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Zeng Z, Cai S, Ye C, Li T, Tian Y, Liu E, Cai J, Yuan X, Yang H, Liang Q, Li K, Peng C. Neural influences in colorectal cancer progression and therapeutic strategies. Int J Colorectal Dis 2025; 40:120. [PMID: 40379990 PMCID: PMC12084286 DOI: 10.1007/s00384-025-04887-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2025] [Indexed: 05/19/2025]
Abstract
PURPOSE This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC. METHODS A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology. RESULTS Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets. CONCLUSION Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.
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Affiliation(s)
- Zhibin Zeng
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Shirong Cai
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Chenle Ye
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Tongduan Li
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Yan Tian
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Enyuan Liu
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Junbin Cai
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Xiaojun Yuan
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Heng Yang
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Quanqi Liang
- Division of Gastroenterology, Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China
| | - Kaishu Li
- Institute of Digestive Diseases, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China.
| | - Cui Peng
- Department of Gynaecology and Obstetrics, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, China.
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Annor E, Atarere J, Glover Q, Ubah N, Odo C, Bene-Alhasan Y, Orhurhu V, Hasoon J, Ufondu WC, Osman M, Thompson C. E-cigarette Smoking and Colorectal Cancer Screening. Am J Health Promot 2025; 39:574-580. [PMID: 39606814 DOI: 10.1177/08901171241304726] [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] [Indexed: 11/29/2024]
Abstract
PurposeTo evaluate how CRC screening practices differ between e-cigarette users and non-users.DesignCross-sectional study design.SettingNational Cancer Institute's Health Information National Trends Survey (HINTS 5).SubjectsRespondents aged 45 to 75 years.MeasuresDemographics, CRC screening, e-cigarette use, cancer history, presence of comorbidities, and access to a primary care provider.AnalysisThe demographic characteristics of the study participants were evaluated by their e-cigarette smoking status using chi-squared tests. The differences in CRC screening between e-cigarette users and non-users were evaluated using a multivariate logistic regression model.ResultsWe identified a total of 6963 participants, of which 181 (2.6%) were e-cigarette users. The prevalence of e-cigarette use was inversely related to age. A significant portion were uninsured (10.7% vs 5.9% of non-users), and almost half (49.9%) were current tobacco smokers. E-cigarette users were as likely to undergo CRC screening compared to non-users [OR 1.40; 95% CI (0.74, 2.66)]. Increasing age, educational level, health insurance, comorbidity, access to a primary care provider, personal history of cancer, and presence of a comorbidity were associated with increased participation in CRC screening. However, e-cigarette use was not associated with increased screening.ConclusionOur study found no significant difference in CRC screening rates between e-cigarette users and non-users. While screening behaviors appear unaffected for now, ongoing surveillance is important as more users reach screening age given the uncertainties surrounding the long-term effects of e-cigarette use.
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Affiliation(s)
- Eugene Annor
- Department of Medicine, University of Illinois College of Medicine, Peoria, IL, USA
| | - Joseph Atarere
- Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD, USA
| | - Quarshie Glover
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Nneoma Ubah
- Department of Medicine, Montefiore St Luke's Cornwall Hospital, Newburgh, NY, USA
| | - Chinenye Odo
- Department of Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Vwaire Orhurhu
- Department of Anesthesiology, University of Pittsburgh Medical Center, Williamsport, PA, USA
| | - Jamal Hasoon
- Department of Anesthesia and Pain Medicine, UT Health McGovern Medical School, Houston, TX, USA
| | | | - Moyasar Osman
- Department of Psychology, New York University, New York, NY, USA
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Zhou C, Cao R, Wang Q, Mo J, Qian W, Feng Z, Zhang S, Chen X, Hao J, Ma Q, Wu Z, Wang Z. Tobacco carcinogen NNK promotes pancreatic cancer proliferation via LINC00857/β-catenin. Tob Induc Dis 2025; 23:TID-23-50. [PMID: 40303426 PMCID: PMC12039305 DOI: 10.18332/tid/203455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 03/14/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
INTRODUCTION Smoking is a key risk factor for pancreatic cancer (PC). Nicotine-derived nitrosamine ketone (NNK), a major tobacco smoke constituent, has been shown to promote cancer growth, but its specific role in PC progression remains unclear. While long non-coding RNA LINC00857 (lnc RNA) is implicated in cancer progression, its regulation by NNK is unknown. This study aims to investigate whether NNK can drive PC growth and elucidate the underlying mechanisms. METHODS Employing an experimental methodology, this investigation treated human pancreatic cancer cell lines (CFPAC-1 and Panc-1) with NNK and utilized various assays (CCK-8, colony formation, and EdU cell proliferation) to assess the effects on cell proliferation. The interplay between LINC00857 expression profiles, PC, and smoking was systematically investigated through cross-database bioinformatic interrogation encompassing public resources and institutional biobank data. Experiments were performed to knock down LINC00857 in PC cells using siRNA technology. We used Western blotting and quantitative real-time PCR (qRT-PCR) to assess β-catenin expression and elucidate the mechanism by which the tobacco carcinogen NNK promotes PC formation. RESULTS Some evidence that NNK enhanced the proliferative capacity of PC cells was found. Bioinformatic analysis of public databases, combined with data from our center's database, revealed that LINC00857 was up-regulated in PC and correlated with smoking. Moreover, we discovered that knockdown of LINC00857 inhibited PC cell proliferation, with β-catenin identified as a potential downstream molecule. Importantly, after LINC00857 knockdown, we observed suppression of NNK-induced β-catenin upregulation at both protein and transcriptional levels. CONCLUSIONS NNK potentially induces PC progression through the LINC00857/β-catenin axis. These findings provide new perspectives on the mechanisms of PC progression and highlight the clinical relevance of smoking cessation for preventing PC.
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Affiliation(s)
- Cancan Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Ruiqi Cao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Qiqi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Jiantao Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Zhengyuan Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Shengzhan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Xin Chen
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jie Hao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Pancreas Center, Xi’an Jiaotong University, Xi’an, China
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Long C, Li X, Liu J, Mo X, Zhong H, Tang W, Yu J. Exploring the Role of Epithelial-Mesenchymal Transition During Colorectal Cancer Peritoneal Metastasis: Update on Their Mechanisms. J Biochem Mol Toxicol 2025; 39:e70166. [PMID: 39871529 DOI: 10.1002/jbt.70166] [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: 12/29/2024] [Accepted: 01/22/2025] [Indexed: 01/29/2025]
Abstract
Colorectal cancer is a common malignant tumor worldwide. The prognosis of patients with colorectal cancer peritoneal metastasis is very poor. The study of the specific mechanisms of colorectal cancer peritoneal metastasis plays an important role in the treatment of patients with this disease. The mechanisms of colorectal cancer peritoneal metastasis are mainly pathological and biological. Biologically, the epithelial-mesenchymal transition process is an important precursor to tumor cell metastasis. Therefore, it is necessary to study the mechanisms of colorectal cancer peritoneal metastasis, especially the epithelial-mesenchymal transition, to identify new methods for the prevention and treatment of colorectal cancer peritoneal cancer, reduce the incidence of colorectal cancer peritoneal metastasis, and improve patient prognosis.
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Affiliation(s)
- Chenyan Long
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Xiang Li
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Jungang Liu
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Xianwei Mo
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Huage Zhong
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Weizhong Tang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
| | - Junfeng Yu
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Medical College of Cancer, Guangxi Medical University, Nanning, China
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Sampaio Moura N, Schledwitz A, Alizadeh M, Kodan A, Njei LP, Raufman JP. Cholinergic Mechanisms in Gastrointestinal Neoplasia. Int J Mol Sci 2024; 25:5316. [PMID: 38791353 PMCID: PMC11120676 DOI: 10.3390/ijms25105316] [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: 03/29/2024] [Revised: 05/09/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Asha Kodan
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland, Baltimore County, Baltimore, MD 21250, USA;
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.S.M.); (A.S.); (A.K.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD 21201, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Jiang M, Han J, Ma Q, Chen X, Xu R, Wang Q, Zheng J, Wang W, Song J, Huang Y, Chen Y. Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner. JOURNAL OF HAZARDOUS MATERIALS 2024; 467:133692. [PMID: 38341886 DOI: 10.1016/j.jhazmat.2024.133692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/13/2024]
Abstract
Cigarette smoking substantially promotes tumorigenesis and progression of colorectal cancer; however, the underlying molecular mechanism remains unclear. Among 662 colorectal cancer patients, our investigation revealed a significant correlation between cigarette smoking and factors, such as large tumor size, poor differentiation, and high degree of invasion. Among the nicotine-derived nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) emerged as the most critical carcinogen, which significantly promoted the malignant progression of colorectal cancer both in vivo and in vitro. The results of methylated RNA immunoprecipitation and transcriptome sequencing indicated that NNK upregulated transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) via N6-adenosine methylation, which was regulated by methyltransferase-like 14 (METTL14) and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Elevated TMUB1 levels were associated with a higher risk of cancer invasion and metastasis, leading to a high mortality risk in patients with colorectal cancer. Additionally, TMUB1 promoted lysine63-linked ubiquitination of AKT by interacting with AMFR, which led to the induction of malignant proliferation and metastasis in colorectal cancer cells exposed to NNK. In summary, this study provides a new insight, indicating that targeting TMUB1 expression via METTL14/YTHDF2 mediated N6-adenosine methylation may be a potential therapeutic and prognostic target for patients with colorectal cancer who smoke.
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Affiliation(s)
- Min Jiang
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Center for Medical Statistics and Data Analysis, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Jingyi Han
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Qun Ma
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Xue Chen
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Renjie Xu
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Qing Wang
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Jia Zheng
- Department of Clinical Epidemiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Weimin Wang
- Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yixing, Jiangsu, PR China
| | - Jun Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
| | - Yefei Huang
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
| | - Yansu Chen
- School of Public Health, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Center for Medical Statistics and Data Analysis, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
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Sun Q, Jin C. Cell signaling and epigenetic regulation of nicotine-induced carcinogenesis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 345:123426. [PMID: 38295934 PMCID: PMC10939829 DOI: 10.1016/j.envpol.2024.123426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 11/22/2023] [Accepted: 01/21/2024] [Indexed: 02/05/2024]
Abstract
Nicotine, a naturally occurring tobacco alkaloid responsible for tobacco addiction, has long been considered non-carcinogenic. However, emerging evidence suggests that nicotine may possess carcinogenic properties in mice and could be a potential carcinogen in humans. This review aims to summarize the potential molecular mechanisms underlying nicotine-induced carcinogenesis, with a specific focus on epigenetic regulation and the activation of nicotinic acetylcholine receptors (nAChRs) in addition to genotoxicity and excess reactive oxygen species (ROS). Additionally, we explore a novel hypothesis regarding nicotine's carcinogenicity involving the downregulation of stem-loop binding protein (SLBP), a critical regulator of canonical histone mRNA, and the polyadenylation of canonical histone mRNA. By shedding light on these mechanisms, this review underscores the need for further research to elucidate the carcinogenic potential of nicotine and its implications for human health.
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Affiliation(s)
- Qi Sun
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10010, USA; Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110013, China; Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China
| | - Chunyuan Jin
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10010, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA.
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Bele T, Turk T, Križaj I. Nicotinic acetylcholine receptors in cancer: Limitations and prospects. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166875. [PMID: 37673358 DOI: 10.1016/j.bbadis.2023.166875] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/09/2023] [Accepted: 08/31/2023] [Indexed: 09/08/2023]
Abstract
Nicotinic acetylcholine receptors (nAChRs) have long been considered to solely mediate neurotransmission. However, their widespread distribution in the human body suggests a more diverse physiological role. Additionally, the expression of nAChRs is increased in certain cancers, such as lung cancer, and has been associated with cell proliferation, epithelial-to-mesenchymal cell transition, angiogenesis and apoptosis prevention. Several compounds that interact with these receptors have been identified as potential therapeutic agents. They have been tested as drugs for treating nicotine addiction, alcoholism, depression, pain and Alzheimer's disease. This review focuses on nAChR-mediated signalling in cancer, presenting opportunities for the development of innovative nAChR-based anticancer drugs. It displays the differences in expression of each nAChR subunit between normal and cancer cells for selected cancer types, highlighting their possible involvement in specific cases. Antagonists of nAChRs that could complement existing cancer therapies are summarised and critically discussed. We hope that this review will stimulate further research on the role of nAChRs in cancer potentially leading to innovative cancer therapies.
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Affiliation(s)
- T Bele
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
| | - T Turk
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, SI-1000 Ljubljana, Slovenia.
| | - I Križaj
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
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Shieh JM, Chang TW, Wang JH, Liang SP, Kao PL, Chen LY, Yen CJ, Chen YJ, Chang WC, Chen BK. RNA-binding protein-regulated fibronectin is essential for EGFR-activated metastasis of head and neck squamous cell carcinoma. FASEB J 2023; 37:e23206. [PMID: 37718485 DOI: 10.1096/fj.202300527r] [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: 03/19/2023] [Revised: 08/24/2023] [Accepted: 09/07/2023] [Indexed: 09/19/2023]
Abstract
There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the role of RNA-binding proteins (RBPs) in EGFR-associated metastasis of HNSCC remains unclear. In this study, we reveal that RBPs, specifically nucleolin (NCL) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), correlated with the mesenchymal phenotype of HNSCC. The depletion of RBPs significantly attenuated EGF-induced HNSCC metastasis. Intriguingly, the EGF-induced EMT markers, such as fibronectin, were regulated by RBPs through the ERK and NF-κB pathway, followed by the enhancement of mRNA stability of fibronectin through the 5' untranslated region (5'-UTR) of the gene. The upregulation of fibronectin triggered the integrin signaling activation to enhance tumor cells' attachment to endothelial cells and increase endothelial permeability. In addition, the concurrence of EGFR and RBPs or EGFR and fibronectin was associated with overall survival and disease-free survival of HNSCC. The in vivo study showed that depletion of NCL, hnRNPA2B1, and fibronectin significantly inhibited EGF-promoted extravasation of tumor cells into lung tissues. The depletion of fibronectin or treatment with integrin inhibitors dramatically attenuated EGF-induced HNSCC metastatic nodules in the lung. Our data suggest that the RBPs/fibronectin axis is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.
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Affiliation(s)
- Jiunn-Min Shieh
- Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan, ROC
| | - Ting-Wei Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Jing-He Wang
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Song-Ping Liang
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pei-Lu Kao
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Liang-Yi Chen
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yun-Ju Chen
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan, ROC
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan, ROC
| | - Wen-Chang Chang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Ben-Kuen Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
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Papapostolou I, Ross-Kaschitza D, Bochen F, Peinelt C, Maldifassi MC. Contribution of the α5 nAChR Subunit and α5SNP to Nicotine-Induced Proliferation and Migration of Human Cancer Cells. Cells 2023; 12:2000. [PMID: 37566079 PMCID: PMC10417634 DOI: 10.3390/cells12152000] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/12/2023] Open
Abstract
Nicotine in tobacco is known to induce tumor-promoting effects and cause chemotherapy resistance through the activation of nicotinic acetylcholine receptors (nAChRs). Many studies have associated the α5 nicotinic receptor subunit (α5), and a specific polymorphism in this subunit, with (i) nicotine administration, (ii) nicotine dependence, and (iii) lung cancer. The α5 gene CHRNA5 mRNA is upregulated in several types of cancer, including lung, prostate, colorectal, and stomach cancer, and cancer severity is correlated with smoking. In this study, we investigate the contribution of α5 in the nicotine-induced cancer hallmark functions proliferation and migration, in breast, colon, and prostate cancer cells. Nine human cell lines from different origins were used to determine nAChR subunit expression levels. Then, selected breast (MCF7), colon (SW480), and prostate (DU145) cancer cell lines were used to investigate the nicotine-induced effects mediated by α5. Using pharmacological and siRNA-based experiments, we show that α5 is essential for nicotine-induced proliferation and migration. Additionally, upon downregulation of α5, nicotine-promoted expression of EMT markers and immune regulatory proteins was impaired. Moreover, the α5 polymorphism D398N (α5SNP) caused a basal increase in proliferation and migration in the DU145 cell line, and the effect was mediated through G-protein signaling. Taken together, our results indicate that nicotine-induced cancer cell proliferation and migration are mediated via α5, adding to the characterization of α5 as a putative therapeutical target.
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Affiliation(s)
| | | | | | | | - Maria Constanza Maldifassi
- Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland; (I.P.); (D.R.-K.); (F.B.); (C.P.)
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11
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R I A, Vatsyayan A, Damodaran D, Sivadas A, Van der Speeten K. Multi-omics Analysis Classifies Colorectal Cancer into Distinct Methylated Immunogenic and Angiogenic Subtypes Based on Anatomical Laterality. Indian J Surg Oncol 2023; 14:209-219. [PMID: 37359923 PMCID: PMC10284779 DOI: 10.1007/s13193-023-01760-6] [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: 09/19/2022] [Accepted: 04/25/2023] [Indexed: 06/28/2023] Open
Abstract
We employed supervised machine learning algorithms to a cohort of colorectal cancer patients from the NCI to differentiate and classify the heterogenous disease based on anatomical laterality and multi-omics stratification, in a first of its kind. Multi-omics integrative analysis shows distinct clustering of left and right colorectal cancer with disentangled representation of methylome and delineation of transcriptome and genome. We present novel multi-omics findings consistent with augmented hypermethylation of genes in right CRC, epigenomic biomarkers on the right in conjunction with immune-mediated pathway signatures, and lymphocytic invasion which unlocks unique therapeutic avenues. Contrarily, left CRC multi-omics signature is found to be marked by angiogenesis, cadherins, and epithelial-mesenchymal transition (EMT). An integrated multi-omics molecular signature of RNF217-AS1, hsa-miR-10b, and panel of FBX02, FBX06, FBX044, MAD2L2, and MIIP copy number altered genes have been found by the study. Overall survival analysis reveals genomic biomarkers ABCA13 and TTN in 852 LCRC cases, and SOX11 in 170 RCRC cases that predicts a significant survival benefit. Our study exemplifies the translational competence and robustness of machine learning in effective translational bridging of research and clinic. Supplementary Information The online version contains supplementary material available at 10.1007/s13193-023-01760-6.
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Affiliation(s)
- Anu R I
- Department of Cancer Biology and Therapeutics, MVR Cancer Center and Research Institute, Calicut, Kerala India
- Department of Clinical Biochemistry, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Aastha Vatsyayan
- CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dileep Damodaran
- Department of Surgical Oncology, MVR Cancer Center and Research Institute, Calicut, Kerala India
| | - Ambily Sivadas
- Division of Nutrition, St. John’s Research Institute, Bangalore, India
| | - Kurt Van der Speeten
- Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium
- Faculty of Medicine and Life Sciences, BIOMED Research Institute, University Hasselt, Hasselt, Belgium
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12
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Rong J, Pu R, Sun H, Liu Y, Tian T, Bi H, Xia T, Zhang L, Zhang Y, Zhao Y, Zhu L. Association between the Methylation of CpG Islands in JAK-STAT Pathway-Related Genes and Colorectal Cancer. Gene 2023; 868:147357. [PMID: 36914143 DOI: 10.1016/j.gene.2023.147357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/21/2023] [Accepted: 03/07/2023] [Indexed: 03/13/2023]
Abstract
BACKGROUND Aberrant promoter methylation of CpG islands plays an important role in carcinogenesis. However, the association between the DNA methylation of JAK-STAT pathway-related genes in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility remains unclear. METHODS We conducted a case-control study of 403 patients with CRC and 419 cancer free controls, and the DNA methylation levels of JAK2, STAT1, STAT3, and SOCS3 in peripheral blood samples from all subjects were assessed using a methylation-sensitive high-resolution melting (MS-HRM) analysis. RESULTS Compared with controls, the methylation of the JAK2, STAT1 and SOCS3 genes increased the CRC risk (ORadjusted=1.96, 95% CI, 1.12-3.41, P=0.01; ORadjusted=5.37, 95% CI, 3.74-7.71, P<0.01; ORadjusted=3.30, 95% CI, 1.58-6.87, P<0.01). In the multiple CpG site methylation (MCSM) analysis, a high MCSM value denoted an increased CRC risk (ORadjusted=4.97, 95% CI, 3.34-7.37, P<0.01). CONCLUSION In peripheral blood, the methylation of JAK2, STAT1, and high levels of MCSM are promising biomarkers for CRC risk.
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Affiliation(s)
- Jiesheng Rong
- Second Department of Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Rui Pu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tian Tian
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Haoran Bi
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tingting Xia
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
| | - Lin Zhu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
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13
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Tae HS, Adams DJ. Nicotinic acetylcholine receptor subtype expression, function, and pharmacology: Therapeutic potential of α-conotoxins. Pharmacol Res 2023; 191:106747. [PMID: 37001708 DOI: 10.1016/j.phrs.2023.106747] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
The pentameric nicotinic acetylcholine receptors (nAChRs) are typically classed as muscle- or neuronal-type, however, the latter has also been reported in non-neuronal cells. Given their broad distribution, nAChRs mediate numerous physiological and pathological processes including synaptic transmission, presynaptic modulation of transmitter release, neuropathic pain, inflammation, and cancer. There are 17 different nAChR subunits and combinations of these subunits produce subtypes with diverse pharmacological properties. The expression and role of some nAChR subtypes have been extensively deciphered with the aid of knock-out models. Many nAChR subtypes expressed in heterologous systems are selectively targeted by the disulfide-rich α-conotoxins. α-Conotoxins are small peptides isolated from the venom of cone snails, and a number of them have potential pharmaceutical value.
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14
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Battaglin F, Jayachandran P, Strelez C, Lenz A, Algaze S, Soni S, Lo JH, Yang Y, Millstein J, Zhang W, Roussos Torres ET, Shih JC, Mumenthaler SM, Neman J, Lenz HJ. Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment. Oncogene 2022; 41:4769-4778. [PMID: 36182970 PMCID: PMC10591256 DOI: 10.1038/s41388-022-02479-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/08/2022]
Abstract
The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.
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Affiliation(s)
- Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Priya Jayachandran
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carly Strelez
- Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, USA
| | - Annika Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sandra Algaze
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yan Yang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joshua Millstein
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Evanthia T Roussos Torres
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jean C Shih
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Shannon M Mumenthaler
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, USA
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
| | - Josh Neman
- Department of Neurological Surgery, USC Brain Tumor Center, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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15
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Emerging Roles of the Nervous System in Gastrointestinal Cancer Development. Cancers (Basel) 2022; 14:cancers14153722. [PMID: 35954387 PMCID: PMC9367305 DOI: 10.3390/cancers14153722] [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: 05/30/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Nerve–cancer cross-talk has increasingly become a focus of the oncology field, particularly in gastrointestinal (GI) cancers. The indispensable roles of the nervous system in GI tumorigenesis and malignancy have been dissected by epidemiological, experimental animal and mechanistic data. Herein, we review and integrate recent discoveries linking the nervous system to GI cancer initiation and progression, and focus on the molecular mechanisms by which nerves and neural receptor pathways drive GI malignancy. Abstract Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy.
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16
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Li H, Su YS, He W, Zhang JB, Zhang Q, Jing XH, Zhan LB. The nonneuronal cholinergic system in the colon: A comprehensive review. FASEB J 2022; 36:e22165. [PMID: 35174565 DOI: 10.1096/fj.202101529r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 01/07/2023]
Abstract
Acetylcholine (ACh) is found not only in cholinergic nerve termini but also in the nonneuronal cholinergic system (NNCS). ACh is released from cholinergic nerves by vesicular ACh transporter (VAChT), but ACh release from the NNCS is mediated by organic cation transporter (OCT). Recent studies have suggested that components of the NNCS are located in intestinal epithelial cells (IECs), crypt-villus organoids, immune cells, intestinal stem cells (ISCs), and vascular endothelial cells (VECs). When ACh enters the interstitial space, its self-modulation or effects on adjacent tissues are part of the range of its biological functions. This review focuses on the current understanding of the mechanisms of ACh synthesis and release in the NNCS. Furthermore, studies on ACh functions in colonic disorders suggest that ACh from the NNCS contributes to immune regulation, IEC and VEC repair, ISC differentiation, colonic movement, and colonic tumor development. As indicated by the features of some colonic disorders, ACh and the NNCS have positive and negative effects on these disorders. Furthermore, the NNCS is located in multiple colonic organs, and the specific effects and cross-talk involving ACh from the NNCS in different colonic tissues are explored.
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Affiliation(s)
- Han Li
- Changzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, China.,Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang-Shuai Su
- Research Center of Meridians, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei He
- Research Center of Meridians, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jian-Bin Zhang
- The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qi Zhang
- Changzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, China
| | - Xiang-Hong Jing
- Research Center of Meridians, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li-Bin Zhan
- Nanjing University of Chinese Medicine, Nanjing, China.,Liaoning University of Traditional Chinese Medicine, Shenyang, China
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17
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Cigarette Smoking Associated with Colorectal Cancer Survival: A Nationwide, Population-Based Cohort Study. J Clin Med 2022; 11:jcm11040913. [PMID: 35207186 PMCID: PMC8879005 DOI: 10.3390/jcm11040913] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/29/2022] [Accepted: 02/07/2022] [Indexed: 02/04/2023] Open
Abstract
We investigate whether cigarette smoking is associated with survival in patients with colorectal cancer (CRC) through a nationwide population-based cohort study in Taiwan. The Taiwan Cancer Registry and National Health Insurance Research Database were used to identify data from patients with CRC from 2011 to 2017. Tobacco use was evaluated based on the smoking status, intensity, and duration before cancer diagnosis. A total of 18,816 patients was included. A Kaplan–Meier survival analysis indicated smoking to be significantly associated with the CRC mortality risk (log-rank p = 0.0001). A multivariable Cox model indicated that smoking patients had a 1.11-fold higher mortality risk (HR = 1.11, 95% CI = 1.05–1.19) than nonsmoking patients did. This increased risk was also present in patients with CRC who smoked 11–20 cigarettes per day (HR = 1.16; 95% CI = 1.07–1.26) or smoked for >30 years (HR = 1.14; 95% CI = 1.04–1.25). Stratified analyses of sex and cancer subsites indicated that the effects of smoking were higher in male patients and in those with colon cancer. Our results indicate that cigarette smoking is significantly associated with poor survival in patients with CRC. An integrated smoking cessation campaign is warranted to prevent CRC mortality.
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18
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Pandey S, Fish SS, Roy HK. Increasing colorectal cancer in the young population and tailoring of the colorectal cancer screening recommendations in subpopulation: a retrospective single-center study. Int J Colorectal Dis 2021; 36:1515-1524. [PMID: 33934174 DOI: 10.1007/s00384-021-03934-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE The United States Preventive Services Task Force (USPSTF) newly drafted recommendations for colorectal cancer (CRC) screening age in average-risk individuals decreased to 45 years from 50 years. This study evaluates the change in the incidence of CRC, compares the demographic characteristics, characteristics of CRC, survival, and factors affecting the survival of younger (< 50 years) with the older (> 50 years) CRC-diagnosed population of Boston Medical Center (BMC). Also tailors the screening recommendations of CRC based on subpopulations. METHODS A retrospective cohort study was conducted from 2004 to 2019 at BMC who underwent colonoscopy, to see newly diagnosed CRC. The analysis was done in R studio version 1.2.5033. RESULTS The incidence rate of CRC is increasing in the younger population. The CRC in younger population was 350 and older was 2019. The most prevalent site among the younger population was rectum (33.33%), and most of the CRC were diagnosed at an advanced stage. Hispanics were less likely to be diagnosed with CRC in older age group (OR= 0.468, 95% CI 0.285, 0.796). Lower BMI was associated with a higher risk of mortality (p= 0.012). There was no difference in survival in younger and older populations. CONCLUSIONS CRC is increasing in the younger population, and Hispanics are diagnosed with CRC usually at a younger age. Early screening in young populations with average risk and even earlier screening in high-risk populations like Hispanics is warranted for timely recognition for prevention, early management, and reduction of mortality.
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Affiliation(s)
- Samiksha Pandey
- MS in Clinical Research, Boston University School of Medicine, Boston, MA, USA. .,William Beaumont Hospital-Royal Oak, Royal Oak, MI, USA.
| | - Susan S Fish
- Boston University Schools of Public Health and Medicine, Boston, MA, USA
| | - Hemant K Roy
- Boston University School of Medicine, Boston, MA, USA.,Baylor College of Medicine, Houston, TX, USA
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19
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Croese A, Gartrell R, Hiscock R, Lee M, Gibbs P, Faragher I, Yeung J. The effect of smoking, obesity and diabetes on recurrence-free and overall survival in patients with stage III colon cancer receiving adjuvant chemotherapy. Cancer Rep (Hoboken) 2021; 4:e1346. [PMID: 33554476 PMCID: PMC8222556 DOI: 10.1002/cnr2.1346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Background The association between smoking, diabetes and obesity and oncological outcomes in patients with stage III colon cancer treated with surgery and adjuvant chemotherapy is unclear. Aim To evaluate whether smoking, obesity and diabetes are associated with the disease‐free survival and overall survival rates of patients with stage III colon cancer who have received adjuvant chemotherapy. Methods Patients were selected from the prospectively maintained Australian Cancer Outcomes and Research Database (ACCORD). All stage III colon cancer patients who received adjuvant chemotherapy between January 2003 to December 2015 were retrospectively analyzed. The three primary exposures of interest were smoking status, body mass index (BMI) and diabetic (DM) status. The primary outcomes of interest were disease‐free survival (DFS) and overall survival (OS). Results A total of 785 patients between 2003 and 2015 were included for analysis. Using Kaplan‐Meier survivorship curves, there was no association between OS and smoking (P = .71), BMI (P = .3) or DM (P = .72). Similarly, DFS did not reveal an association with smoking (P = .34), BMI (P = .2) and DM (P = .34). Controlling for other covariates the results did not reach statistical significance in adjusted multiple regression models. Conclusion Smoking, obesity and DM were not shown to influence DFS or OS for patients with stage III colon cancer who have received adjuvant chemotherapy.
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Affiliation(s)
- Alex Croese
- Department of Surgery, Footscray Hospital, Footscray, Victoria, Australia
| | - Richard Gartrell
- Melbourne Medical School - Western Health Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, St Albans, Victoria, Australia.,Department of Surgery, Sunshine Hospital, St Albans, Victoria, Australia
| | - Richard Hiscock
- Specialist Anesthetist Department of Anesthesia, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Margaret Lee
- Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia.,Department of Medical Oncology, Western Health, Footscray, Victoria, Australia.,Faculty of Medicine, Nursing and Health Sciences, Monash University Eastern Health Clinical School, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Department of Medical Oncology, Western Health, Footscray, Victoria, Australia.,Laboratory Head, Walter and Eliza Hall Institute Medical Research, Parkville, Victoria, Australia
| | - Ian Faragher
- Western Health Head of Colorectal Unit, Western Health, Footscray, Victoria, Australia
| | - Justin Yeung
- Department of Surgery, Sunshine Hospital, St Albans, Victoria, Australia.,Colorectal Surgical Department, Western Health, Footscray, Victoria, Australia.,Australia Head of Department of Surgery, Melbourne Medical School - Western Health Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
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20
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Wang J, Li R, Li M, Wang C. Fibronectin and colorectal cancer: signaling pathways and clinical implications. J Recept Signal Transduct Res 2020; 41:313-320. [PMID: 32900261 DOI: 10.1080/10799893.2020.1817074] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer deaths worldwide, with poor prognosis mainly related to metastasis. Fibronectin (FN), a vital component of the extracellular matrix (ECM), has been found involved in tumorigenesis and malignant progression in different types of malignancy. Numerous studies have indicated the distinct expression of FN in various cancers and demonstrated the different functions of FN in the proliferation, migration, and invasion of cancers. Meanwhile, FN isoforms have been extensively used for targeted drug delivery and imaging for tumors. Although a growing number of studies on FN in CRC have been reported, integrated reviews on the relationship between FN and CRC are rare. In this review, we will summarize the association between FN and CRC, including the signaling pathways and molecules involved in, as well as potential diagnostic and therapeutic values of FN for patients with CRC.
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Affiliation(s)
- Jianan Wang
- Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, P. R. China
| | - Ruibing Li
- Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, P. R. China
| | - Mianyang Li
- Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, P. R. China
| | - Chengbin Wang
- Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, P. R. China
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21
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Role of the parasympathetic nervous system in cancer initiation and progression. Clin Transl Oncol 2020; 23:669-681. [PMID: 32770391 DOI: 10.1007/s12094-020-02465-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/21/2020] [Indexed: 12/29/2022]
Abstract
The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts stimulatory effects on carcinogenesis and cancer growth. However, the role of the parasympathetic nervous system in cancer has been much less elucidated. Whereas retrospective studies in vagotomized patients and experiments employing vagotomized animals indicate the parasympathetic nervous system has an inhibitory effect on cancer, clinical studies in patients with prostate cancer indicate it has stimulatory effects. Therefore, the aim of this paper is a critical evaluation of the available data related to the role of the parasympathetic nervous system in cancer.
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22
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α7-Nicotine acetylcholine receptor mediated nicotine induced cell survival and cisplatin resistance in oral cancer. Arch Oral Biol 2020; 111:104653. [DOI: 10.1016/j.archoralbio.2020.104653] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 12/20/2022]
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23
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Hajiasgharzadeh K, Somi MH, Sadigh-Eteghad S, Mokhtarzadeh A, Shanehbandi D, Mansoori B, Mohammadi A, Doustvandi MA, Baradaran B. The dual role of alpha7 nicotinic acetylcholine receptor in inflammation-associated gastrointestinal cancers. Heliyon 2020; 6:e03611. [PMID: 32215331 PMCID: PMC7090353 DOI: 10.1016/j.heliyon.2020.e03611] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 12/10/2019] [Accepted: 02/10/2020] [Indexed: 02/07/2023] Open
Abstract
Alpha7 nicotinic acetylcholine receptor (α7nAChR) is one of the main subtypes of nAChRs that modulates various cancer-related properties including proliferative, anti-apoptotic, pro-angiogenic and pro-metastatic activities in most of the cancers. It also plays a crucial role in inflammation control through the cholinergic anti-inflammatory pathway in numerous pathophysiological contexts. Such diverse physiological and pathological functions that initiate from this receptor may have significant impacts in determining the outcome of different cancers. Various tissues of gastrointestinal (GI) cancers such as gastric, colorectal, pancreatic and liver cancers have shown the up-regulated expression of α7nAChR as compared to normal adjacent tissues. According to the well-established connection between inflammation and tumorigenesis in the digestive system, there are mounting studies demonstrated either stimulatory or inhibitory effects of α7nAChR signaling in the development of GI cancers. To date, the precise underlying mechanisms related to this receptor in patients with GI cancers have not been fully elucidated. Regarding the paradoxical modulatory effects of this receptor in carcinogenesis, in this review, we aim to summarize the accumulated evidence about the involvement of α7nAChR in inflammation-associated GI cancers. It seems that the complex influences of α7nAChR may be a promising target in designing novel strategies in the treatment of such pathologic conditions.
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Affiliation(s)
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Moon SJ, Kim JH, Kong SH, Shin CS. Protein Expression of Cyclin B1, Transferrin Receptor, and Fibronectin Is Correlated with the Prognosis of Adrenal Cortical Carcinoma. Endocrinol Metab (Seoul) 2020; 35:132-141. [PMID: 32207273 PMCID: PMC7090291 DOI: 10.3803/enm.2020.35.1.132] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/25/2019] [Accepted: 01/13/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Adrenal cortical carcinoma (ACC) is a rare cancer with a variable prognosis. Several prognostic factors of ACC have been previously reported, but a proteomic analysis has not yet been performed. This study aimed to investigate prognostic biomarkers for ACC using a proteomic approach. METHODS We used reverse-phase protein array data from The Cancer Proteome Atlas, and identified differentially expressed proteins in metastatic ACCs. Multivariate Cox regression analysis adjusted by age and staging was used for survival analysis, and the C-index and category-free net reclassification improvement (cfNRI) were utilized to evaluate additive prognostic value. RESULTS In 46 patients with ACC, cyclin B1, transferrin receptor (TfR1), and fibronectin were significantly overexpressed in patients with distant metastasis. In multivariate models, high expression of cyclin B1 and TfR1 was significantly associated with mortality (hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.02 to 36.7; and HR, 6.59; 95% CI, 1.14 to 38.2; respectively), whereas high fibronectin expression was not (HR, 3.92; 95% CI, 0.75 to 20.4). Combinations of high cyclin B1/high TfR1, high cyclin B1/high fibronectin, and high TfR1/high fibronectin were strongly associated with mortality ([HR, 13.72; 95% CI, 1.89 to 99.66], [HR, 9.22; 95% CI, 1.34 to 63.55], and [HR, 18.59; 95% CI, 2.54 to 135.88], respectively). In reclassification analyses, cyclin B1, TfR1, fibronectin, and combinations thereof improved the prognostic performance (C-index, 0.78 to 0.82-0.86; cfNRI, all P values <0.05). CONCLUSION In ACC patients, the overexpression of cyclin B1, TfR1, and fibronectin and combinations thereof were associated with poor prognosis.
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Affiliation(s)
- Sun Joon Moon
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul, Korea.
| | - Sung Hye Kong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Chan Soo Shin
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Lee KS, Nam GS, Baek J, Kim S, Nam KS. Inhibition of TPA‑induced metastatic potential by morin hydrate in MCF‑7 human breast cancer cells via the Akt/GSK‑3β/c‑Fos signaling pathway. Int J Oncol 2020; 56:630-640. [PMID: 31939617 DOI: 10.3892/ijo.2020.4954] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/08/2019] [Indexed: 11/06/2022] Open
Abstract
Plant flavonoid 2',3,4',5,7‑pentahydroxyflavone (morin hydrate), isolated from the family Moraceae (Morus alba L.), is known to have anti‑inflammatory and anticancer effects. However, its pharmaceutical effects on metastasis have not been fully elucidated to date. Therefore, the current study investigated the effects of morin hydrate on cancer metastasis in MCF‑7 human breast cancer cells. The results showed that morin hydrate suppressed 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced cell migration and invasion via the inhibition of matrix metalloproteinase (MMP)‑9 activity. Furthermore, gene expression level of MMP‑9, MMP‑7, urokinase plasminogen activator (uPA), uPA receptor (uPAR) and fibronectin were significantly decreased by morin hydrate treatment. Morin hydrate inhibited the phosphorylation of Akt and glycogen synthase kinase (GSK)‑3β, and downregulated the expression of an activator protein‑1 subunit c‑Fos. In addition, the GSK‑3β phosphorylation and c‑Fos expression were suppressed by PI3K/Akt pathway inhibitors, LY294002 and wortmannin. Taken together, these results demonstrated that morin hydrate reduced the metastatic potential in TPA‑treated MCF‑7 human breast cancer cells via the inhibition of MMPs, uPA and uPAR, and the underlying Akt/GSK‑3β/c‑Fos pathway. Therefore, the present investigation suggested that morin hydrate may be a natural substance with a preventive potential for metastasis in breast cancer cells.
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Affiliation(s)
- Kyu-Shik Lee
- Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, Gyeongsangbuk 38066, Republic of Korea
| | - Gi Suk Nam
- Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, Gyeongsangbuk 38066, Republic of Korea
| | - Junyoung Baek
- Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, Gyeongsangbuk 38066, Republic of Korea
| | - Soyoung Kim
- Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, Gyeongsangbuk 38066, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, Gyeongsangbuk 38066, Republic of Korea
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Rigoglio NN, Rabelo ACS, Borghesi J, de Sá Schiavo Matias G, Fratini P, Prazeres PHDM, Pimentel CMMM, Birbrair A, Miglino MA. The Tumor Microenvironment: Focus on Extracellular Matrix. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1245:1-38. [PMID: 32266651 DOI: 10.1007/978-3-030-40146-7_1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The extracellular matrix (ECM) regulates the development and maintains tissue homeostasis. The ECM is composed of a complex network of molecules presenting distinct biochemical properties to regulate cell growth, survival, motility, and differentiation. Among their components, proteoglycans (PGs) are considered one of the main components of ECM. Its composition, biomechanics, and anisotropy are exquisitely tuned to reflect the physiological state of the tissue. The loss of ECM's homeostasis is seen as one of the hallmarks of cancer and, typically, defines transitional events in tumor progression and metastasis. In this chapter, we discuss the types of proteoglycans and their roles in cancer. It has been observed that the amount of some ECM components is increased, while others are decreased, depending on the type of tumor. However, both conditions corroborate with tumor progression and malignancy. Therefore, ECM components have an increasingly important role in carcinogenesis and this leads us to believe that their understanding may be a key in the discovery of new anti-tumor therapies. In this book, the main ECM components will be discussed in more detail in each chapter.
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Affiliation(s)
- Nathia Nathaly Rigoglio
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Carolina Silveira Rabelo
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Jessica Borghesi
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Gustavo de Sá Schiavo Matias
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Paula Fratini
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | - Alexander Birbrair
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria Angelica Miglino
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil.
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Identification of nicotinic acetylcholine receptor subunits in different lung cancer cell lines and the inhibitory effect of alpha-conotoxin TxID on lung cancer cell growth. Eur J Pharmacol 2019; 865:172674. [PMID: 31634461 DOI: 10.1016/j.ejphar.2019.172674] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 09/08/2019] [Accepted: 09/18/2019] [Indexed: 12/24/2022]
Abstract
Lung cancer is an aggressive tumor with high incidence and mortality rate. There was growing evidence supporting that nicotinic acetylcholine receptors (nAChRs) play vital role inlung cancer development. In this study, the expression of α3, α4, α5, α6, α7, α9, α10, β2, β3, β4 nAChR subunits on protein and mRNA level were studied in A549, NCI-H1299, NCI-H1688, DMS114 and normal human embryonic lung fibroblast (HEL) cell lines by real-time quantitative PCR (qPCR) and Western blot assay respectively. The results indicated that most of these nAChR subunits were expressed in these five cell lines. Compared with normal cells, the expression of α3 and β4 nAChR subunits were upregulated in A549 and NCI-H1299. Thus, we treated A549 and NCI-H1299 with an antagonist α-conotoxin TxID which potently and selectively blocks α3β4 nAChRs. TxID treatment could inhibit A549 and NCI-H1299 cell growth and enhance the inhibitory effect of adriamycin when treated simultaneously. To sum up, our study identified the expression of nAChR subunits in different lung cells and the anti-tumor effect of α-conotoxin TxID, which may provide novel strategies for lung cancer therapy.
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Chen S, Kang X, Liu G, Zhang B, Hu X, Feng Y. α7-Nicotinic Acetylcholine Receptor Promotes Cholangiocarcinoma Progression and Epithelial-Mesenchymal Transition Process. Dig Dis Sci 2019; 64:2843-2853. [PMID: 30949902 DOI: 10.1007/s10620-019-05609-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/27/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cholangiocarcinoma is one of the most deadly malignant tumors characterized by a tendency of local invasiveness and metastasis at the early phase, high recurrence rate, and difficulty in treatment. Alpha7-nicotinic acetylcholine receptor (α7-nAChR) is highly expressed in a variety of tumors, including cholangiocarcinoma, and may promote tumor progression, but the mechanisms are largely unknown. AIMS Our study is the first to expound upon the role that α7-nAChR plays in cholangiocarcinoma. METHODS We assessed 50 human cholangiocarcinoma tissue samples and 20 normal biliary samples using immunohistochemical staining to find the correlation between α7-nAChR expression and clinicopathological characteristics. We used human cholangiocarcinoma cell lines QBC939 and RBE and α7-nAChR gene knockdown RBE cell lines generated by shRNA lentivirus transfection to investigate the biological functions of α7-nAChR in proliferation, apoptosis, migration, and invasiveness in vitro. Further, western blotting was used to detect apoptosis and epithelial-mesenchymal transition (EMT)-related signaling proteins. Cholangiocarcinoma xenografts in nude mice were used for tumorigenicity assays in vivo. RESULTS The expression of α7-nAChR was high in cholangiocarcinoma tissues and was closely related to a shorter survival time in patients. α7-nAChR knockdown decreased cell proliferation ability, increased early apoptosis, and weakened cell migration and invasion. Apoptosis-related proteins and components of the EMT process were altered after α7-nAChR knockdown. Moreover, nude mice xenograft experiments confirmed that α7-nAChR could promote cholangiocarcinoma in vitro. CONCLUSIONS Overexpression of α7-nAChR induces cholangiocarcinoma progression by blocking apoptosis and promoting the EMT process. As an effective molecular biomarker and prognostic factor, α7-nAChR is a promising therapeutic target in cholangiocarcinoma.
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Affiliation(s)
- Shuhai Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Xiaoliang Kang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Guangwei Liu
- Department of Outpatient, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Bingyuan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Xiao Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Yujie Feng
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China.
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Li CL, Lin YK, Chen HA, Huang CY, Huang MT, Chang YJ. Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis. J Clin Med 2019; 8:jcm8091391. [PMID: 31492006 PMCID: PMC6780871 DOI: 10.3390/jcm8091391] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 08/29/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective clinical therapeutic strategy for HCC. Smoking is associated with several malignant diseases including cancers. EXPERIMENTAL APPROACH However, the impact of smoking on HCC is still unresolved. Retrospectively reviewed HCC patients diagnosed between 1 January 2010 and 31 December 2015 at Taipei Medical University-Shuang Ho Hospital (Ministry of Health and Welfare). We found that smoking was associated with a poor prognosis, especially recurrence and patient survival after curative surgery using a clinicopathological analysis. RESULTS Our univariate and multivariate analyses showed that the α7-nicotinic acetylcholine receptor (α7-nAChR) was an oncogene and risk factor for post-resection recurrence. The α7-nAChR was overexpressed in HCC tissues compared to their non-tumor counterparts. Silencing the α7-nAChR reduced the viability of HCC cells, suppressed cellular proliferation, attenuated migration and invasion, and diminished the tumor's sphere-formation ability, with concurrent downregulation of expression levels of the TGR5, p-JAK2, p-STAT3 (Tyr705/Ser727), RhoA, ROCK1, MMP2, and MMP9 proteins. Furthermore, a positive correlation was found between α7-nAChR and JAK2 expressions (p = 0.01) in HCC specimens, as well as their membranous co-localization. CONCLUSION Together, we demonstrated that the α7-nAChR may be an independent prognosticator of the progression and prognosis of HCC patients. These findings suggest that the α7-nAChR drives the progression and recurrence of HCC through JAK2/STAT3 signaling and is a novel target for anti-HCC therapy.
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Affiliation(s)
- Ching-Li Li
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Surgery, Sijhih Cathay General Hospital, New Taipei City 221, Taiwan.
| | - Yen-Kuang Lin
- Biostatistics Center, Taipei Medical University, Taipei 110, Taiwan.
| | - Hsin-An Chen
- Department of Surgery, Taipei Medical University, Shuang Ho Hospital, New Taipei City 235, Taiwan.
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Chien-Yu Huang
- Department of Surgery, Taipei Medical University, Shuang Ho Hospital, New Taipei City 235, Taiwan.
| | - Ming-Te Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Surgery, Taipei Medical University, Shuang Ho Hospital, New Taipei City 235, Taiwan.
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- International PhD Program in Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
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Roy NK, Monisha J, Padmavathi G, Lalhruaitluanga H, Kumar NS, Singh AK, Bordoloi D, Baruah MN, Ahmed GN, Longkumar I, Arfuso F, Kumar AP, Kunnumakkara AB. Isoform-Specific Role of Akt in Oral Squamous Cell Carcinoma. Biomolecules 2019; 9:E253. [PMID: 31252679 PMCID: PMC6681224 DOI: 10.3390/biom9070253] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/05/2019] [Accepted: 06/22/2019] [Indexed: 12/15/2022] Open
Abstract
Protein kinase B (Akt) plays a very significant role in various cancers including oral cancer. However, it has three isoforms (Akt1, Akt2, and Akt3) and they perform distinct functions and even play contrasting roles in different cancers. Therefore, it becomes essential to evaluate the isoform-specific role of Akt in oral cancer. In the present study, an attempt has been made to elucidate the isoform-specific role of Akt in oral cancer. The immunohistochemical analysis of oral cancer tissues showed an overexpression of Akt1 and 2 isoforms but not Akt3. Moreover, the dataset of "The Cancer Genome Atlas" for head and neck cancer has suggested the genetic alterations of Akt1 and 2 tend to be associated with the utmost poor clinical outcome in oral cancer. Further, treatment of oral cancer cells with tobacco and its components such as benzo(a)pyrene and nicotine caused increased mRNA levels of Akt1 and 2 isoforms and also enhanced the aggressiveness of oral cancer cells in terms of proliferation, and clonogenic and migration potential. Finally, silencing of Akt1 and 2 isoforms caused decreased cell survival and induced cell cycle arrest at the G2/M phase. Akt1/2 silencing also reduced tobacco-induced aggressiveness by decreasing the clonogenic and migration potential of oral cancer cells. Moreover, silencing of Akt1 and 2 isoforms was found to decrease the expression of proteins regulating cancer cell survival and proliferation such as cyclooxygenase-2, B-cell lymphoma 2 (Bcl-2), cyclin D1, and survivin. Thus, the important role of Akt1 and 2 isoforms have been elucidated in oral cancer with in-depth mechanistic analysis.
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Affiliation(s)
- Nand Kishor Roy
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Javadi Monisha
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ganesan Padmavathi
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - H Lalhruaitluanga
- Department of Biotechnology, Mizoram University, Aizawl, Mizoram 796 004, India
| | | | - Anuj Kumar Singh
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | | | - Gazi Naseem Ahmed
- North-East Cancer Hospital and Research Institute, Guwahati, Assam 781023, India
| | - Imliwati Longkumar
- North-East Cancer Hospital and Research Institute, Guwahati, Assam 781023, India
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6009, Australia
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Medical School, Faculty of Health Sciences, Curtin University, Perth, WA 6845, Australia
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
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Rawat JK, Roy S, Singh M, Guatam S, Yadav RK, Ansari MN, Aldossary SA, Saeedan AS, Kaithwas G. Transcutaneous Vagus Nerve Stimulation Regulates the Cholinergic Anti-inflammatory Pathway to Counteract 1, 2-Dimethylhydrazine Induced Colon Carcinogenesis in Albino wistar Rats. Front Pharmacol 2019; 10:353. [PMID: 31164817 PMCID: PMC6536668 DOI: 10.3389/fphar.2019.00353] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/21/2019] [Indexed: 12/12/2022] Open
Abstract
The present work was undertaken to study the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 1, 2-dimethyhydrazine (DMH) induced colon cancer and role of the cholinergic anti-inflammatory pathways (CAP) in the same. Groups of rats were randomly divided into ten groups (n = 8). DMH administration was very well apparent for autonomic dysfunction as observed through distorted hemodynamic (electrocardiogram and heart rate variability), increased aberrant crypt foci and flat neoplastic lesions (methylene blue staining, scanning electron microscopy and Hematoxylin and eosin staining). DMH administration was also recorded for per-oxidative damage. taVNS application restored the autonomic function, cellular morphology and curtailed the oxidative damage. DMH application conspicuously inhibited the mitochondrial apoptosis which was restored back after taVNS application, when scrutinized through immunoblotting and quantitative real time polymerase chain reaction studies. taVNS application up-regulated the CAP as perceived through increased expression for α7 nicotinic acetylcholine receptor(α7nAchR) and decreased expression for nuclear factor kappa-ligand-chain-enhancer of activated B cells (NFκBp65), tissue necrosis factor-α and high mobility group box-1 at protein and mRNA levels. All in all, taVNS up-surged the CAP to counteract DMH induced colon carcinogenesis. Among all the stimulation parameters used, taVNS 3 (pulse width-1 ms, frequency-6 Hz, voltage-6 v, duration-240 min) was observed to be the most effective. Since only chemotherapy and surgery are available options for management of CRC, which are troublesome and painful, there is currently no non-invasive method available for management of CRC. Results of the current study affirmed the effectiveness of taVNS against DMH induced colon cancer. The present study established taVNS as a novel and non-invasive approach toward the management of CRC.
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Affiliation(s)
- Jitendra K. Rawat
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
| | - Subhadeep Roy
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
| | - Manjari Singh
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
| | - Swetlana Guatam
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
| | - Rajnish K. Yadav
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
| | - Mohd Nazam Ansari
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Sara A. Aldossary
- Department of Pharmaceutical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Abdulaziz S. Saeedan
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Gaurav Kaithwas
- Department of Pharmaceutical Sciences, Baba Saheb Bhimrao Ambedkar Central University Lucknow, Lucknow, India
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Fararjeh AFS, Tu SH, Chen LC, Cheng TC, Liu YR, Chang HL, Chang HW, Huang CC, Wang HCR, Hwang-Verslues WW, Wu CH, Ho YS. Long-term exposure to extremely low-dose of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce non-malignant breast epithelial cell transformation through activation of the a9-nicotinic acetylcholine receptor-mediated signaling pathway. ENVIRONMENTAL TOXICOLOGY 2019; 34:73-82. [PMID: 30259641 DOI: 10.1002/tox.22659] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/03/2018] [Accepted: 09/06/2018] [Indexed: 06/08/2023]
Abstract
Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been detected in cases of second-hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non-tumorigenic breast epithelial cell line, HBL-100 used for a time-course assay, was exposed to very low levels of either Nic or NNK, or both. The time-course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL-100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL-100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co-exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9-nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24- cells, increase Nanog expression and mammosphere-forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses.
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MESH Headings
- Acetylcholine/metabolism
- Breast Neoplasms/chemically induced
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinogens/toxicity
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Cell Transformation, Neoplastic/drug effects
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cells, Cultured
- Dose-Response Relationship, Drug
- Epithelial Cells/drug effects
- Epithelial Cells/physiology
- Female
- Humans
- Mammary Glands, Human/drug effects
- Mammary Glands, Human/pathology
- Mammary Glands, Human/physiology
- Nicotine/toxicity
- Nitrosamines/toxicity
- Receptors, Nicotinic/genetics
- Receptors, Nicotinic/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Time Factors
- Toxicity Tests, Chronic
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Affiliation(s)
- Abdul-Fattah Salah Fararjeh
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
| | - Shih-Hsin Tu
- Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Li-Ching Chen
- Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Chun Cheng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yun-Ru Liu
- TMU Research Center of cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan
| | - Hang-Lung Chang
- Department of General Surgery, En Chun Kong Hospital, New Taipei City, Taiwan
| | - Hui-Wen Chang
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chi-Cheng Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
- Department of Surgery, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan
| | - Hwa-Chain Robert Wang
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA
| | | | - Chih-Hsiung Wu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of General Surgery, En Chun Kong Hospital, New Taipei City, Taiwan
| | - Yuan-Soon Ho
- TMU Research Center of cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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Brenner H, Chen C. The colorectal cancer epidemic: challenges and opportunities for primary, secondary and tertiary prevention. Br J Cancer 2018; 119:785-792. [PMID: 30287914 PMCID: PMC6189126 DOI: 10.1038/s41416-018-0264-x] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 07/27/2018] [Accepted: 08/01/2018] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is both one of the most common and one of the most preventable cancers globally, with powerful but strongly missed potential for primary, secondary and tertiary prevention. CRC incidence has traditionally been the highest in affluent Western countries, but it is now increasing rapidly with economic development in many other parts of the world. CRC shares several main risk factors, such as smoking, excessive alcohol consumption, physical inactivity and being overweight, with other common diseases; therefore, primary prevention efforts to reduce these risk factors are expected to have multiple beneficial effects that extend beyond CRC prevention, and should have high public health impact. A sizeable reduction in the incidence and mortality of CRC can also be achieved by offering effective screening tests, such as faecal immunochemical tests, flexible sigmoidoscopy and colonoscopy, in organised screening programmes which have been implemented in an increasing number of countries. Countries with early and high uptake rates of effective screening have exhibited major declines in CRC incidence and mortality, in contrast to most other countries. Finally, increasing evidence shows that the prognosis and quality of life of CRC patients can be substantially improved by tertiary prevention measures, such as the administration of low-dose aspirin and the promotion of physical activity.
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Affiliation(s)
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Chen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
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34
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Lei Z, Xiaomin Y, He H, Jian C, Xiaowu X. Nicotine downregulates microRNA‐200c to promote metastasis and the epithelial–mesenchymal transition in human colorectal cancer cells. J Cell Physiol 2018; 234:1369-1379. [PMID: 30076725 DOI: 10.1002/jcp.26933] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 06/12/2018] [Indexed: 01/14/2023]
Affiliation(s)
- Zhou Lei
- Department of Gastrointestinal Surgery the 2nd Affiliated Hospital and Children’s Hospital of Wenzhou Medical University Wenzhou China
| | - Yang Xiaomin
- Department of Pathology Wenzhou People’s Hospital Wenzhou China
| | - Huang He
- Department of Gastrointestinal Surgery the 2nd Affiliated Hospital and Children’s Hospital of Wenzhou Medical University Wenzhou China
| | - Chen Jian
- Department of Gastrointestinal Surgery the 2nd Affiliated Hospital and Children’s Hospital of Wenzhou Medical University Wenzhou China
| | - Xu Xiaowu
- Department of Gastrointestinal Surgery the 2nd Affiliated Hospital and Children’s Hospital of Wenzhou Medical University Wenzhou China
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35
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Du X, Qi F, Lu S, Li Y, Han W. Nicotine upregulates FGFR3 and RB1 expression and promotes non-small cell lung cancer cell proliferation and epithelial-to-mesenchymal transition via downregulation of miR-99b and miR-192. Biomed Pharmacother 2018. [PMID: 29518612 DOI: 10.1016/j.biopha.2018.02.113] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Tobacco smoke is by far the greatest risk factor for non-small-cell lung cancer (NSCLC). Nicotine, an active alkaloid in tobacco, is unable to initiate tumorigenesis in humans and rodents, but can promote the growth and metastasis of various tumors, including NSCLC, initiated by tobacco carcinogens. Recently, cigarette smoke is reported to downregulate 24 miRNAs more than 3-fold in the lungs of rats, and most of these downregulated miRNAs are associated with NSCLC initiation and development. Nicotine as the major tobacco component might be associated with the expression changes of some miRNAs. METHODS qRT-PCR was performed to determine the miRNA and mRNA expression, and western blot was conducted to measure protein expression. MTT assay was used to detect cell proliferation. RESULTS The effects of nicotine on the expression of 24 miRNAs in NSCLC cell lines were determined, and the results showed that nicotine treatment decreased miR-99b and miR-192 expression. Cell proliferation and epithelial-to-mesenchymal transition (EMT) detection showed that nicotine promoted NSCLC cell proliferation and EMT, and restoration of miR-99b or miR-192 expression relieved the effects of nicotine on NSCLC cell proliferation and EMT. Subsequently, fibroblast growth factor receptor 3 (FGFR3) and retinoblastoma 1 (RB1) were confirmed to be the targets of miR-99b and miR-192, respectively, and were upregulated by nicotine in NSCLC cells. In addition, FGFR3 or RB1 knockdown inhibited NSCLC cell proliferation and EMT. CONCLUSION This study, for the first time, elucidates nicotine-miR-99b/miR-192-FGFR3/RB1 regulatory network that nicotine promotes NSCLC cell proliferation and EMT by downregulating miR-99b and miR-192, and upregulating their targets FGFR3 and RB1. These findings offer novel insights into the understanding of underlying molecular mechanisms of NSCLC related with the nicotine effects.
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Affiliation(s)
- Xuemei Du
- Department of Pulmonary Medicine, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266011, China
| | - Fei Qi
- Department of Health Education, Qingdao Center for Disease Control and Prevention, Qingdao 266033, China
| | - Sheyu Lu
- Department of Health Education, Laoshan District Center for Disease Control and Prevention, Qingdao 266071, China
| | - Yongchun Li
- Department of Pulmonary Medicine, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266011, China.
| | - Wei Han
- Department of Pulmonary Medicine, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266011, China.
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36
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Tu SH, Lin YC, Huang CC, Yang PS, Chang HW, Chang CH, Wu CH, Chen LC, Ho YS. Protein phosphatase Mg2+/Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated-p53-induced signals. Oncotarget 2018; 7:77516-77531. [PMID: 27769050 PMCID: PMC5363601 DOI: 10.18632/oncotarget.12717] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 10/04/2016] [Indexed: 12/24/2022] Open
Abstract
We previously demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy.
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Affiliation(s)
- Shih-Hsin Tu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.,Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Yin-Ching Lin
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Cheng Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.,Breast Center, Cathay General Hospital, Taipei, Taiwan
| | - Po-Sheng Yang
- Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Hui-Wen Chang
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chien-Hsi Chang
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chih-Hsiung Wu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Surgery, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Li-Ching Chen
- Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.,Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yuan-Soon Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.,Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan.,School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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37
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Ordóñez-Mena JM, Walter V, Schöttker B, Jenab M, O'Doherty MG, Kee F, Bueno-de-Mesquita B, Peeters PHM, Stricker BH, Ruiter R, Hofman A, Söderberg S, Jousilahti P, Kuulasmaa K, Freedman ND, Wilsgaard T, Wolk A, Nilsson LM, Tjønneland A, Quirós JR, van Duijnhoven FJB, Siersema PD, Boffetta P, Trichopoulou A, Brenner H. Impact of prediagnostic smoking and smoking cessation on colorectal cancer prognosis: a meta-analysis of individual patient data from cohorts within the CHANCES consortium. Ann Oncol 2018; 29:472-483. [PMID: 29244072 PMCID: PMC6075220 DOI: 10.1093/annonc/mdx761] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited. Patients and methods For this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology. Results A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04-1.20] and current smoking (HR = 1.29; 95% CI = 1.04-1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69-0.88; HR≥10 years = 0.78; 95% CI = 0.63-0.97) and CRC-specific survival (HR≥10 years = 0.76; 95% CI = 0.67-0.85). Conclusion In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.
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Affiliation(s)
- J M Ordóñez-Mena
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Network Aging Research, University of Heidelberg, Heidelberg, Germany; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - V Walter
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - B Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Network Aging Research, University of Heidelberg, Heidelberg, Germany; Institute of Health Care and Social Sciences, FOM University, Essen, Germany
| | - M Jenab
- International Agency for Research on Cancer (IARC), Lyon, France
| | - M G O'Doherty
- UKCRC Centre of Excellence for Public Health, Queens University of Belfast, Belfast, UK
| | - F Kee
- UKCRC Centre of Excellence for Public Health, Queens University of Belfast, Belfast, UK
| | - B Bueno-de-Mesquita
- Department of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Division of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK; Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - P H M Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - B H Stricker
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - R Ruiter
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - A Hofman
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA
| | - S Söderberg
- Department of Public Health and Clinical Medicine, Cardiology, and Heart Center, Umeå University, Umeå, Sweden
| | - P Jousilahti
- National Institute for Health and Welfare (THL), Helsinki, Finland
| | - K Kuulasmaa
- National Institute for Health and Welfare (THL), Helsinki, Finland
| | - N D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, USA
| | - T Wilsgaard
- Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - A Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - L M Nilsson
- Nutritional Research, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; Arcum, Arctic Research Centre at Umeå University, Umeå, Sweden
| | - A Tjønneland
- Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - J R Quirós
- Public Health Directorate, Asturias, Spain
| | | | - P D Siersema
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - P Boffetta
- Hellenic Health Foundation, Athens, Greece; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - A Trichopoulou
- Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - H Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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38
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Zhang C, Ding XP, Zhao QN, Yang XJ, An SM, Wang H, Xu L, Zhu L, Chen HZ. Role of α7-nicotinic acetylcholine receptor in nicotine-induced invasion and epithelial-to-mesenchymal transition in human non-small cell lung cancer cells. Oncotarget 2018; 7:59199-59208. [PMID: 27409670 PMCID: PMC5312305 DOI: 10.18632/oncotarget.10498] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 06/29/2016] [Indexed: 12/04/2022] Open
Abstract
Nicotine via nicotinic acetylcholine receptors (nAChRs) stimulates non-small cell lung cancer (NSCLC) cell invasion and epithelial to mesenchymal transition (EMT) which underpin the cancer metastasis. However, the receptor subtype-dependent effects of nAChRs on NSCLC cell invasion and EMT, and the signaling pathway underlying the effects remain not fully defined. We identified that nicotine induced NSCLC cell invasion, migration, and EMT; the effects were suppressed by pharmacological intervention using α7-nAChR selective antagonists or by genetic intervention using α7-nAChR knockdown via RNA inference. Meanwhile, nicotine induced activation of MEK/ERK signaling in NSCLC cells; α7-nAChR antagonism or MEK/ERK signaling pathway inhibition suppressed NSCLC cell invasion and EMT marker expression. These results indicate that nicotine induces NSCLC cell invasion, migration, and EMT; the effects are mediated by α7-nAChRs and involve MEK/ERK signaling pathway. Delineating the effect of nicotine on the NSCLC cell invasion and EMT at receptor subtype level would improve the understanding of cancer biology and offer potentials for the exploitation of selective ligands for the control of the cancer metastasis.
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Affiliation(s)
- Chun Zhang
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu-Ping Ding
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qing-Nan Zhao
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xin-Jie Yang
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shi-Min An
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hao Wang
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lu Xu
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Liang Zhu
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hong-Zhuan Chen
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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39
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Dinicola S, Masiello MG, Proietti S, Coluccia P, Fabrizi G, Catizone A, Ricci G, de Toma G, Bizzarri M, Cucina A. Nicotine increases colon cancer cell migration and invasion through epithelial to mesenchymal transition (EMT): COX-2 involvement. J Cell Physiol 2018; 233:4935-4948. [PMID: 29215713 DOI: 10.1002/jcp.26323] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022]
Abstract
Cigarette smoking is a recognized risk factor for colon cancer and nicotine, the principal active component of tobacco, plays a pivotal role in increasing colon cancer cell growth and survival. The aim of this study was to determine the effect of nicotine on cellular Caco-2 and HCT-8 migration and invasion, focusing on epithelial to mesenchymal transition (EMT) induction, and COX-2 pathway involvement. In both these cell lines, treatment with nicotine increased COX-2 expression and the release of its enzymatic product PGE2 . Moreover, nicotine-stimulated cells showed increased migratory and invasive behavior, mesenchymal markers up-regulation and epithelial markers down-regulation, nuclear translocation of the β-catenin, increase of MMP-2 and MMP-9 activity, and enhanced NF-κB expression. Noticeably, all these effects are largely mediated by COX-2 activity, as simultaneous treatment of both cell lines with nicotine and NS-398, a selective COX-2 inhibitor, greatly reduced the number of migrating and invading cells and reverted nicotine-induced EMT. These findings emphasize that nicotine triggers EMT, leading hence to increased migration and invasiveness of colon cancer cells. Thereby, the use of COX-2 inhibitor drugs might likely counteract nicotine-mediated EMT effects on colon cancer development and progression.
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Affiliation(s)
- Simona Dinicola
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.,Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria G Masiello
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.,Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Sara Proietti
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Pierpaolo Coluccia
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Gianmarco Fabrizi
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Angela Catizone
- Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy
| | - Giulia Ricci
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Giorgio de Toma
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Cucina
- Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.,Policlinico Umberto I, Rome, Italy
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40
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Wang DL, Qian XD, Lin YH, Tian BB, Liang HY, Chang L, Wu HY, Zhu DY, Luo CX. ZL006 promotes migration and differentiation of transplanted neural stem cells in male rats after stroke. J Neurosci Res 2017; 95:2409-2419. [PMID: 28512996 DOI: 10.1002/jnr.24068] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 03/29/2017] [Accepted: 03/31/2017] [Indexed: 01/17/2023]
Abstract
New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.
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Affiliation(s)
- Dong-Liang Wang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Xiao-Dan Qian
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Yu-Hui Lin
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Bin-Bin Tian
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Hai-Ying Liang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Lei Chang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.,Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, China
| | - Hai-Yin Wu
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.,Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, China
| | - Dong-Ya Zhu
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.,Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, China.,Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, China
| | - Chun-Xia Luo
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.,Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, China.,Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, China
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41
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Wang JP, Hielscher A. Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting. J Cancer 2017; 8:674-682. [PMID: 28367247 PMCID: PMC5370511 DOI: 10.7150/jca.16901] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/23/2016] [Indexed: 11/24/2022] Open
Abstract
Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis. The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance. In particular, this review will focus on the interactions between cell receptor ligands and fibronectin and how this interaction influences downstream signaling events that aid tumor progression. This review will further discuss the possible implications of therapeutic drugs directed against fibronectin and/or cellular interactions with fibronectin and will additionally discuss novel approaches by which to limit intra- and extra-tumoral fibronectin expression and the cellular events which lead to aberrant fibronectin expression. It is anticipated that these studies will set a basis for future research that will not only aid understanding of fibronectin and its prognostic significance, but will further elucidate novel targets for therapeutics.
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Affiliation(s)
- Jennifer Peyling Wang
- Department of Biomedical Sciences, Georgia-Philadelphia College of Osteopathic Medicine, Suwanee, GA 30024, USA
| | - Abigail Hielscher
- Department of Biomedical Sciences, Georgia-Philadelphia College of Osteopathic Medicine, Suwanee, GA 30024, USA
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42
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Paulo JA, Gygi SP. Nicotine-induced protein expression profiling reveals mutually altered proteins across four human cell lines. Proteomics 2016; 17. [PMID: 27862958 DOI: 10.1002/pmic.201600319] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 10/11/2016] [Accepted: 11/10/2016] [Indexed: 11/10/2022]
Abstract
Mass spectrometry-based proteomic strategies can profile the expression level of proteins in response to external stimuli. Nicotine affects diverse cellular pathways, however, the nicotine-induced alterations on the global proteome across human cell lines have not been fully elucidated. We measured perturbations in protein levels resulting from nicotine treatment in four cell lines-HEK, HeLa, PaSC, and SH-SY5Y-in a single experiment using tandem mass tags (TMT10-plex) and high-resolution mass spectrometry. We quantified 8590 proteins across all cell lines. Of these, nicotine increased the abundance of 31 proteins 1.5-fold or greater in all cell lines. Likewise, considering proteins with altered levels in at least three of the four cell lines, 64 were up-regulated, while one was down-regulated. Gene ontology analysis revealed that ∼40% of these proteins were membrane bound, and functioned in transmembrane signaling and receptor activity. We highlighted proteins, including APP, APLP2, LAPTM4B, and NCOA4, which were dysregulated by nicotine in all cell lines investigated and may have implications in downstream signaling pathways, particularly autophagy. Using the outlined methodology, studies in additional (including primary) cell lines will provide further evidence that alterations in the levels of these proteins are indeed a general response to nicotine and thereby merit further investigation.
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Affiliation(s)
- Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
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43
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Chang YJ, Cheng YW, Lin RK, Huang CC, Chen WTL, Ke TW, Wei PL. Thrombomodulin Influences the Survival of Patients with Non-Metastatic Colorectal Cancer through Epithelial-To-Mesenchymal Transition (EMT). PLoS One 2016; 11:e0160550. [PMID: 27512995 PMCID: PMC4981396 DOI: 10.1371/journal.pone.0160550] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 07/21/2016] [Indexed: 12/29/2022] Open
Abstract
Background Treatment resistance and metastasis are the major causes of death among patients with colorectal cancer (CRC). Approximately 20% of surgically treated patients ultimately develop metastases during the follow-up period. Currently, the TNM system is the only available prognostic test. Therefore, the identification of new markers for CRC remains important. Thrombomodulin (TM), a glycoprotein, is involved in angiogenesis and has been linked to many malignant diseases. However, the function of TM in CRC remains unclear. Methods A total of 170 patients with CRC participated in this study. TM expression was analyzed via immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze patient outcomes, including overall survival (OS) and disease-free survival (DFS). TM expression was manipulated using shRNA or an overexpression system. Transwell migration assays, wound healing migration assays, and the xCELLigence biosensor system were used to detect cell proliferative and migratory capacities. Results TM expression in the tumor tissues significantly and positively correlated with the DFS and OS of non-metastatic patients with CRC (ps = 0.036 and 0.0218, respectively). Suppression of TM expression increased the proliferation and migration of DLD-1 cells. TM overexpression reduced the cells’ proliferative and migratory capacities. Cyclooxygenase (COX)-2 expression was up-regulated following TM silencing. Furthermore, the association between the migration of colon cancer cells and the levels of TM and epithelial-to-mesenchymal transition (EMT) markers (fibronectin, vimentin and ezrin) was confirmed in HT29 and DLD-1 cells. Conclusions Our study demonstrates that patients with non-metastatic CRC display low TM expression in their tumors and exhibit reduced DFS and OS. The enhanced expression of mesenchymal markers and COX-2 may be involved in the mechanisms that underlie recurrence in patients with cancer displaying low TM expression.
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Affiliation(s)
- Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Ya-Wen Cheng
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology,Taipei Medical University, Taipei, Taiwan, ROC
| | - Ruo-Kai Lin
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, ROC
| | - Chi-Chou Huang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
- Department of Surgery, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - William Tzu-Liang Chen
- Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Tao-Wei Ke
- Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, ROC
| | - Po-Li Wei
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology,Taipei Medical University, Taipei, Taiwan, ROC
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC
- * E-mail:
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44
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Lee HM, Kim CW, Hwang KA, Choi DW, Choi KC. Three components of cigarette smoke altered the growth and apoptosis of metastatic colon cancer cells via inducing the synthesis of reactive oxygen species and endoplasmic reticulum stress. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 45:80-9. [PMID: 27262990 DOI: 10.1016/j.etap.2016.05.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 05/16/2016] [Accepted: 05/18/2016] [Indexed: 06/05/2023]
Abstract
Cigarette smoke (CS) is a well-known risk factor for carcinogenesis and has been found to be related to the occurrence and development of colon cancer. In this study, the effect of formaldehyde (FA), benzene (Bz), and isoprene (IP), which are included in main components of CS, on cell viability and apoptosis of SW620 colorectal cancer cells was examined to identify the connection between CS components and colon cancer. In cell viability assay, FA, Bz, and IP decreased cell viability of SW620 cells in a dose dependent manner. In Western blot assay, the protein expression of cell cycle related genes, cyclin D1 & E1, was decreased by FA, Bz, and IP, which corresponded to their inhibitory effect on cell viability. In addition, FA, Bz, and IP increased the protein expression of pro-apoptotic genes, C/EBP homologous protein (CHOP) and Bax, and reduced the protein expression of anti-apoptotic gene, Bcl-2. In reactive oxygen species (ROS) assay using dichlorofluorescin diacetate (DCFH-DA), FA, Bz, and IP increased the ROS production in SW620 cells. In the measurement of apoptotic cells, the numbers of apoptotic cells were increased by the treatment of FA, Bz, and IP. As CHOP is an endoplasmic reticulum (ER)-stress related apoptosis marker of which production is induced by ROS, it was considered that these CS components induce apoptosis of SW620 cells by increasing ROS synthesis and ER-stress. Taken together, these results showed that CS components, i.e., FA, Bz, and IP, inhibited the cell viability of SW620 cells by down-regulating the protein expression of cyclin D1 & E1 and induced apoptosis of SW620 cells by increasing ROS production and simultaneously activating ER-stress.
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Affiliation(s)
- Hae-Miru Lee
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Cho-Won Kim
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-A Hwang
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Dal-Woong Choi
- Department of Public Health Science, Graduate School, Korea University, Seoul, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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45
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Tu CC, Huang CY, Cheng WL, Hung CS, Chang YJ, Wei PL. Silencing A7-nAChR levels increases the sensitivity of gastric cancer cells to ixabepilone treatment. Tumour Biol 2016; 37:9493-501. [PMID: 26790437 DOI: 10.1007/s13277-015-4751-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/29/2015] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer is an important health issue worldwide. Currently, improving the therapeutic efficacy of chemotherapy drugs is an important goal of cancer research. Alpha-7 nicotine acetylcholine receptor (A7-nAChR) is the key molecule that mediates gastric cancer progression, metastasis, and therapy responses; however, the role of A7-nAChR in the therapeutic efficacy of ixabepilone remains unclear. A7-nAChR expression was silenced by small interfering RNA (siRNA) technology. The cytotoxicity of ixabepilone was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and ixabepilone-induced apoptosis was analyzed by flow cytometry and annexin V/propidium iodide (PI) apoptotic assay. The expression patterns of anti-apoptotic proteins (AKT, phospho-AKT, Mcl-1, and Bcl-2) and pro-apoptotic proteins (Bad and Bax) were determined by western blot. Our study found that A7-nAChR knockdown (A7-nAChR-KD) AGS cells were more sensitive to ixabepilone administration than scrambled control AGS cells. We found that A7-nAChR knockdown enhanced ixabepilone-induced cell death as evidenced by the increased number of annexin V-positive (apoptotic) cells. After scrambled control and A7-nAChR-KD cells were treated with ixabepilone, we found that pAKT and AKT levels were significantly reduced in both groups of cells. The levels of Bcl-2 and the anti-apoptotic Mcl-1 isoform increased dramatically after ixabepilone treatment in scrambled control cells but not in A7-nAChR-KD cells. Bad and Bax levels did not change between the treatment group and vehicle group in both A7-nAChR-KD and scrambled control cells, whereas cleaved PARP levels dramatically increased in ixabepilone-treated A7-nAChR-KD cells. Our results demonstrated that knockdown of A7-nAChR enhanced the sensitivity of gastric cancer cells to ixabepilone administration. Thus, the A7-nAChR expression level in patients with gastric cancer may be a good indicator of ixabepilone sensitivity.
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Affiliation(s)
- Chao-Chiang Tu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, New Taipei Hospital, Taipei, Taiwan
| | - Chien-Yu Huang
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wan-Li Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chin-Sheng Hung
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, 250 Wu-Xin Street, Taipei City, 110, Taiwan
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, 250 Wu-Xin Street, Taipei City, 110, Taiwan.
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, 250 Wu-Xin Street, Taipei City, 110, Taiwan.
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Xiang T, Yu F, Fei R, Qian J, Chen W. CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling. Oncol Rep 2015; 35:999-1005. [PMID: 26719016 DOI: 10.3892/or.2015.4462] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 10/23/2015] [Indexed: 11/06/2022] Open
Abstract
The α7 neuronal nicotinic receptor gene (CHRNA7) is widely expressed in both the brain and periphery whereas its encoding protein of α7 neuronal acetylcholine receptor (α7nAChR) belongs to the nicotinic acetylcholine receptor family. Considerable evidence suggests that α7nAChR plays an important role in chronic inflammatory and neuropathic pain signaling and thus has been proposed as a potential target for treating cognitive deficits in patients with schizophrenia, attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease. The aim of the present study was to determine the role of endogenous α7nAChR signaling in human colorectal cancer growth and metastasis. pLVX‑CHRNA7 encoding the full length of CHRNA7 was constructed and transfected into LoVo human colorectal cancer cells. Cell proliferation was measured by Cell Counting Kit‑8 (CCK‑8), and cell migration and invasion were detected by Transwell chamber assays. Expression and activity of metastasis‑related metalloproteinases (MMPs) were analyzed by western blotting and gelatin zymography, respectively. Activation of metastasis-related signaling molecules was detected by western blotting. LY294002 was used to specifically block the phosphatidylinositol 3‑kinase/v‑akt murine thymoma viral oncogene homologue (PI3K/Akt) pathway. We showed that concomitantly with an increase in α7nAChR expression after transfection, LoVo cells presented reduced abilities for migration and invasion, which was accompanied by reduced expression levels of MMP‑1 and MMP‑9 as well as activation of the PI3K/Akt signaling pathway. The application of LY294002 restored the migration and invasion abilities of the LoVo cells bearing CHRNA7. Collectively, we conclude that overexpression of CHRNA7 negatively controls colorectal cancer LoVo cell invasion and metastasis via PI3K/Akt pathway activation and may serve as either a diagnostic marker or a therapeutic target for colorectal cancer metastasis.
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Affiliation(s)
- Tao Xiang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Feng Yu
- Anorectal Department, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
| | - Rushan Fei
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jing Qian
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Research Center of Infection and Immunity, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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Xiang T, Fei R, Wang Z, Shen Z, Qian J, Chen W. Nicotine enhances invasion and metastasis of human colorectal cancer cells through the nicotinic acetylcholine receptor downstream p38 MAPK signaling pathway. Oncol Rep 2015; 35:205-10. [PMID: 26530054 DOI: 10.3892/or.2015.4363] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 09/04/2015] [Indexed: 12/20/2022] Open
Abstract
Nicotine as a cigarette component is an established risk factor for colorectal cancer tumorigenesis. The downstream signaling pathways of nicotinic acetylcholine receptors (nAchRs) are believed to be responsible for the cellular effects. In the present study, we evaluated the effects and novel mechanisms for nicotine on the capacity for colorectal cancer cell invasion and metastasis. LOVO and SW620 colorectal cancer cells were stimulated with nicotine in vitro. A Transwell chamber model was applied to detect the capacity for tumor cell invasion. Assays for gelatin zymography and western blotting were applied to detect the activity and expression of metastasis-related matrix metalloproteinases (MMPs), respectively. Signal transduction was assessed by immunoblotting for the phosphorylation of relevant signal molecules and the application of pharmaceutical inhibitors. We showed that nicotine increased LOVO and SW620 colorectal cancer cell invasion along with enhanced activity and expression of MMP-1, -2 and -9. Nicotine increased phosphorylation of p38, ERK, Akt and PI3K p85 but had no effect on phosphorylation of JNK, or NF-κB. Of the pharmaceutical inhibitors of U0126 (ERK1/2 inhibitor), LY294002 (Akt activation inhibitor), SB239063 (p38 MAPK activation inhibitor) and hexamethonium (Hex) (nAchRs inhibitor), the cellular and molecular effects were reduced by the applications of SB239063 and Hex. We concluded that nicotine stimulates the invasion and metastasis of colon cancer cells in vitro via activation of the nAchRs and the p38 MAPK downstream signaling pathway. Therefore, p38 MAPK may have potential as a therapeutic target for smoking-related human colorectal cancer metastasis.
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Affiliation(s)
- Tao Xiang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Rushan Fei
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhe Wang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhonglei Shen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jing Qian
- Research Center of Infection and Immunity, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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Chen WY, Huang CY, Cheng WL, Hung CS, Huang MT, Tai CJ, Liu YN, Chen CL, Chang YJ. Alpha 7-nicotinic acetylcholine receptor mediates the sensitivity of gastric cancer cells to 5-fluorouracil. Tumour Biol 2015; 36:9537-44. [PMID: 26136123 DOI: 10.1007/s13277-015-3668-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Accepted: 06/15/2015] [Indexed: 11/25/2022] Open
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Ochieng J, Nangami GN, Ogunkua O, Miousse IR, Koturbash I, Odero-Marah V, McCawley L, Nangia-Makker P, Ahmed N, Luqmani Y, Chen Z, Papagerakis S, Wolf GT, Dong C, Zhou BP, Brown DG, Colacci A, Hamid RA, Mondello C, Raju J, Ryan EP, Woodrick J, Scovassi I, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Al-Temaimi R, Al-Mulla F, Bisson WH, Eltom SE. The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis. Carcinogenesis 2015; 36 Suppl 1:S128-S159. [PMID: 26106135 PMCID: PMC4565611 DOI: 10.1093/carcin/bgv034] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 11/14/2014] [Accepted: 11/19/2014] [Indexed: 12/12/2022] Open
Abstract
The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.
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Affiliation(s)
- Josiah Ochieng
- *To whom correspondence should be addressed. Tel: +1 615 327 6119; Fax: +1 615 327 6442;
| | - Gladys N. Nangami
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Olugbemiga Ogunkua
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Valerie Odero-Marah
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Lisa McCawley
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | | | - Nuzhat Ahmed
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
| | - Yunus Luqmani
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Zhenbang Chen
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Silvana Papagerakis
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
| | - Gregory T. Wolf
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
| | - Chenfang Dong
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Binhua P. Zhou
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Roslida A. Hamid
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
| | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
| | - Rabeah Al-Temaimi
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Fahd Al-Mulla
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Sakina E. Eltom
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
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Glucose-regulated protein 78 (GRP78) regulates colon cancer metastasis through EMT biomarkers and the NRF-2/HO-1 pathway. Tumour Biol 2014; 36:1859-69. [PMID: 25431258 DOI: 10.1007/s13277-014-2788-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 10/29/2014] [Indexed: 12/31/2022] Open
Abstract
Glucose-regulated protein 78 (GRP78) is a key chaperone and stress response protein. Previous studies have demonstrated that high GRP78 expression may be correlated with cancer progression and therapeutic response. However, the role of GRP78 in the metastasis of colon cancer is unclear. In this study, we used small interfering RNA (siRNA) to knock down GRP78 expression in colon cancer cells (HT-29 and DLD-1 cells). In wound-healing migration assays, we found that GRP78-knockdown (GRP78KD) cells showed better wound-healing ability than control cells. We also found that GRP78KD cells displayed a better migratory ability than control cells in migration and invasion assays. As we further dissected the underlying molecular mechanism, we found that silencing GRP78 may cause an increase in vimentin expression and a decrease in the E-cadherin level, which was correlated with the increase in migratory ability. In addition, we found that GRP78KD may activate the NRF-2/HO-1 pathway, and this activation was also correlated with the increase in cell invasiveness. Furthermore, we examined GRP78 expression in a tissue array and found that the GRP78 expression in metastatic adenocarcinoma in lymph nodes tended to be weaker than that in primary colonic adenocarcinoma. In conclusion, a low level of GRP78 may cause an increase in metastasis ability in colon cancer cells by altering E-cadherin and vimentin expression and activating the NRF-2/HO-1 signaling pathway. Our study demonstrates that low expression of GRP78 may correlate with a high risk of metastasis in colon cancer.
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