 05/25/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition. METHODS We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a "candidate pathways" approach focusing on pre-defined inflammation-related pathways. RESULTS In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The "apoptosis signalling" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women. CONCLUSION Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.
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Affiliation(s)
- Saverio Caini
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
| | - Giovanni Fiorito
- Laboratory of Biostatistics, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College, London, UK
| | - Domenico Palli
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy.
| | - Benedetta Bendinelli
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
| | - Silvia Polidoro
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College, London, UK.,Italian Institute for Genomic Medicine (IIGM), Turin, Italy
| | | | - Laura Ottini
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniela Ambrogetti
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
| | - Ines Zanna
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
| | - Calogero Saieva
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
| | - Giovanna Masala
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy
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Easwaran M, Martinez JD, Ramirez DJ, Gall PA, Erickson-DiRenzo E. Short-term whole body cigarette smoke exposure induces regional differences in cellular response in the mouse larynx. Toxicol Rep 2021; 8:920-937. [PMID: 33996505 PMCID: PMC8099918 DOI: 10.1016/j.toxrep.2021.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/11/2021] [Accepted: 04/16/2021] [Indexed: 11/29/2022] Open
Abstract
The larynx is an essential organ in the respiratory tract and necessary for airway protection, respiration, and phonation. Cigarette smoking is a significant risk factor associated with benign and malignant laryngeal diseases. Despite this association, the underlying mechanisms by which cigarette smoke (CS) drives disease development are not well elucidated. In the current study, we developed a short-term murine whole body inhalation model to evaluate the first CS-induced cellular responses in the glottic [i.e. vocal fold (VF)] and subglottic regions of the larynx. Specifically, we investigated epithelial cell proliferation, cell death, surface topography, and mucus production, at various time points (1 day, 5 days, 10 days) after ∼ 2 h exposure to 3R4F cigarettes (Delivered dose: 5.6968 mg/kg per cigarette) and following cessation for 5 days after a 5 day CS exposure (CSE). CSE elevated levels of BrdU labeled proliferative cells and p63 labeled epithelial basal cells on day 1 in the VF. CSE increased proliferative cells in the subglottis at days 5, 10 and following cessation in the subglottis. Cleaved caspase-3 apoptotic activity was absent in VF at all time points and increased at day 1 in the subglottis. Evaluation of the VF surface by scanning electron microscopy (SEM) revealed significant epithelial microprojection damage at day 10 and early signs of necrosis at days 5 and 10 post-CSE. SEM visualizations additionally indicated the presence of deformed cilia at days 5 and 10 after CSE and post-cessation in the respiratory epithelium lined subglottis. In terms of mucin content, the impact of short-term CSE was observed only at day 10, with decreasing acidic mucin levels and increasing neutral mucin levels. Overall, these findings reveal regional differences in murine laryngeal cellular responses following short-term CSE and provide insight into potential mechanisms underlying CS-induced laryngeal disease development.
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Key Words
- AB/PAS, Alcian blue/Periodic acid Schiff
- BLOQ, below limits of quantitation
- BSA, bovine serum albumin
- BrdU, 5-bromo-2′-deoxyuridine
- CBF, ciliary beat frequency
- CC3, cleaved caspase-3
- CO, Carbon monoxide
- CS, cigarette smoke
- CSE, cigarette smoke exposure
- Cell death
- Cell proliferation
- Cigarette smoke
- DAB, 3,3′-diaminobenzidine
- FTC/ISO, Federal Trade Commission/International Standard Organization
- GSD, geometric standard deviation
- H&E, Hematoxylin and Eosin
- HIER, heat-induced antigen retrieval
- HPF, high power field
- MCC, mucociliary clearance
- MMAD, Mass median aerodynamic diameter
- Mucus production
- Murine larynx
- NMR, nicotine metabolite ratio
- OECD, organization for economic co-operation and development
- PAHs, polycyclic aromatic hydrocarbons
- RE, respiratory epithelium
- REV, reversibility
- ROS, reactive oxygen species
- SCIREQ, Scientific Respiratory Equipment Inc
- SEM, scanning electron microscopy
- SSE, stratified squamous epithelium
- SWGTOX, Scientific Working Group for Forensic Toxicology
- Surface topography
- TBST, tris-buffered saline-tween 20
- TPM, total particulate matter
- TSNA, tobacco-specific nitrosamines
- UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometer
- VF, vocal fold
- VSC, veterinary service center
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Affiliation(s)
- Meena Easwaran
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua D. Martinez
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Daniel J. Ramirez
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Phillip A. Gall
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Elizabeth Erickson-DiRenzo
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
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19
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Was H, Borkowska A, Olszewska A, Klemba A, Marciniak M, Synowiec A, Kieda C. Polyploidy formation in cancer cells: How a Trojan horse is born. Semin Cancer Biol 2021; 81:24-36. [PMID: 33727077 DOI: 10.1016/j.semcancer.2021.03.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/29/2021] [Accepted: 03/03/2021] [Indexed: 01/04/2023]
Abstract
Ploidy increase has been shown to occur in different type of tumors and participate in tumor initiation and resistance to the treatment. Polyploid giant cancer cells (PGCCs) are cells with multiple nuclei or a single giant nucleus containing multiple complete sets of chromosomes. The mechanism leading to formation of PGCCs may depend on: endoreplication, mitotic slippage, cytokinesis failure, cell fusion or cell cannibalism. Polyploidy formation might be triggered in response to various genotoxic stresses including: chemotherapeutics, radiation, hypoxia, oxidative stress or environmental factors like: air pollution, UV light or hyperthermia. A fundamental feature of polyploid cancer cells is the generation of progeny during the reversal of the polyploid state (depolyploidization) that may show high aggressiveness resulting in the formation of resistant disease and tumor recurrence. Therefore, we propose that modern anti-cancer therapies should be designed taking under consideration polyploidization/ depolyploidization processes, which confer the polyploidization a hidden potential similar to a Trojan horse delayed aggressiveness. Various mechanisms and stress factors leading to polyploidy formation in cancer cells are discussed in this review.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland.
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Olszewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; Postgraduate School of Molecular Medicine, Zwirki i Wigury 61 Street, Warsaw, Poland
| | - Aleksandra Klemba
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland; College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Banacha 2c Street, Warsaw, Poland
| | - Marta Marciniak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Agnieszka Synowiec
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Szaserow 128 Street, Warsaw, Poland
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20
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Chakraborty B, Mukhopadhyay D, Roychowdhury A, Basu M, Alam N, Chatterjee K, Chakrabarti J, Panda CK. Differential Wnt-β- catenin pathway activation in HPV positive and negative oral epithelium is transmitted during head and neck tumorigenesis: clinical implications. Med Microbiol Immunol 2020; 210:49-63. [PMID: 33226516 DOI: 10.1007/s00430-020-00697-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022]
Abstract
The aim of this study is to understand the association of HPV infection and wnt-β-catenin self-renewal pathway in development of head and neck squamous cell carcinoma (HNSCC). For this reason, the molecular profiles (methylation/deletion/expression) of antagonists (SFRP1/2 and DKK1), agonists (FZD7 and LRP6) and effector protein β-catenin of the pathway were analyzed in HPV positive/negative oral epithelium at first, followed by its changes during development of the tumor along with correlations with different clinico-pathological parameters. HPV infection alone or in combination with tobacco habit could activate p- β-catenin expression in basal/parabasal layers of oral epithelium through high expression of FZD7 and significant down regulation of SFRP1/2 through promoter hypermethylation due to over expression of DNMT1 with ubiquitous down regulation of DKK1 and up-regulation of LRP6. This phenomenon has been seen in respective HPV positive and negative HNSCC tumors with additional deletion/microsatellite size alterations in the antagonists. Overall alterations (methylation/deletion) of SFRP1/2, DKK1 gradually increased from Group I (HPV-/Tobacco-) to Group IV(HPV+/Tobacco+) tumors, leading to the worst prognosis of the patients. Thus, the transmission of differentially activated wnt-β-catenin pathway from HPV positive/negative basal/parabasal layers of oral epithelium to HNSCC tumors determines differences in molecular pathogenesis of the disease.
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Affiliation(s)
- Balarko Chakraborty
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Debalina Mukhopadhyay
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Anirban Roychowdhury
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Mukta Basu
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Neyaz Alam
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Kabita Chatterjee
- Consultant Oral and Maxillofacial Pathologist. 3, Raja Manindra Road, Kolkata, West Bengal, 700037, India
| | - Jayanta Chakrabarti
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India.
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21
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Rothenberger NJ, Stabile LP. Induction of Lung Tumors and Mutational Analysis in FVB/N Mice Treated with the Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone. Methods Mol Biol 2020; 2102:149-160. [PMID: 31989553 DOI: 10.1007/978-1-0716-0223-2_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lung cancer remains the leading cause of cancer-related deaths worldwide. In order to understand lung cancer biology and evaluate novel therapeutic strategies, preclinical mouse models have been developed that mimic early and advanced-stage lung cancer. Among autochthonous models, carcinogen-induced systems are valuable preclinical tools since tobacco smoking remains the number one risk factor for lung tumor development. Among the several thousand chemicals within cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen with tumorigenic effects described in both mice and humans. Herein, we describe the methodology for inducing lung tumors in mice using the tobacco carcinogen NNK and subsequent lung fixation for quantitative assessment of tumor development and analysis of oncogenic mutations in tumors.
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Affiliation(s)
| | - Laura P Stabile
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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22
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Hasan F, Katiyar T, Maurya SS, Yadav V, Yadav S, Pandey R, Mehrotra D, Hadi R, Singh S, Bhatt ML, Parmar D. Similarities in mRNA expression of peripheral blood drug metabolizing enzymes and cancer marker genes with biopsy samples of head and neck cancer patients. Biomarkers 2019; 24:574-583. [PMID: 31002268 DOI: 10.1080/1354750x.2019.1609090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Purpose: To develop peripheral blood mRNA expression profiles of drug metabolizing enzymes (DMEs) as a surrogate to monitor tobacco induced head and neck squamous cell carcinoma (HNSCC), attempts were made to investigate (i) similarities in alterations with the cancer marker genes in biopsy samples and (ii) if alterations similar to that seen in biopsy samples are reflected in peripheral blood. Methods: Total RNA from eight soft gingival tissues and eight biopsy samples of HNSCC patients and total DNA and RNA from blood of healthy controls (n = 150) and HNSCC patients (n = 150) was processed for expression and genotyping studies. Blood from patients receiving chemo-radiotherapy was processed for follow-up study. Results: qRT-PCR revealed significant increase in mRNA expression of DMEs in biopsy and blood samples of HNSCC patients when compared to controls. Similar alterations were observed in cancer marker genes in these samples. Patients with variant genotypes of DMEs showed greater magnitude of alterations in mRNA expression when compared to wild type controls. Responders of chemo-radiotherapy showed significant decline in induction of mRNA expression of DMEs and cancer marker genes Conclusions: The data suggest that peripheral blood expression profiles could be used to monitor tobacco-induced HNSCC as well as the treatment response.
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Affiliation(s)
- Feza Hasan
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India.,b School of Dental Sciences, Department of Biochemistry, Babu Banarsi Das University , Lucknow , India
| | - Tridiv Katiyar
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India.,b School of Dental Sciences, Department of Biochemistry, Babu Banarsi Das University , Lucknow , India
| | - Shailendra S Maurya
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India
| | - Vinay Yadav
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India
| | - Sanjay Yadav
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India
| | - Rahul Pandey
- c Department of Radiotherapy & Department of Oral and Maxillofacial Surgery, King George's Medical University , Lucknow , India
| | - Divya Mehrotra
- c Department of Radiotherapy & Department of Oral and Maxillofacial Surgery, King George's Medical University , Lucknow , India
| | - Rahat Hadi
- d Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences , Lucknow , India
| | - Sudhir Singh
- c Department of Radiotherapy & Department of Oral and Maxillofacial Surgery, King George's Medical University , Lucknow , India
| | - Madan L Bhatt
- c Department of Radiotherapy & Department of Oral and Maxillofacial Surgery, King George's Medical University , Lucknow , India
| | - Devendra Parmar
- a Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR) , Lucknow , India
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23
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Hasan F, Yadav V, Katiyar T, Yadav S, Pandey R, Mehrotra D, Hadi R, Singh S, Bhatt MLB, Parmar D. Validation of gene expression profiles of candidate genes using low density array in peripheral blood of tobacco consuming head and neck cancer patients and auto/taxi drivers with preneoplastic lesions. Genomics 2019; 112:513-519. [PMID: 30951801 DOI: 10.1016/j.ygeno.2019.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/11/2019] [Accepted: 04/01/2019] [Indexed: 12/17/2022]
Abstract
TaqMan Low-Density Array (TLDA) based Real-Time PCR (RT-PCR) of selected genes showed increased expression of polycyclic aromatic hydrocarbons (PAHs) metabolizing cytochrome P450s (CYPs), glutathione S-transferases (GSTs) and associated transcription factors in biopsy and peripheral blood samples isolated from head and neck squamous cell carcinoma (HNSCC) patients when compared to the controls. The genes involved in DNA repair, signal transduction pathway, EMT pathway, apoptosis, and cell adhesion/motility were found to be altered in both peripheral blood and biopsy samples of HNSCC patients. Transcription profiles in blood isolated from auto/taxi drivers, with pre-neoplastic lesions and history of tobacco use, also showed similar alterations. The present TLDA data thus demonstrates that low-density array of selected genes in peripheral blood has the potential to be used as a surrogate for providing insight into cancer progression pathways and possibly as an early biomarker for monitoring tobacco induced HNSCC.
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Affiliation(s)
- Feza Hasan
- Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, U.P., India; Babu Banarsi Das University, Faizabad Road, Lucknow 226028, U.P., India
| | - Vinay Yadav
- Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, U.P., India
| | - Tridiv Katiyar
- Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, U.P., India; Babu Banarsi Das University, Faizabad Road, Lucknow 226028, U.P., India
| | - Sanjay Yadav
- Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, U.P., India
| | - Rahul Pandey
- Department of Radiotherapy, Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow 226003, U.P., India
| | - Divya Mehrotra
- Department of Radiotherapy, Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow 226003, U.P., India
| | - Rahat Hadi
- Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow 226010, U.P., India
| | - Sudhir Singh
- Department of Radiotherapy, Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow 226003, U.P., India
| | - Madan L B Bhatt
- Department of Radiotherapy, Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow 226003, U.P., India
| | - Devendra Parmar
- Developmental Toxicology Laboratory, System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, U.P., India.
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24
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Kim IA, Lee JS, Kim HJ, Kim WS, Lee KY. Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs: a retrospective study. BMC Cancer 2018; 18:768. [PMID: 30055587 PMCID: PMC6064083 DOI: 10.1186/s12885-018-4691-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/24/2018] [Indexed: 02/04/2023] Open
Abstract
Background Although lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations is common in never smokers, one-third of the patients are ever-smokers. We aimed to investigate the effect of cumulative smoking dose(CSD) on clinical outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-tyrosine kinase inhibitors (TKIs). Methods We retrospectively analyzed 142 patients with EGFR-mutation positive advanced or recurrent lung adenocarcinoma who were administered gefitinib, erlotinib, afatinib, and osimertinib. These patients were classified based on their CSD as never smokers, light smokers (≤10 pack-years [PYs]), moderate smokers (11–30 PYs), and heavy smokers (> 30 PYs). PFS and OS were analyzed according to smoking subgroups via Kaplan-Meier curves. Results Among the 142 patients, 91 (64.1%), 12 (8.5%), 22 (15.5%), and 17 (12%) were never, light, moderate, and heavy smokers, respectively. CSD was inversely associated with median PFS in a statistically significant dose-dependent manner (11.8 months (mo), 11.0 mo, 7.4 mo, and 3.9 mo; p < 0.001). Statistically significant negative association was observed between CSD and median OS (33.6 mo, 26.3 mo, 20 mo, and 8.9 mo; p < 0.001). In the multivariate analysis adjusted for age, sex, performance status, stage, and timing of EGFR-TKIs, CSD was an independent predictive factor for disease progression (hazard ratio [HR], 4.00; 95% confidence interval [CI], 1.95–8.23; p = 0.012) and OS (HR, 3.9; 95% CI, 1.84–8.28; p < 0.001). Conclusion CSD is an important predictive and prognostic factor in patients with EGFR-mutated lung adenocarcinoma, and associated smoking-related gene signatures might affect the outcomes. Electronic supplementary material The online version of this article (10.1186/s12885-018-4691-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- In Ae Kim
- Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.,Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea
| | - Jong Sik Lee
- Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea
| | - Hee Joung Kim
- Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.,Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea
| | - Wan Seop Kim
- Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.,Department of Pathology, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Kye Young Lee
- Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea. .,Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.
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25
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Yoshida S, Yokohira M, Yamakawa K, Nakano-Narusawa Y, Kanie S, Hashimoto N, Imaida K. Effects of the expectorant drug ambroxol hydrochloride on chemically induced lung inflammatory and neoplastic lesions in rodents. J Toxicol Pathol 2018; 31:255-265. [PMID: 30393429 PMCID: PMC6206285 DOI: 10.1293/tox.2018-0012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/14/2018] [Indexed: 11/21/2022] Open
Abstract
Ambroxol hydrochloride (AH) is an expectorant drug used to stimulate pulmonary
surfactant and serous airway secretion. Surfactant proteins (SPs) are essential for
maintaining respiratory structure and function, although SP expression has also been
reported in lung inflammatory and proliferative lesions. To determine whether AH exerts
modulatory effects on these lung lesions, we examined its effects on pleural thickening
induced by intrathoracic administration of dipotassium titanate (TISMO) in A/JJmsSlc (A/J)
mice. We also analyzed the modulatory effects of AH on neoplastic lung lesions induced by
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice and by N-nitrosobis
(2-hydroxypropyl) amine (DHPN) in F344/DuCrlCrj (F344) rats. A/J mice treated with TISMO
showed decreased body weight, increased white blood cell (WBC) counts, and pleural
thickening caused by pleuritis and poor general condition. However, A/J mice treated with
TISMO + 120 ppm showed significant recovery of body weight and WBC counts to the same
levels as those of A/J mice not treated with TISMO, although no significant differences
were observed in histopathological changes including the immunohistopathological
expression of IL-1β in the lung and maximum pleural thickness regardless of AH treatment.
In the NNK and DHPN experiments, no significant differences in body weight, hematology,
plasma biochemistry, and histopathological changes were associated with AH concentration.
These results suggest that AH potentially exerts anti-inflammatory effects but does not
have a direct suppressive effect on lung tumorigenesis in rodents.
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Affiliation(s)
- Shota Yoshida
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.,Toxicology Laboratory, Discovery and Preclinical Research Division, TAIHO Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
| | - Masanao Yokohira
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Keiko Yamakawa
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Yuko Nakano-Narusawa
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Shohei Kanie
- Toxicology Laboratory, Discovery and Preclinical Research Division, TAIHO Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
| | - Nozomi Hashimoto
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Katsumi Imaida
- Onco-Pathology, Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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26
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Role of protein kinase N2 (PKN2) in cigarette smoke-mediated oncogenic transformation of oral cells. J Cell Commun Signal 2018; 12:709-721. [PMID: 29480433 DOI: 10.1007/s12079-017-0442-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/10/2017] [Indexed: 02/06/2023] Open
Abstract
Smoking is the leading cause of preventable death worldwide. Though cigarette smoke is an established cause of head and neck cancer (including oral cancer), molecular alterations associated with chronic cigarette smoke exposure are poorly studied. To understand the signaling alterations induced by chronic exposure to cigarette smoke, we developed a cell line model by exposing normal oral keratinocytes to cigarette smoke for a period of 12 months. Chronic exposure to cigarette smoke resulted in increased cellular proliferation and invasive ability of oral keratinocytes. Proteomic and phosphoproteomic analyses showed dysregulation of several proteins involved in cellular movement and cytoskeletal reorganization in smoke exposed cells. We observed overexpression and hyperphosphorylation of protein kinase N2 (PKN2) in smoke exposed cells as well as in a panel of head and neck cancer cell lines established from smokers. Silencing of PKN2 resulted in decreased colony formation, invasion and migration in both smoke exposed cells and head and neck cancer cell lines. Our results indicate that PKN2 plays an important role in oncogenic transformation of oral keratinocytes in response to cigarette smoke. The current study provides evidence that PKN2 can act as a potential therapeutic target in head and neck squamous cell carcinoma, especially in patients with a history of smoking.
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27
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Di Giacomo S, Abete L, Cocchiola R, Mazzanti G, Eufemi M, Di Sotto A. Caryophyllane sesquiterpenes inhibit DNA-damage by tobacco smoke in bacterial and mammalian cells. Food Chem Toxicol 2018; 111:393-404. [PMID: 29154797 DOI: 10.1016/j.fct.2017.11.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/11/2017] [Accepted: 11/13/2017] [Indexed: 01/23/2023]
Abstract
In the present study, the ability of the natural sesquiterpene β-caryophyllene (CRY) and its metabolite β-caryophyllene oxide (CRYO) to inhibit the genotoxicity of a condensate of cigarette smoke (CSC) was evaluated both in bacterial and mammalian cells. Also, the inhibition of the CSC-mediated STAT3 phosphorylation and intracellular oxidative stress was evaluated as potential chemopreventive mechanism. Under our experimental conditions, both the sesquiterpenes exhibited antimutagenic properties, being CRY the most potent compound. The antimutagenicity was highlighted in all experimental protocols, being particularly strong in the co- and post-treatments. The test substances also reduced the micronuclei frequency induced by CSC, with a major effectiveness of CRY. CRY was also able to reduce the CSC-mediated increase of the Y705- pSTAT3 levels, in spite of a lacking effect of CRYO. Furthermore, the sesquiterpenes CRY and CRYO displayed a moderate antioxidant activity, with a 25 % and 40 % inhibition of the ROS-levels increased by CSC, respectively. On the basis of these results, CRY seems to be a multi-target chemopreventive agent, although the genoprotective and antioxidant effects of CRYO suggest that both compounds deserve to be deeply investigated for a possible application in the prevention and treatment of different smoke-related ailments.
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Affiliation(s)
- Silvia Di Giacomo
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Lorena Abete
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Rossana Cocchiola
- Department of Biochemical Science "A. Rossi Fanelli", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Gabriela Mazzanti
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Margherita Eufemi
- Department of Biochemical Science "A. Rossi Fanelli", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Antonella Di Sotto
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
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Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers. Int J Mol Sci 2017; 18:ijms18061210. [PMID: 28587272 PMCID: PMC5486033 DOI: 10.3390/ijms18061210] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/26/2017] [Accepted: 06/02/2017] [Indexed: 12/16/2022] Open
Abstract
Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.
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Kadimisetty K, Malla S, Rusling JF. Automated 3-D Printed Arrays to Evaluate Genotoxic Chemistry: E-Cigarettes and Water Samples. ACS Sens 2017; 2:670-678. [PMID: 28723166 DOI: 10.1021/acssensors.7b00118] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A novel, automated, low cost, three-dimensional (3-D) printed microfluidic array was developed to detect DNA damage from metabolites of chemicals in environmental samples. The electrochemiluminescent (ECL) detection platform incorporates layer-by-layer (LbL) assembled films of microsomal enzymes, DNA and an ECL-emitting ruthenium metallopolymer in ∼10 nm deep microwells. Liquid samples are introduced into the array, metabolized by the human enzymes, products react with DNA if possible, and DNA damage is detected by ECL with a camera. Measurements of relative DNA damage by the array assess the genotoxic potential of the samples. The array analyzes three samples simultaneously in 5 min. Measurement of cigarette and e-cigarette smoke extracts and polluted water samples was used to establish proof of concept. Potentially genotoxic reactions from e-cigarette vapor similar to smoke from conventional cigarettes were demonstrated. Untreated wastewater showed a high genotoxic potential compared to negligible values for treated wastewater from a pollution control treatment plant. Reactivity of chemicals known to produce high rates of metabolite-related DNA damage were measured, and array results for environmental samples were expressed in terms of equivalent responses from these standards to assess severity of possible DNA damage. Genotoxic assessment of wastewater samples during processing also highlighted future on-site monitoring applications.
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Affiliation(s)
- Karteek Kadimisetty
- Department
of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Spundana Malla
- Department
of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
| | - James F. Rusling
- Department
of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
- Institute of Material Science, Storrs, Connecticut 06269, United States
- Department
of Surgery and Neag Cancer Center, UConn Health, Farmington, Connecticut 06032, United States
- School
of Chemistry, National University of Ireland at Galway, Galaway, Ireland
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30
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Ren N, Atyah M, Chen WY, Zhou CH. The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications. J Transl Med 2017; 15:110. [PMID: 28532423 PMCID: PMC5440915 DOI: 10.1186/s12967-017-1218-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 05/18/2017] [Indexed: 12/15/2022] Open
Abstract
Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alterations, which translate into a variety of diseases, cancer included. This concise review discusses, from both a genetic and epigenetic point of view, the current detection methods of different agents’ genotoxicity, along with their basic and clinical relation to human cancer, chemotherapy, germ cells and stem cells.
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Affiliation(s)
- Ning Ren
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China. .,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People's Republic of China.
| | - Manar Atyah
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People's Republic of China
| | - Wan-Yong Chen
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People's Republic of China
| | - Chen-Hao Zhou
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People's Republic of China
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Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study. Breast Cancer Res Treat 2017; 163:349-361. [PMID: 28275920 DOI: 10.1007/s10549-017-4178-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/26/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression. METHODS Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status. RESULTS Modest differences in CpG methylation were detected at p < 0.05 in breast tumors from current or ever smokers compared with never smokers. In stratified analyses, HR- tumors from smokers exhibited primarily hypomethylation compared with tumors from never smokers; hypomethylation was similarly detected within the more homogeneous basal-like subtype. Most current smoking-associated CpG loci exhibited methylation levels in former smokers that were intermediate between those in current and never smokers and exhibited progressive changes in methylation with increasing duration of smoking. Among former smokers, restoration of methylation toward baseline (never smoking) levels was observed with increasing time since quitting. Moreover, smoking-related hypermethylation was stronger in HR+ breast tumors from blacks than in whites. CONCLUSIONS Our results suggest that breast tumor methylation patterns differ with tobacco smoke exposure; however, additional studies are needed to confirm these findings.
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Chen X, Wang L, Liu J, Huang L, Yang L, Gao Q, Shi X, Li J, Li F, Zhang Z, Zhao S, Zhang B, Van der Bruggen P, Zhang Y. Expression and prognostic relevance of MAGE-A3 and MAGE-C2 in non-small cell lung cancer. Oncol Lett 2017; 13:1609-1618. [PMID: 28454298 PMCID: PMC5403542 DOI: 10.3892/ol.2017.5665] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 11/21/2016] [Indexed: 01/06/2023] Open
Abstract
Melanoma-associated antigen (MAGE)-A3 and MAGE-C2 are antigens encoded by cancer-germline genes, and have been recognized as potential prognostic biomarkers and attractive targets for immunotherapy in multiple types of cancer. The present study aimed to analyze the clinicopathological significance of MAGE-A3/C2 expression in non-small cell lung cancer (NSCLC). The association between MAGE-A3/C2 mRNA and protein expression, and the pathological characteristics and overall survival of patients with NSCLC was analyzed. In addition, the functional role of MAGE-A3 in human NSCLC cell line A549 was examined in vitro. MAGE-A3/C2 mRNA expression was identified in 73% (151/206) and 53% (109/206) of patients with NSCLC, respectively. MAGE-A3/C2 protein expression was identified in 58% (44/76) and 53% (40/76) of NSCLC cases, respectively. MAGE-A3 mRNA expression was observed to be associated with smoking history, disease stage and lymph node metastasis. However, no association was identified between MAGE-C2 mRNA expression and the clinicopathological characteristics of patients with NSCLC. MAGE-A3/C2-positive patients had a poorer survival rate compared with MAGE-A3/C2-negative patients. Multivariate analysis identified that MAGE-A3 expression may serve as an independent marker of poor prognosis in patients with NSCLC. Downregulation of MAGE-A3 mRNA expression in A549 cells resulted in lower migration and colony formation rates, and a higher amount of epithelial marker and lower amount of mesenchymal marker expression compared with the control group. These results indicate that MAGE-A3 serves a role in NSCLC cell metastasis through the induction of epithelial-mesenchymal transition. In conclusion, MAGE-A3 may serve as a diagnostic and prognostic biomarker for patients with NSCLC, due to its association with tumor progression and poor clinical outcome.
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Affiliation(s)
- Xinfeng Chen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Liping Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jinyan Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lan Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Qun Gao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaojuan Shi
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jieyao Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feng Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Song Zhao
- Department of Cerebral Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Bin Zhang
- Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Pierre Van der Bruggen
- Ludwig Institute for Cancer Research Brussels Branch, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Engineering Key Laboratory for Cell Therapy of Henan, Zhengzhou, Henan 450052, P.R. China
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SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer. Oncogene 2016; 35:5826-5838. [PMID: 27181202 PMCID: PMC5116054 DOI: 10.1038/onc.2016.124] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 03/01/2016] [Accepted: 03/11/2016] [Indexed: 12/19/2022]
Abstract
Hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) has been found in various types of human cancers, including head and neck cancer (HNC). Although smoking is critical in the development and progression of HNC, how tobacco components activate STAT3 is unclear. We demonstrated that exposure of HNC cell lines to a tobacco extract induced a rapid Y705 phosphorylation of STAT3 and a rapid increase in the SUMO protease SENP3 that depended on a simultaneous increase in reactive oxygen species. We identified that SUMOylation at the lysine 451 site facilitated STAT3 binding to the phosphatase TC45 through an SUMO-interacting motif of TC45. SENP3 could thus enhance STAT3 phosphorylation by de-conjugating the SUMO2/3 modification of STAT3. Knocking-down of SENP3 greatly impaired basal and induced STAT3 phosphorylation by tobacco extract or interleukin 6. A correlation between SENP3 protein levels and STAT3 Y705 phosphorylation levels in human laryngeal carcinoma specimens was found, which was more significant in the specimens derived from the smoker patients and with poor clinicopathological parameters. Our data identified SUMOylation as a previously undescribed post-translational modification of STAT3 and SENP3 as a critical positive modulator of tobacco- or cytokine-induced STAT3 activation. These findings provide novel insights into the hyperphosphorylation of STAT3 in development of HNC.
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Urvalek AM, Osei-Sarfo K, Tang XH, Zhang T, Scognamiglio T, Gudas LJ. Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis. Alcohol Clin Exp Res 2016. [PMID: 26207766 DOI: 10.1111/acer.12772] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a cancer that is characterized by its high morbidity and mortality rates. While tobacco use and alcohol consumption are 2 major contributing factors for HNSCC carcinogenesis, how the combination of tobacco and alcohol increases HNSCC risk is not understood. METHODS We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis and Meadows-Cook alcohol mouse models to elucidate the molecular events and to identify the novel biomarkers associated with oral cancer development. RESULTS By genome-wide RNA-seq of tongue samples (3 mice per group), we identified changes in transcripts that mediate alcohol metabolism and oxidative stress (Aldh2, Aldh1a3, Adh1, Adh7, and Cyp2a5) in mice treated with 4-NQO followed by ethanol (4-NQO/EtOH) as compared to the vehicle control/untreated (V.C./Untr.) samples. We measured major, global increases in specific histone acetylation and methylation epigenetic marks (H3K27ac, H3K9/14ac, H3K27me3, and H3K9me3) in the oral cavities of V.C./EtOH, 4-NQO/Untr., and 4-NQO/EtOH treatment groups compared to the V.C./Untr. group. We detected changes in histone epigenetic marks near regulatory regions of genes involved in ethanol metabolism by chromatin immunoprecipitation. For instance, the Aldh2 promoter showed increased H3K27me3 marks, and Aldh2 mRNA levels were reduced by 10-fold in 4NQO/EtOH versus V.C./Untr. tongue samples. 4-NQO/EtOH treatment also caused increases in markers of oxidative stress, including 4-HNE, MCT4/SLC16a3, and TOM20, as measured by immunohistochemistry. CONCLUSIONS We delineate a mechanism by which 4-NQO and ethanol can regulate gene expression during the development of HNSCC and suggest that histone epigenetic marks and oxidative stress markers could be the novel biomarkers and targets for the prevention of HNSCC.
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Affiliation(s)
- Alison M Urvalek
- Department of Pharmacology, Weill Cornell Medical College, New York, New York
| | - Kwame Osei-Sarfo
- Department of Pharmacology, Weill Cornell Medical College, New York, New York
| | - Xiao-Han Tang
- Department of Pharmacology, Weill Cornell Medical College, New York, New York
| | - Tuo Zhang
- Genomics Resources Core Facility, Weill Cornell Medical College, New York, New York
| | | | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College, New York, New York
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35
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Koo JB, Han JS. Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells. J Toxicol Sci 2016; 41:77-89. [DOI: 10.2131/jts.41.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Jun Bon Koo
- Biomedical Research Institute and Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Korea
| | - Joong-Soo Han
- Biomedical Research Institute and Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Korea
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36
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Yokohira M, Hashimoto N, Nakagawa T, Nakano Y, Yamakawa K, Kishi S, Kanie S, Ninomiya F, Saoo K, Imaida K. Long-Term Chronic Toxicity and Mesothelial Cell Reactions Induced by Potassium Octatitanate Fibers (TISMO) in the Left Thoracic Cavity in A/J Female Mice. Int J Toxicol 2015; 34:325-35. [PMID: 26023052 DOI: 10.1177/1091581815587744] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The present study was conducted to examine the chronic effects of potassium octatitanate fibers (trade name TISMO; chemical formula K2O·6TiO2) on the mouse lung and thoracic cavity. This method of infusion was employed to examine the direct effects of the fibers to the pleura. In the present study, 52- and 65-week experiments were employed to examine the long-term chronic effects after infusion of fiber-shaped TISMO into the thoracic cavities of A/J mice. Following this infusion, TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura. The additional histopathological detection of TISMO fibers in the liver, spleen, kidneys, ovary, heart, bone marrow, and brain of TISMO-infused mice indicated migration of the fibers out from the thoracic cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. This study demonstrated that intrathoracic infusion of TISMO fiber did not cause malignant mesothelioma but did cause severe chronic inflammation and proliferation of pleural mesothelial cells.
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Affiliation(s)
- Masanao Yokohira
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Nozomi Hashimoto
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Toshitaka Nakagawa
- Faculty of Medicine, Life Science Research Center, Kagawa University, Kagawa, Japan
| | - Yuko Nakano
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Keiko Yamakawa
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Sosuke Kishi
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Shohei Kanie
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Fumiko Ninomiya
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Kousuke Saoo
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
| | - Katsumi Imaida
- Onco-Pathology, Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
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Peña N, Carrillo D, Muñoz JP, Chnaiderman J, Urzúa U, León O, Tornesello ML, Corvalán AH, Soto-Rifo R, Aguayo F. Tobacco smoke activates human papillomavirus 16 p97 promoter and cooperates with high-risk E6/E7 for oxidative DNA damage in lung cells. PLoS One 2015; 10:e0123029. [PMID: 25830243 PMCID: PMC4382149 DOI: 10.1371/journal.pone.0123029] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 02/16/2015] [Indexed: 12/29/2022] Open
Abstract
We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage.
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Affiliation(s)
- Nelson Peña
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Diego Carrillo
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Juan P. Muñoz
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Jonás Chnaiderman
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Ulises Urzúa
- Cellular and Molecular Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Oscar León
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Maria L. Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"—IRCCS, Naples, Italy
| | - Alejandro H. Corvalán
- Advanced Center for Chronic Diseases (ACCDiS) and UC—Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ricardo Soto-Rifo
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Francisco Aguayo
- Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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Miyata Y, Mitsunari K, Akihiro A, Watanabe SI, Mochizuki Y, Sakai H. Smoking-induced changes in cancer-related factors in patients with upper tract urothelial cancer. Mol Clin Oncol 2014; 3:287-294. [PMID: 25798255 DOI: 10.3892/mco.2014.471] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 11/14/2014] [Indexed: 11/06/2022] Open
Abstract
Cigarette smoking is a major risk factor for urothelial cancer (UC) development. However, the associations between smoking and changes in the pathological characteristics and molecular expression of cancer-related molecules in upper tract (UT) UC have not been fully elucidated. We investigated the associations between smoking status and cancer-related factors, including cancer cell proliferation, apoptosis, angiogenesis, lymphangiogenesis and expression of vascular endothelial growth factor-A and -C, matrix metalloproteinase (MMP)-2 and -9, cyclooxygenase (COX)-2 and urokinase-type plasminogen activator, in patients with UTUC. A total of 134 patients who underwent nephroureterectomy were retrospectively investigated. Proliferation index (PI), microvessel density and lymphatic vessel density (LVD) were measured using anti-Ki-67, anti-CD105 and anti-D2-40 antibodies in formalin-fixed specimens. The apoptotic index was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. Other cancer-related molecules were investigated by immunohistochemistry in similar specimens. The patients were divided into three groups; non-smoker (n=54, 40.3%), former smoker (n=46, 34.3%) and current smoker (n=34, 25.4%). The PI and the apoptotic index were not found to be correlated with smoking status; however, the mean/standard deviation level of LVD in current smokers (40.9/12.9) was significantly higher (P=0.034) compared to that in patients who had never smoked (34.4/10.6). In addition, smoking status was positively correlated with the presence of intratumoral lymphatic vessels (iLV) (P=0.010) and the expression of COX-2 and MMP-9 (P=0.032). The multivariate analysis demonstrated that current smoking was independently associated with all the abovementioned smoking-related factors. However, former smoking was correlated with LVD and the presence of iLV. In the survival analysis, LVD, the presence of iLV and the expression of COX-2 and MMP-9 were identified as predictive factors for metastasis following surgery. In conclusion, lymphangiogenesis and the expression levels of COX-2 and MMP-9 were found to be associated with the smoking status of UTUC patients. Our results may provide important insights into the pathological changes precipitated by smoking in these patients.
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Affiliation(s)
- Yasuyoshi Miyata
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kensuke Mitsunari
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Asai Akihiro
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Shin-Ichi Watanabe
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yasushi Mochizuki
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hideki Sakai
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Chen RJ, Siao SH, Hsu CH, Chang CY, Chang LW, Wu CH, Lin P, Wang YJ. TCDD promotes lung tumors via attenuation of apoptosis through activation of the Akt and ERK1/2 signaling pathways. PLoS One 2014; 9:e99586. [PMID: 24927102 PMCID: PMC4057150 DOI: 10.1371/journal.pone.0099586] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 05/16/2014] [Indexed: 12/14/2022] Open
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.
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Affiliation(s)
- Rong-Jane Chen
- Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shih-He Siao
- Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
| | - Chung-Huei Hsu
- Department of Nuclear Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chu-Yung Chang
- Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
| | - Louis W. Chang
- National Environmental Health Research Center, National Health Research Institutes, Zhunan Town, Taiwan
| | - Chih-Hsiung Wu
- Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
- Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan
| | - Pinpin Lin
- National Environmental Health Research Center, National Health Research Institutes, Zhunan Town, Taiwan
- Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan Town, Taiwan
- * E-mail: (Y-JW); (PL)
| | - Ying-Jan Wang
- Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
- Department of Biomedical Informatics, Asia University, Taichung, Taiwan
- * E-mail: (Y-JW); (PL)
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The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice. PLoS One 2014; 9:e93152. [PMID: 24682076 PMCID: PMC3969372 DOI: 10.1371/journal.pone.0093152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 03/02/2014] [Indexed: 11/25/2022] Open
Abstract
Epidemiological studies indicate that women are at a higher risk developing lung cancer than men are. It is suggested that estrogen is one of the most important factors in lung cancer development in females. Additionally, cigarette smoke, and environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play salient roles in female lung carcinogenesis. However, the mechanisms responsible for the interaction of these factors in the promotion of lung cancer are still poorly understood. The present study was designed to explore two ideas: first, the synergistic lung tumorigenic effects of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNK) combined with TCDD, 17β-estradiol (E2) or both through a long-term treatment experiment, and second, to identify early changes in the inflammatory and signaling pathways through short-term treatment experiments. The results indicate that A/J mice given E2 had strong effects in potentiating NNK-induced activation of MAPK signaling, NFκB, and COX-2 expression. In the long-term exposure model, E2 had a strong tumor promoting effect, whereas TCDD antagonized this effect in A/J mice. We conclude that treatment with NNK combined with either E2 or TCDD induces lung carcinogenesis and the promotion effects could be correlated with lung inflammation. E2 was shown to potentiate NNK-induced inflammation, cell proliferation, thereby leading to lung tumorigenesis.
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Wang YJ, Chen RJ. Pterostilbene Protection and Bladder Cancer Cells. Cancer 2014. [DOI: 10.1016/b978-0-12-405205-5.00027-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Ninomiya F, Yokohira M, Kishi S, Nakano Y, Yamakawa K, Inoue T, Kuno T, Imaida K. Gender-dependent effects of gonadectomy on lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female and male A/J mice. Oncol Rep 2013; 30:2632-8. [PMID: 24085151 PMCID: PMC3839949 DOI: 10.3892/or.2013.2759] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 09/13/2013] [Indexed: 01/19/2023] Open
Abstract
The present study was conducted to investigate the effects of gonadectomy on lung carcinogenesis in female and male mice, and to determine an association between sex hormone and lung carcinogenesis. Female and male A/J mice were divided into gonadectomized and unoperated control groups and all animals were treated intraperitoneally with 1 or 2 injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at the dose of 2 mg/mouse. The mice were sacrificed 18 or 56 weeks after surgery. Serum levels of estradiol in females and testosterone in males were confirmed to be decreased by gonadectomy. Lung white nodules were detected in all mice of all groups. In the control groups of 18- and 56-week studies, the multiplicities of lung nodules in females were significantly greater than in males. In males in the 56-week study, the multiplicity of macroscopical lung nodules, bronchiolo-alveolar hyperplasias, adenomas and tumors (adenomas and adenocarcinomas) showed significant increase with castration. In females in the 18-week study, the multiplicity of adenomas decreased significantly by ovariectomy. Based on the results of the present study, female A/J mice were confirmed to be more susceptible to NNK-induced lung carcinogenesis than males. Furthermore, it was suggested that the process is inhibited by testosterone and accelerated by estradiol. These findings indicate the possibility that sex hormones play important roles in determining sex differences in lung carcinogenesis in the A/J mice initiated by NNK.
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Affiliation(s)
- Fumiko Ninomiya
- Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Han MA, Kim YW, Choi IJ, Oh MG, Kim CG, Lee JY, Cho SJ, Eom BW, Yoon HM, Ryu KW. Association of smoking history with cancer recurrence and survival in stage III-IV male gastric cancer patients. Cancer Epidemiol Biomarkers Prev 2013; 22:1805-12. [PMID: 23904463 DOI: 10.1158/1055-9965.epi-13-0385] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Smoking and drinking alcohol are major risk factors for cancer development, and we investigated their effects on gastric cancer prognosis following initial resection. METHODS Data from male patients with stage III-IV gastric adenocarcinoma who underwent surgery between 2001 and 2006 were retrospectively reviewed. Patients were followed up until 2011. Kaplan-Meier plots and Cox proportional hazards regressions were applied for survival rates. RESULTS Among 238 patients, 151 (63.4%) smoked and 146 (61.3%) drank alcohol. Current smokers had an increased risk of cancer recurrence or death from any cause [adjusted HR (aHR), 1.94; 95% confidence interval (CI), 1.18-3.21], cancer recurrence (aHR, 1.89; 95% CI, 1.12-3.21), and overall mortality (aHR, 2.14; 95% CI, 1.23-3.73) compared with never-smokers. Patients with a lifetime cigarette smoking of <40 and ≥ 40 pack-years had increased cancer recurrence or death from any cause (aHR, 1.72 and 2.43, respectively; 95% CI, 1.03-2.86 and 1.38-4.30, respectively), cancer recurrence (aHR, 1.63 and 2.61, respectively; 95% CI, 0.95-2.79 and 1.43-4.77, respectively), and overall mortality (aHR, 1.92 and 2.75, respectively; 95% CI, 1.09-3.38 and 1.47-5.12, respectively) compared with never-smokers. However, drinking alcohol was not associated with postsurgery survival. CONCLUSIONS Cigarette-smoking history at the time of diagnosis, but not drinking history, is associated with cancer recurrence and poor survival after surgery in male patients with stage III-IV gastric cancer. IMPACT These findings encourage physicians to advise patients with gastric cancer to stop smoking to obtain a general health benefit and likely improvement in the gastric cancer course.
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Affiliation(s)
- Mi Ah Han
- Authors' Affiliations: Department of Preventive Medicine, College of Medicine; Department of Medicine, Graduate School, Chosun University, Gwangju; Center for Gastric Cancer, National Cancer Center, Goyang; and Department of Internal Medicine, Haengchon Medical Foundation, Haenam General Hospital, Haenam, Republic of Korea
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Park SY, Lee JG, Kim J, Bae MK, Lee CY, Kim DJ, Chung KY. The influence of smoking intensity on the clinicopathologic features and survival of patients with surgically treated non-small cell lung cancer. Lung Cancer 2013; 81:480-486. [PMID: 23896023 DOI: 10.1016/j.lungcan.2013.07.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 05/12/2013] [Accepted: 07/03/2013] [Indexed: 02/03/2023]
Abstract
BACKGROUND Smoking is a well-known carcinogen for lung cancer. However, whether smoking affects the biological behavior of lung cancer remains uncertain. This study aimed to investigate the influences of smoking intensity on the clinicopathologic characteristics of and survival in non-small cell lung cancer (NSCLC). METHODS We retrospectively reviewed 2238 consecutive patients who underwent surgical resection for NSCLC between 1990 and 2010. Smoking intensity was defined as pack-years (PY). The patients were divided into three groups according to the median value of smoking intensity (40 PY): group A (never smokers), group B (smoking intensity less than 40 PY) and group C (smoking intensity more than 40 PY). RESULTS There were 1629 (72.8%) male patients, and the mean age was 61.71 ± 13.17 years. Adenocarcinoma was reported in 1058 (47.3%) patients. The median follow-up period was 30.7 months (range: 0.0-261.7 months). The 5-year overall survivals for groups A, B and C were 60.1%, 51.6% and 43.2%, respectively (p < 0.001). In subset analysis by histology, the 5-year overall survival was significantly different according to smoking intensity in adenocarcinoma (p < 0.001), but there was no difference in the non-adenocarcinoma. In adenocarcinoma, the incidences of vascular invasion (p = 0.028), pleural invasion (p = 0.013) and poor differentiation (p < 0.001) were higher and tumor sizes (p < 0.001) were greater in group C than others. On multivariate analysis, smoking intensity was an adverse risk factor for overall survival in surgically treated adenocarcinoma patients (hazard ratio = 1.008, p = 0.028). CONCLUSION Smoking intensity was an adverse prognostic factor after surgical resection of adenocarcinoma. Heavy smoking was correlated with poor pathologic characteristics in adenocarcinoma.
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Affiliation(s)
- Seong Yong Park
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Jin Gu Lee
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Jieun Kim
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Mi Kyung Bae
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Chang Young Lee
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Dae Joon Kim
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea
| | - Kyung Young Chung
- Department of Thoracic and Cardiovascular Surgery, Yonsei University, College of Medicine, Seoul, Republic of Korea.
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Khoi PN, Park JS, Kim JH, Xia Y, Kim NH, Kim KK, Jung YD. (-)-Epigallocatechin-3-gallate blocks nicotine-induced matrix metalloproteinase-9 expression and invasiveness via suppression of NF-κB and AP-1 in endothelial cells. Int J Oncol 2013; 43:868-76. [PMID: 23835612 DOI: 10.3892/ijo.2013.2006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 06/17/2013] [Indexed: 11/05/2022] Open
Abstract
Cigarette smoke, specifically the nicotine contained within, has been shown to correlate closely with cell invasion and strategies to downregulate their expression may ultimately be of clinical utility. Matrix metalloproteinase-9 (MMP-9) is critically involved in the cell invasion and metastasis processes. Since nicotine plays a crucial role in the regulation of MMP-9 expression, the investigation of plant-derived compounds capable of modulating nicotine-induced signaling is an issue of concern. In this study, the effects of (-)-epigallocatechin-3-gallate (EGCG), a major green tea catechin, on nicotine-induced cell invasion and MMP-9 activity in ECV304 human endothelial cells were examined. EGCG treatment was found to reduce the MMP-9 expression and transcriptional activity in a dose-dependent manner. EGCG inhibited nicotine-activated production of reactive oxygen species (ROS), which are known as important signaling molecules to activate MMP-9. To further study the mechanisms for the EGCG-mediated regulation of MMP-9, the transcription factors NF-κB and AP-1 activities were examined. EGCG suppressed the nicotine-induced NF-κB and AP-1 activation. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated MMP-9 expression. EGCG also abrogated the nicotine-induced activation of AP-1 subunits c-fos and c-jun. The above studies demonstrate that EGCG may exert at least part of its anti-invasive effect in ECV304 human endothelial cells by controlling MMP-9 expression through the suppression of ROS, NF-κB and AP-1.
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Affiliation(s)
- Pham Ngoc Khoi
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
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Zeigler-Johnson C, Morales KH, Spangler E, Chang BL, Rebbeck TR. Relationship of early-onset baldness to prostate cancer in African-American men. Cancer Epidemiol Biomarkers Prev 2013; 22:589-96. [PMID: 23532004 DOI: 10.1158/1055-9965.epi-12-0944] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Early-onset baldness has been linked to prostate cancer; however, little is known about this relationship in African-Americans who are at elevated prostate cancer risk. METHODS We recruited 219 African-American controls and 318 African-American prostate cancer cases. We determined age-stratified associations of baldness with prostate cancer occurrence and severity defined by high stage (T3/T4) or high grade (Gleason 7+.) Associations of androgen metabolism genotypes (CYP3A4, CYP3A5, CYP3A43, AR-CAG, SRD5A2 A49T, and SRD5A2 V89L), family history, alcohol intake, and smoking were examined by baldness status and age group by using multivariable logistic regression models. RESULTS Baldness was associated with odds of prostate cancer [OR = 1.69; 95% confidence interval (CI), 1.05-2.74]. Frontal baldness was associated with high-stage (OR = 2.61; 95% CI, 1.10-6.18) and high-grade (OR = 2.20; 95% CI, 1.05-4.61) tumors. For men diagnosed less than the age of 60 years, frontal baldness was associated with high stage (OR = 6.51; 95% CI, 2.11-20.06) and high grade (OR = 4.23; 95% CI, 1.47-12.14). We also observed a suggestion of an interaction among smoking, median age, and any baldness (P = 0.02). CONCLUSIONS We observed significant associations between early-onset baldness and prostate cancer in African-American men. Interactions with age and smoking were suggested in these associations. Studies are needed to investigate the mechanisms influencing the relationship between baldness and prostate cancer in African-American men. IMPACT African-American men present with unique risk factors including baldness patterns that may contribute to prostate cancer disparities.
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Affiliation(s)
- Charnita Zeigler-Johnson
- Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 220 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA.
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Abstract
Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.
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Affiliation(s)
- Stephen S Hecht
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
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Muñoz JP, González C, Parra B, Corvalán AH, Tornesello ML, Eizuru Y, Aguayo F. Functional interaction between human papillomavirus type 16 E6 and E7 oncoproteins and cigarette smoke components in lung epithelial cells. PLoS One 2012; 7:e38178. [PMID: 22662279 PMCID: PMC3360647 DOI: 10.1371/journal.pone.0038178] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 05/04/2012] [Indexed: 12/25/2022] Open
Abstract
The smoking habit is the most important, but not a sufficient cause for lung cancer development. Several studies have reported the human papillomavirus type 16 (HPV16) presence and E6 and E7 transcripts expression in lung carcinoma cases from different geographical regions. The possible interaction between HPV infection and smoke carcinogens, however, remains unclear. In this study we address a potential cooperation between tobacco smoke and HPV16 E6 and E7 oncoproteins for alterations in proliferative and tumorigenic properties of lung epithelial cells. A549 (alveolar, tumoral) and BEAS-2B (bronchial, non-tumoral) cell lines were stably transfected with recombinant pLXSN vectors expressing HPV16 E6 and E7 oncoproteins and exposed to cigarette smoke condensate (CSC) at different concentrations. HPV16 E6 and E7 expression was associated with loss of p53 stability, telomerase (hTERT) and p16(INK4A) overexpression in BEAS-2B cells as demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). In A549 cells we observed downregulation of p53 but not a significant increase of hTERT transcripts. In addition, the HPV16 E6/E7 transfected cell lines showed an increased proliferation rate and anchorage-independent growth in a HPV16 E6 and E7 expression-dependent manner. Moreover, both HPV16 E6/E7 and mock transfected cells showed an increased proliferation rate and anchorage-independent growth in the presence of 0.1 and 10 µg/mL CSC. However, this increase was significantly greater in HPV16 E6/E7 transfected cells (p<0.001). Data were confirmed by FCSE proliferation assay. The results obtained in this study are suggestive of a functional interaction between tobacco smoke and HPV16 E6/E7 oncoproteins for malignant transformation and tumorigenesis of lung epithelial cells. More studies are warranted in order to dissect the molecular mechanisms involved in this cooperation.
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Affiliation(s)
- Juan Pablo Muñoz
- Virology Program, Instituto de Ciencias Biomédicas (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Carolina González
- Virology Program, Instituto de Ciencias Biomédicas (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Bárbara Parra
- Virology Program, Instituto de Ciencias Biomédicas (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Alejandro H. Corvalán
- Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology and AIDS Reference Centre, National Cancer Institute “Fond. Pascale”, Naples, Italy
| | - Yoshito Eizuru
- Division of Oncogenic and Persistent Viruses, Center for Chronic Viral Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
| | - Francisco Aguayo
- Virology Program, Instituto de Ciencias Biomédicas (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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