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Barouki R, Samson M, Blanc EB, Colombo M, Zucman-Rossi J, Lazaridis KN, Miller GW, Coumoul X. The exposome and liver disease - how environmental factors affect liver health. J Hepatol 2023; 79:492-505. [PMID: 36889360 PMCID: PMC10448911 DOI: 10.1016/j.jhep.2023.02.034] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 03/10/2023]
Abstract
Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses. It is well known that several liver diseases are associated with i) addictive behaviours such as alcohol consumption, smoking, and to a certain extent dietary imbalance and obesity, ii) viral and parasitic infections, and iii) exposure to toxins and occupational chemicals. Recent studies indicate that environmental exposures are also significantly associated with liver diseases, and these include air pollution (particulate matter and volatile chemicals), contaminants such as polyaromatic hydrocarbons, bisphenol A and per-and poly-fluorinated substances, and physical stressors such as radiation. Furthermore, microbial metabolites and the "gut-liver" axis play a major role in liver diseases. Exposomics is poised to play a major role in the field of liver pathology. Methodological advances such as the exposomics-metabolomics framework, the determination of risk factors' genomic and epigenomic signatures, and cross-species biological pathway analysis should further delineate the impact of the exposome on the liver, opening the way for improved prevention, as well as the identification of new biomarkers of exposure and effects, and additional therapeutic targets.
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Affiliation(s)
| | - Michel Samson
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | | | - Massimo Colombo
- San Raffaele Hospital, Liver Center, Via Olgettina 60, 20132, Milan, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, AP-HP, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, F-75006, Paris, France
| | | | - Gary W Miller
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, 10032, USA
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Zhao JY, Yuan XK, Luo RZ, Wang LX, Gu W, Yamane D, Feng H. Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction. Front Immunol 2023; 14:1107239. [PMID: 37063830 PMCID: PMC10102619 DOI: 10.3389/fimmu.2023.1107239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/22/2023] [Indexed: 04/03/2023] Open
Abstract
Phospholipase A and acyltransferase (PLAAT) 4 is a class II tumor suppressor with phospholipid metabolizing abilities. It was characterized in late 2000s, and has since been referred to as 'tazarotene-induced gene 3' (TIG3) or 'retinoic acid receptor responder 3' (RARRES3) as a key downstream effector of retinoic acid signaling. Two decades of research have revealed the complexity of its function and regulatory roles in suppressing tumorigenesis. However, more recent findings have also identified PLAAT4 as a key anti-microbial effector enzyme acting downstream of interferon regulatory factor 1 (IRF1) and interferons (IFNs), favoring protection from virus and parasite infections. Unveiling the molecular mechanisms underlying its action may thus open new therapeutic avenues for the treatment of both cancer and infectious diseases. Herein, we aim to summarize a brief history of PLAAT4 discovery, its transcriptional regulation, and the potential mechanisms in tumor prevention and anti-pathogen defense, and discuss potential future directions of PLAAT4 research toward the development of therapeutic approaches targeting this enzyme with pleiotropic functions.
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Affiliation(s)
- Jian-Yong Zhao
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Xiang-Kun Yuan
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Rui-Zhen Luo
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Li-Xin Wang
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Wei Gu
- School of Medicine, Chongqing University, Chongqing, China
| | - Daisuke Yamane
- Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hui Feng
- School of Medicine, Chongqing University, Chongqing, China
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3
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Hussein D, Alsereihi R, Salwati AAA, Algehani R, Alhowity A, Al-Hejin AM, Schulten HJ, Baeesa S, Bangash M, Alghamdi F, Cross R, Al Zughaibi T, Saka M, Chaudhary A, Abuzenadah A. The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses. Cancer Cell Int 2022; 22:387. [PMID: 36482387 PMCID: PMC9730595 DOI: 10.1186/s12935-022-02814-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Glioblastomas (GBs) are characterised as one of the most aggressive primary central nervous system tumours (CNSTs). Single-cell sequencing analysis identified the presence of a highly heterogeneous population of cancer stem cells (CSCs). The proteins anterior gradient homologue 2 (AGR2) and glucose-regulated protein 78 (GRP78) are known to play critical roles in regulating unfolded protein response (UPR) machinery. The UPR machinery influences cell survival, migration, invasion and drug resistance. Hence, we investigated the role of AGR2 in drug-resistant recurrent glioblastoma cells. METHODS Immunofluorescence, biological assessments and whole exome sequencing analyses were completed under in situ and in vitro conditions. Cells were treated with CNSTs clinical/preclinical drugs taxol, cisplatin, irinotecan, MCK8866, etoposide, and temozolomide, then resistant cells were analysed for the expression of AGR2. AGR2 was repressed using single and double siRNA transfections and combined with either temozolomide or irinotecan. RESULTS Genomic and biological characterisations of the AGR2-expressed Jed66_GB and Jed41_GB recurrent glioblastoma tissues and cell lines showed features consistent with glioblastoma. Immunofluorescence data indicated that AGR2 co-localised with the UPR marker GRP78 in both the tissue and their corresponding primary cell lines. AGR2 and GRP78 were highly expressed in glioblastoma CSCs. Following treatment with the aforementioned drugs, all drug-surviving cells showed high expression of AGR2. Prolonged siRNA repression of a particular region in AGR2 exon 2 reduced AGR2 protein expression and led to lower cell densities in both cell lines. Co-treatments using AGR2 exon 2B siRNA in conjunction with temozolomide or irinotecan had partially synergistic effects. The slight reduction of AGR2 expression increased nuclear Caspase-3 activation in both cell lines and caused multinucleation in the Jed66_GB cell line. CONCLUSIONS AGR2 is highly expressed in UPR-active CSCs and drug-resistant GB cells, and its repression leads to apoptosis, via multiple pathways.
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Affiliation(s)
- Deema Hussein
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Reem Alsereihi
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Biological Sciences, Faculty of Science, King Abdulaziz University, 80203, Jeddah, 21589 Saudi Arabia ,College of Health Sciences, Al-Rayan Colleges, 41411, Madinah AL-Munawarah, Saudi Arabia
| | - Abdulla Ahmed A. Salwati
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Rinad Algehani
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Alazouf Alhowity
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Ahmed M. Al-Hejin
- grid.412125.10000 0001 0619 1117Department of Biological Sciences, Faculty of Science, King Abdulaziz University, 80203, Jeddah, 21589 Saudi Arabia
| | - Hans-Juergen Schulten
- grid.412125.10000 0001 0619 1117Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Saleh Baeesa
- grid.412125.10000 0001 0619 1117Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Mohammed Bangash
- grid.412125.10000 0001 0619 1117Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Fahad Alghamdi
- grid.412125.10000 0001 0619 1117Pathology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Richard Cross
- grid.48815.300000 0001 2153 2936School of Engineering and Sustainable Development, Emerging Technologies Research Centre (EMTERC), De Montfort University, The Gateway, Leicester, LE1 9BH UK
| | - Torki Al Zughaibi
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Mohamad Saka
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Adeel Chaudhary
- grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Centre of Innovation for Personalized Medicine, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Adel Abuzenadah
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Centre of Innovation for Personalized Medicine, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
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Chen L, Yuan F, Chen S, Li X, Kong L, Zhang W. Potential Role of Host Microbiome in Areca Nut-Associated Carcinogenesis and Addiction. Molecules 2022; 27:8171. [PMID: 36500264 PMCID: PMC9739811 DOI: 10.3390/molecules27238171] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/21/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Areca nut (AN) is widely consumed all over the world, bringing great harm to human health and economy. Individuals with AN chewing are at high risk of cardiovascular disease and impaired immune system and metabolic system. Despite a growing number of studies having reported on the adverse effects brought by AN chewing, the exact mechanism of it is limited and the need for additional exploration remains. In recent years, the interaction between microorganisms, especially intestinal microorganism and host, has been extensively studied. AN chewing might disrupt the oral and intestinal microbiota communities through direct connect with the microbes it contains, altering PH, oxygen of oral and intestinal microenvironment, and disturbing the immune homeostasis. These mechanisms provide insights into the interplay between areca nut and host microbiota. Emerging studies have proposed that bidirectional interaction between polyphenols and intestinal microbes might play a potential role in the divergence of polyphenol, extracted from AN, among individuals with or without AN-induced cancer development and progression. Although some AN chewers have been aware of the harmful effects brought by AN, they cannot abolish this habit because of the addiction of AN. Increasing studies have tried to revealed that gut microbiota might influence the onset/development of addictive behaviors. Altogether, this review summarizes the possible reasons for the disturbance of host microbiota caused by areca nut chewing and clarifies the complex interaction between human microbiome and major constituents and the addiction and carcinogenicity of AN, tempting to provide novel insights into the development and utilization of it, and to control the adverse consequences caused by AN chewing.
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Affiliation(s)
- Lihui Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410078, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 110 Xiangya Road, Changsha 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, China
| | - Fulai Yuan
- Health Management Center, Xiangya Hospital, Central South University, Changsha 410078, China
| | - Sifang Chen
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen 361000, China
| | - Xiong Li
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510060, China
| | - Lingyu Kong
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410078, China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 110 Xiangya Road, Changsha 410078, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, China
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Licata P, Piccione G, Fazio F, Lauriano ER, Calò M. Protective effects of genistein on cytochrome P-450 and vitellogenin expression in liver of zebrafish after PCB-126 exposure. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 674:71-76. [PMID: 31004905 DOI: 10.1016/j.scitotenv.2019.03.467] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/25/2019] [Accepted: 03/30/2019] [Indexed: 06/09/2023]
Abstract
The objective of the research is to study the action of Vitellogenin and P-4501A1 following coexposure at different times to genistein and PCB-126 using zebrafish as a model system. Polychlorinated biphenyls are ubiquitous substances in environment. The genistein is a phytoestrogen extracted from soybeans and it's contained in food for humans and animals. For this study, 200 adult zebrafish were used. Our findings show a marked immunoreactivity of Vtg at 12h in liver than the control with only PCB-126. Regarding effects of PCB-126 on Vtg after pretreatment with genistein in fishes, the immunohistochemistry results show a minor increase at 12h. After 24h the immunoreactivity is lower than 12h and then slightly increased at 72h with only PCB-126 and PCB-126 and genistein together. CYP1A1 progressively increases from 12h to 72h in all groups with minor immunoreactivity when we treated fish with genistein and PCB-126. We show a reduction in the estrogenic effect when the fishes were treated with genistein and PCB-126 together at 12h than the group treated with only PCB-126. Moreover, low concentrations of genistein decrease the marked P450 expression induced by PCB-126. This shows that genistein decreases the expression of P450 target genes mediated by AhR.
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Affiliation(s)
- Patrizia Licata
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy.
| | - Giuseppe Piccione
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy
| | - Francesco Fazio
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy
| | - Eugenia Rita Lauriano
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Margherita Calò
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy
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Alsereihi R, Schulten HJ, Bakhashab S, Saini K, Al-Hejin AM, Hussein D. Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer. Cancers (Basel) 2019; 11:890. [PMID: 31247903 PMCID: PMC6678570 DOI: 10.3390/cancers11070890] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 12/15/2022] Open
Abstract
Effective diagnostic, prognostic and therapeutic biomarkers can help in tracking disease progress, predict patients' survival, and considerably affect the drive for successful clinical management. The present review aims to determine how the metastatic-linked protein anterior gradient homologue 2 (AGR2) operates to affect cancer progression, and to identify associated potential diagnostic, prognostic and therapeutic biomarkers, particularly in central nervous system (CNS) tumors. Studies that show a high expression level of AGR2, and associate the protein expression with the resilience to chemotherapeutic treatments or with poor cancer survival, are reported. The primary protein structures of the seven variants of AGR2, including their functional domains, are summarized. Based on experiments in various biological models, this review shows an orchestra of multiple molecules that regulate AGR2 expression, including a feedback loop with p53. The AGR2-associated molecular functions and pathways including genomic integrity, proliferation, apoptosis, angiogenesis, adhesion, migration, stemness, and inflammation, are detailed. In addition, the mechanisms that can enable the rampant oncogenic effects of AGR2 are clarified. The different strategies used to therapeutically target AGR2-positive cancer cells are evaluated in light of the current evidence. Moreover, novel associated pathways and clinically relevant deregulated genes in AGR2 high CNS tumors are identified using a meta-analysis approach.
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Affiliation(s)
- Reem Alsereihi
- Neurooncology Translational Group, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Saudi Arabia.
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia.
| | - Hans-Juergen Schulten
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Sherin Bakhashab
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Jeddah 21589, Saudi Arabia.
| | - Kulvinder Saini
- School of Biotechnology, Eternal University, Baru Sahib-173101, Himachal Pradesh, India.
| | - Ahmed M Al-Hejin
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia.
- Microbiology Unit, King Fahad Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
| | - Deema Hussein
- Neurooncology Translational Group, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Saudi Arabia.
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study. Cancer Lett 2019; 449:125-134. [PMID: 30685412 DOI: 10.1016/j.canlet.2019.01.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/27/2018] [Accepted: 01/21/2019] [Indexed: 11/24/2022]
Abstract
Increased drug resistance and acute side effects on normal organs are the major disadvantages of traditional cancer chemotherapy and radiotherapy. This has increased the focus on targeted therapeutic strategies such as monoclonal antibody-based cancer therapies. The major advantage of antibody-based therapies is the specific inhibition of cancer-related targets, with reduced off-target side effects. Anterior gradient-2 (AGR2) is a prometastatic and proangiogenic tumor marker that is overexpressed in multiple cancers. Therefore, anti-AGR2 antibodies may be potential therapeutic agents for treating different cancers. In the present study, we examined a novel anti-AGR2 monoclonal antibody mAb18A4 and found that this antibody inhibited lung cancer progression and metastasis without exerting any adverse side effects on the major organs and blood in mice. Moreover, we found that mAb18A4 activated p53 pathway and attenuated ERK1/2-MAPK pathway. Furthermore, mAb18A4-treated cancer cell lines showed attenuated proliferation and colony formation, enhanced apoptosis, increased p53 expression, and reduced phosphorylated ERK1/2 expression. Treatment with mAb18A4 significantly reduced tumor size and suppressed tumor metastasis in and increased the survival of different xenograft tumor models. In addition, mAb18A4 potently suppressed AGR2-induced angiogenesis. Results of pharmacokinetic and toxicological analyses confirmed the safety of mAb18A4 as an antitumor treatment.
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8
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Xue P, Fu J, Zhou Y. The Aryl Hydrocarbon Receptor and Tumor Immunity. Front Immunol 2018; 9:286. [PMID: 29487603 PMCID: PMC5816799 DOI: 10.3389/fimmu.2018.00286] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 01/31/2018] [Indexed: 01/31/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor. Emerging evidence suggests the promoting role of the AhR in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Studies on various tumor types and tumor cell lines have shown high AhR expression, suggesting that AhR is activated constitutively in tumors and facilitates their growth. Interestingly, immune evasion has been recognized as an emerging hallmark feature of cancer. A connection between the AhR and immune system has been recognized, which has been suggested as an immunosuppressive effector on different types of immune cells. Certain cancers can escape immune recognition via AhR signaling pathways. This review discusses the role of the AhR in tumor immunity and its potential mechanism of action in the tumor microenvironment.
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Affiliation(s)
- Ping Xue
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jinrong Fu
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yufeng Zhou
- Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Neonatal Diseases, Ministry of Health, Shanghai, China
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Flores-Pérez A, Elizondo G. Apoptosis induction and inhibition of HeLa cell proliferation by alpha-naphthoflavone and resveratrol are aryl hydrocarbon receptor-independent. Chem Biol Interact 2018; 281:98-105. [DOI: 10.1016/j.cbi.2017.12.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 11/30/2017] [Accepted: 12/18/2017] [Indexed: 12/20/2022]
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10
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Xue X, Fei X, Hou W, Zhang Y, Liu L, Hu R. miR-342-3p suppresses cell proliferation and migration by targeting AGR2 in non-small cell lung cancer. Cancer Lett 2017; 412:170-178. [PMID: 29107102 DOI: 10.1016/j.canlet.2017.10.024] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/18/2017] [Accepted: 10/18/2017] [Indexed: 01/13/2023]
Abstract
AGR2 is a well-studied secreted protein that is involved in multiple biological processes including cell proliferation and migration. The mechanism by which AGR2 increases the growth and migration of non-small cell lung cancer cells (NSCLC) is still unknown. In this study, we report that AGR2 is directly targeted by miR-342-3p. Functional studies suggest that overexpression of miR-342-3p inhibits the proliferation and migration of non-small cell lung cancer cells. Overexpression of AGR2 counteracts the phenotypes induced by miR-342-3p. Moreover, AGR2 expression is up-regulated and negatively correlated with miR-342-3p levels in NSCLC cells and tissues. A meta-analysis of survival data indicates that NSCLC patients with high levels of AGR2 in their tumors have a worse prognosis. Collectively, the identification of miR-342-3p and AGR2 might facilitate the development of biomarkers and therapeutic targets for this devastating disease.
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Affiliation(s)
- Xiaofeng Xue
- The First Affiliated Hospital of Soochow University, Jiangsu, 215006, China.
| | - Xiaoyan Fei
- Department of Biochemistry, University of Texas Southwestern Medical Center, 5390 Harry Hines, Dallas, TX, 75390, USA
| | - Wenjie Hou
- The First Affiliated Hospital of Soochow University, Jiangsu, 215006, China
| | - Yajie Zhang
- Department of Biochemistry, University of Texas Southwestern Medical Center, 5390 Harry Hines, Dallas, TX, 75390, USA
| | - Liu Liu
- Department of General Surgery, Anhui Provincial Hospital Affiliated to the an Hui Medical University, Hefei, China
| | - Rongkuan Hu
- Department of Biochemistry, University of Texas Southwestern Medical Center, 5390 Harry Hines, Dallas, TX, 75390, USA; Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, China.
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11
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Calò M, Licata P, Bitto A, Lo Cascio P, Giarratana F, Altavilla D. Effects of PCB-126 on aryl hydrocarbon receptor, ubiquitin and p53 expression levels in Sparus aurata. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2017:S0940-2993(16)30221-4. [PMID: 28552628 DOI: 10.1016/j.etp.2017.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 04/06/2017] [Indexed: 06/07/2023]
Abstract
The aim of the present study is to determine if Ahr ligands as PCB-126, a dioxin-like, might contribute to inhibition of the tumor suppressor p53 by promoting its degradation through proteasome-ubiquitin system (UPS). The findings show, in the presence of PCB-126, a significant increase of p53 immunoreactivity in fish compared to the control. Subsequently, there is a decrease of p53 immunoreactivity at 24h which is maintained even at 72h. At the same time there is a slight decrease of ubiquitin immunoreactivity to 12h compared to the control and a marked decrease to 24 and 72h. The induction of ubiquitin expression is resulted very marked in the control and preserved at 12h. It's very important to underline as in our study we demonstrate a marked decrease of ubiquitin and p53 immunoreactivity at 24h and 72h. AHR activation, by ligands as PCB-126, increases p53 ubiquitation inhibiting its expression, in addition it decreases the free ubiquitin promoting disruption of Ub homeostasis; this is the first report that establishes a relationship between AhR, increases p53 ubiquitation, and reduction of free ubiquitin. Our result emphasize the need to deeply the role of this receptor in UPS regulation as potential therapeutic target for cancer treatment.
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Affiliation(s)
- M Calò
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy.
| | - P Licata
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy
| | - A Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica, 5th Floor, AOU Policlinico "G. Martino", Via C. Valeria Gazzi, 98125, Messina, Italy
| | - P Lo Cascio
- Department of Biological and Environmental Sciences, University of Messina, Salita Sperone 31, S. Agata, Messina, 98166, Italy
| | - F Giarratana
- Department of Veterinary Science, University of Messina, Polo SS Annunziata, 98168 Messina, Italy
| | - D Altavilla
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica, 5th Floor, AOU Policlinico "G. Martino", Via C. Valeria Gazzi, 98125, Messina, Italy
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12
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Calò M, Bitto A, Lo Cascio P, Giarratana F, Altavilla D, Gervasi T, Campone L, Cicero N, Licata P. PCB-126 effects on aryl hydrocarbon receptor, ubiquitin and p53 expression levels in a fish product (Sparus aurata L.). Nat Prod Res 2017; 32:1136-1144. [DOI: 10.1080/14786419.2017.1320794] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Margherita Calò
- Department of Veterinary Science, University of Messina, Messina, Italy
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Patrizia Lo Cascio
- Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy
| | | | - Domenica Altavilla
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Teresa Gervasi
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Luca Campone
- Department of Pharmacy, University of Salerno, Fisciano SA, Italy
| | - Nicola Cicero
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
- Science4Life, Spin Off Company, University of Messina, Messina, Italy
| | - Patrizia Licata
- Department of Veterinary Science, University of Messina, Messina, Italy
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13
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Siest G, Auffray C, Taniguchi N, Ingelman-Sundberg M, Murray H, Visvikis-Siest S, Ansari M, Marc J, Jacobs P, Meyer U, Van Schaik RHN, Müller MM, Wevers RA, Simmaco M, Kussmann M, Manolopoulos VG, Alizadeh BZ, Beastall G, Németh G. Systems medicine, personalized health and therapy. Pharmacogenomics 2015; 16:1527-39. [PMID: 26401575 DOI: 10.2217/pgs.15.103] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The 7th Santorini Conference was held in Santorini, Greece, and brought together 200 participants from 40 countries in several continents, including Europe, USA but also Japan, Korea, Brazil and South Africa. The attendees had the opportunity to: listen to 60 oral presentations; participate in two lunch symposia; look at 103 posters, which were divided in two groups ('systems medicine and environment' and 'pharmacogenomics and cancer') and attend a dedicated exhibition with six companies. The meeting was organized by the Institut National de la Santé et de la Recherche Médicale (INSERM) U1122; IGE-PCV and by 'Biologie Prospective' with the collaboration of the European Society of Pharmacogenomics and Theranostics (ESPT), under the auspices of international organizations (e.g., International Federation of Clinical Chemistry and Laboratory medicine [IFCC], European Federation of Clinical Chemistry and Laboratory Medicine [EFLM], European Diagnostic Manufacturers Association [EDMA], Federation of European Pharmacological Societies [EPHAR], European Science Foundation [ESF]). The 3 days of the conference stimulated intensive discussions on systems biology and the influence of omics technologies on personalized health. Sixty speakers were invited or selected from early abstracts and gave presentations on the following topics: From systems biology to systems medicine/pharmacology; Omics/translating pharmacogenomics/proteomic biomarkers/metabolomics; Human nutrition and health/personalized medicine. We are summarizing here the main topics and presentations, according to the successive sessions.
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Affiliation(s)
- Gérard Siest
- University of Lorraine, UMR INSERM U1122, IGE-PCV, Nancy, France
| | - Charles Auffray
- European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, France
| | | | | | - Helena Murray
- Randox Laboratories Limited, Crumlin, Co. Antrim, UK
| | | | - Marc Ansari
- Pediatric Department, Onco-Hematology Unit, Geneva University Hospital, Geneva Switzerland/Geneva University Medical School, CANSEARCH Research Laboratory, Geneva, Switzerland
| | - Janja Marc
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | | | - Urs Meyer
- Biozentrum, University of Basel, Basel, Switzerland
| | | | - Mathias M Müller
- Austrian Society of Quality Assurance and standardisation, ÖQUASTA
| | - Ron A Wevers
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Maurizio Simmaco
- Department of Neurosciences, Faculty of Medicine & Psychology, Sapienza University of Rome, Rome, Italy
| | | | - Vangelis G Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University Medical Center Groningen, The Netherlands
| | - Graham Beastall
- International Federation of Clinical Chemistry & Laboratory Medicine President, US
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14
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Spryszyńska S, Smok-Pieniążek A, Ferlińska M, Roszak J, Nocuń M, Stępnik M. The influence of ATM, ATR, DNA-PK inhibitors on the cytotoxic and genotoxic effects of dibenzo[def,p]chrysene on human hepatocellular cancer cell line HepG2. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2015; 791:12-24. [PMID: 26338538 DOI: 10.1016/j.mrgentox.2015.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/09/2015] [Accepted: 07/21/2015] [Indexed: 02/06/2023]
Abstract
The effect of inhibitors of phosphatidylinositol-3-kinase related kinases (PIKK): ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR) and DNA-dependent protein kinase (DNA-PK) on the response of HepG2 human liver cancer cells to dibenzo[def,p]chrysene (DBC) was investigated. High cytotoxicity of DBC (IC50=0.1μM) was observed after 72h incubation. PIKK inhibitors: KU55933 (5μM), NU7026 (10μM) or caffeine (1 and 2mM) when used alone did not significantly influence the cytotoxicity. However, two combinations: KU55933/NU7026 and caffeine/NU7026 significantly increased HepG2 viability (by 25%) after treatment with DBC at 0.5μM. The cytoprotective effect was confirmed by cell cycle and apoptosis/necrosis analysis. DNA damage level after exposure to DBC assessed by comet assay (single strand breaks) showed a long persistence and significant decrease after incubation of the cells in the presence the inhibitors (the combination of KU55933+NU7026 showed the strongest effect). Weak induction of reactive oxygen species (ROS) by DBC (0.5μM) was observed. Although, KU55933 and NU7026 when used alone did not increase ROS levels in the cells, their combination induced the ROS increase and moderately enhanced ROS generation by DBC. We propose a mechanism how cells with damaged DNA after exposure to DBC and under the condition of PIKK inhibition, may be at higher risk of undergoing malignant transformation.
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Affiliation(s)
- Sylwia Spryszyńska
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
| | - Anna Smok-Pieniążek
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
| | - Magdalena Ferlińska
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
| | - Joanna Roszak
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
| | - Marek Nocuń
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
| | - Maciej Stępnik
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland.
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Becker RA, Patlewicz G, Simon TW, Rowlands JC, Budinsky RA. The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor. Regul Toxicol Pharmacol 2015; 73:172-90. [PMID: 26145830 DOI: 10.1016/j.yrtph.2015.06.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/19/2015] [Accepted: 06/22/2015] [Indexed: 12/29/2022]
Abstract
An Adverse Outcome Pathway (AOP) represents the existing knowledge of a biological pathway leading from initial molecular interactions of a toxicant and progressing through a series of key events (KEs), culminating with an apical adverse outcome (AO) that has to be of regulatory relevance. An AOP based on the mode of action (MOA) of rodent liver tumor promotion by dioxin-like compounds (DLCs) has been developed and the weight of evidence (WoE) of key event relationships (KERs) evaluated using evolved Bradford Hill considerations. Dioxins and DLCs are potent aryl hydrocarbon receptor (AHR) ligands that cause a range of species-specific adverse outcomes. The occurrence of KEs is necessary for inducing downstream biological responses and KEs may occur at the molecular, cellular, tissue and organ levels. The common convention is that an AOP begins with the toxicant interaction with a biological response element; for this AOP, this initial event is binding of a DLC ligand to the AHR. Data from mechanistic studies, lifetime bioassays and approximately thirty initiation-promotion studies have established dioxin and DLCs as rat liver tumor promoters. Such studies clearly show that sustained AHR activation, weeks or months in duration, is necessary to induce rodent liver tumor promotion--hence, sustained AHR activation is deemed the molecular initiating event (MIE). After this MIE, subsequent KEs are 1) changes in cellular growth homeostasis likely associated with expression changes in a number of genes and observed as development of hepatic foci and decreases in apoptosis within foci; 2) extensive liver toxicity observed as the constellation of effects called toxic hepatopathy; 3) cellular proliferation and hyperplasia in several hepatic cell types. This progression of KEs culminates in the AO, the development of hepatocellular adenomas and carcinomas and cholangiolar carcinomas. A rich data set provides both qualitative and quantitative knowledge of the progression of this AOP through KEs and the KERs. Thus, the WoE for this AOP is judged to be strong. Species-specific effects of dioxins and DLCs are well known--humans are less responsive than rodents and rodent species differ in sensitivity between strains. Consequently, application of this AOP to evaluate potential human health risks must take these differences into account.
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Affiliation(s)
- Richard A Becker
- Regulatory and Technical Affairs Department, American Chemistry Council (ACC), Washington, DC 20002, USA.
| | - Grace Patlewicz
- DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE 19711, USA
| | - Ted W Simon
- Ted Simon LLC, 4184 Johnston Road, Winston, GA 30187, USA
| | - J Craig Rowlands
- The Dow Chemical Company, Toxicology & Environmental Research & Consulting, 1803 Building Washington Street, Midland, MI 48674, USA
| | - Robert A Budinsky
- The Dow Chemical Company, Toxicology & Environmental Research & Consulting, 1803 Building Washington Street, Midland, MI 48674, USA
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Shishkin SS, Eremina LS, Kovalev LI, Kovaleva MA. AGR2, ERp57/GRP58, and some other human protein disulfide isomerases. BIOCHEMISTRY (MOSCOW) 2014; 78:1415-30. [PMID: 24490732 DOI: 10.1134/s000629791313004x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
This review considers the major features of human proteins AGR2 and ERp57/GRP58 and of other members of the protein disulfide isomerase (PDI) family. The ability of both AGR2 and ERp57/GRP58 to catalyze the formation of disulfide bonds in proteins is the parameter most important for assigning them to a PDI family. Moreover, these proteins and also other members of the PDI family have specific structural features (thioredoxin-like domains, special C-terminal motifs characteristic for proteins localized in the endoplasmic reticulum, etc.) that are necessary for their assignment to a PDI family. Data demonstrating the role of these two proteins in carcinogenesis are analyzed. Special attention is given to data indicating the presence of biomarker features in AGR2 and ERp57/GRP58. It is now thought that there is sufficient reason for studies of AGR2 and ERp57/GRP58 for possible use of these proteins in diagnosis of tumors. There are also prospects for studies on AGR2 and ERp57/GRP58 leading to developments in chemotherapy. Thus, we suppose that further studies on different members of the PDI family using modern postgenomic technologies will broaden current concepts about functions of these proteins, and this will be helpful for solution of urgent biomedical problems.
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Affiliation(s)
- S S Shishkin
- Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow, 119071, Russia.
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17
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Tsai CF, Hsieh TH, Lee JN, Hsu CY, Wang YC, Lai FJ, Kuo KK, Wu HL, Tsai EM, Kuo PL. Benzyl butyl phthalate induces migration, invasion, and angiogenesis of Huh7 hepatocellular carcinoma cells through nongenomic AhR/G-protein signaling. BMC Cancer 2014; 14:556. [PMID: 25081364 PMCID: PMC4131049 DOI: 10.1186/1471-2407-14-556] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 07/18/2014] [Indexed: 01/04/2023] Open
Abstract
Background The widespread use of phthalates as plasticizers has raised public health concerns regarding their adverse effects, including an association with cancer. Although animal investigations have suggested an association between phthalate exposure and hepatocellular carcinoma, the mechanisms are unknown. Methods The hepatocellular carcinoma cell line Huh7 was treated with benzyl butyl phthalate (BBP), and then analyzed by total internal reflection fluorescence microscopy, confocal microscopy and double immunogold transmission electron microscopy. Following BBP treatment, mRNA levels were measured by RT-PCR, protein levels were measured using western blot, and vascular endothelial growth factor levels were measured by an enzyme-linked immunosorbent assay. Cell migration and invasion assays were evaluated by transwell, and angiogenesis were performed by a tube formation assay. Nude mice were used to investigate metastasis and angiogenesis in vivo. Results BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action. BBP treatment promoted cell migration and invasion in vitro and metastasis in vivo via the AhR/Gβ/PI3K/Akt/NF-κB pathway. In addition, BBP induced both in vitro and in vivo angiogenesis through the AhR/ERK/VEGF pathway. Conclusions These findings suggest a novel nongenomic AhR mechanism involving G-protein signaling induced by phthalates, which contributes to tumor progression of hepatocellular carcinoma. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-556) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Eing-Mei Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
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Li H, Wang J, Yang LM, Ning HB. Clinical significance of expression of anterior gradient-2 in colon adenocarcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:1064-1069. [DOI: 10.11569/wcjd.v22.i8.1064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of anterior gradient-2 (AGR2) in colon adenocarcinoma and the relationship between AGR2 expression and clinicopathological features of colon adenocarcinoma.
METHODS: AGR2 mRNA and protein expression in colon adenocarcinoma and tumor-adjacent non-cancerous tissues was detected by semi-quantitative RT-PCR, Western blot and immunohistochemistry.
RESULTS: The expression of AGR2 mRNA and protein in colon adenocarcinoma was significantly higher than that in tumor-adjacent non-cancerous tissues (0.95 ± 0.03 vs 0.21 ± 0.06, 0.93 ± 0.03 vs 0.31 ± 0.02, P < 0.05 for both). The positive rate of AGR2 expression in colon adenocarcinoma was significantly higher than that in tumor-adjacent non-cancerous tissues (75% vs 29.4%, P < 0.05). The expression of AGR2 was correlated with Dukes stage, histopathological grade and lymph node metastasis (P < 0.05 for all), but not with other clinicopathologic factors.
CONCLUSION: Our findings indicate that the expression of AGR2 is closely related to the tumorigenesis, progression and metastasis of colon adenocarcinoma. AGR2 may be used as a diagnostic marker for colon adenocarcinoma.
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Vega L, Elizondo G. Aryl hydrocarbon receptor as a new therapeutic target for cancer and immune disorders. World J Pharmacol 2013; 2:107-114. [DOI: 10.5497/wjp.v2.i4.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 07/20/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) was discovered more than three decades ago, and initially was characterized as a transcription factor with a role in xenobiotic metabolism. However, based on subsequent observations that AhR remains active under physiological conditions, exhibits constitutive expression during development, and has a high degree of conservation among species, it was hypothesized that AhR is responsible for functions in addition to its role in detoxification. Correspondingly, recent studies have elucidated novel physiological roles for this ligand-dependent transcription factor that link it to several pathways associated with disease development. In this review, studies are presented that support a role for AhR in cell proliferation, apoptosis, and immune homeostasis, thereby highlighting the therapeutic potential of this receptor for cancer and immune disorders.
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20
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Budinsky RA, Schrenk D, Simon T, Van den Berg M, Reichard JF, Silkworth JB, Aylward LL, Brix A, Gasiewicz T, Kaminski N, Perdew G, Starr TB, Walker NJ, Rowlands JC. Mode of action and dose–response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study. Crit Rev Toxicol 2013; 44:83-119. [DOI: 10.3109/10408444.2013.835787] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Safe S, Lee SO, Jin UH. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol Sci 2013; 135:1-16. [PMID: 23771949 PMCID: PMC3748760 DOI: 10.1093/toxsci/kft128] [Citation(s) in RCA: 217] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/03/2013] [Indexed: 12/22/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is highly expressed in multiple organs and tissues, and there is increasing evidence that the AHR plays an important role in cellular homeostasis and disease. The AHR is expressed in multiple tumor types, in cancer cell lines, and in tumors from animal models, and the function of the AHR has been determined by RNA interference, overexpression, and inhibition studies. With few exceptions, knockdown of the AHR resulted in decreased proliferation and/or invasion and migration of cancer cell lines, and in vivo studies in mice overexpressing the constitutively active AHR exhibited enhanced stomach and liver cancers, suggesting a pro-oncogenic role for the AHR. In contrast, loss of the AHR in transgenic mice that spontaneously develop colonic tumors and in carcinogen-induced liver tumors resulted in increased carcinogenesis, suggesting that the receptor may exhibit antitumorigenic activity prior to tumor formation. AHR ligands also either enhanced or inhibited tumorigenesis, and these effects were highly tumor specific, demonstrating that selective AHR modulators that exhibit agonist or antagonist activities represent an important new class of anticancer agents that can be directed against multiple tumors.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466, USA.
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Feng S, Cao Z, Wang X. Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta Rev Cancer 2013; 1836:197-210. [PMID: 23711559 DOI: 10.1016/j.bbcan.2013.05.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 05/14/2013] [Accepted: 05/17/2013] [Indexed: 01/01/2023]
Abstract
Aryl hydrocarbon receptor (AHR), a cytosolic ligand-activated transcription factor, belongs to the member of bHLH/PAS family of heterodimeric transcriptional regulators and is widely expressed in a variety of animal species and humans. Recent animal and human data suggested that AHR is involved in various signaling pathways critical to cell normal homeostasis, which covers multiple aspects of physiology, such as cell proliferation and differentiation, gene regulation, cell motility and migration, inflammation and others. Dysregulation of these physiological processes is known to contribute to events such as tumor initiation, promotion, and progression. Increasing epidemiological and experimental animal data provided substantial support for an association between abnormal AHR function and cancer, implicating AHR may be a novel drug-interfering target for cancers. The proposed underlying mechanisms of its actions in cancer involved multiple aspects, (a) inhibiting the functional expression of the key anti-oncogenes (such as p53 and BRCA1), (b) promoting stem cells transforming and angiogenesis, (c) altering cell survival, proliferation and differentiation by influencing the physiologic processes of cell-cycle, apoptosis, cell contact-inhibition, metabolism and remodel of extracellular matrix, and cell-matrix interaction, (d) cross-talking with the signaling pathways of estrogen receptor and inflammation. This review aims to provide a brief overview of recent investigations into the role of AHR and the underlying mechanisms of its actions in cancer, which were explored by the new technologies emerging in recent years.
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Affiliation(s)
- Shaolong Feng
- The School of Public Health, University of South China, Hengyang 421001, China.
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Salmans ML, Zhao F, Andersen B. The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker. Breast Cancer Res 2013; 15:204. [PMID: 23635006 PMCID: PMC3672732 DOI: 10.1186/bcr3408] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Initially discovered as an estrogen-responsive gene in breast cancer cell lines, anterior gradient 2 (AGR2) is a developmentally regulated gene belonging to the protein disulfide isomerase (PDI) gene family. Developmentally, AGR2 is expressed in the mammary gland in an estrogen-dependent manner, and AGR2 knockout and overexpression mouse models indicate that the gene promotes lobuloalveolar development by stimulating cell proliferation. Although AGR2 overexpression alone seems insufficient for breast tumorigenesis in mice, several lines of investigations suggest that AGR2 promotes breast tumorigenesis. Overexpression of AGR2 in several breast cancer cell lines increases cell survival in clonogenic assays and cell proliferation, whereas AGR2 loss of function leads to decreased cell cycle progression and cell death. In addition, AGR2 was shown to promote metastasis of breast epithelial cells in an in vivo metastasis assay. As a PDI, AGR2 is thought to be involved in the unfolded protein response that alleviates endoplasmic reticulum stress. Since cancer has to overcome proteotoxic stress due to excess protein production, AGR2 may be one of many pro-survival factors recruited to assist in protein folding or degradation or both. When AGR2 is secreted, it plays a role in cellular adhesion and dissemination of metastatic tumor cells. In breast cancer, AGR2 expression is associated with estrogen receptor (ER)-positive tumors; its overexpression is a predictor of poor prognosis. The AGR2 gene is directly targeted by ER-alpha, which is preferentially bound in tumors with poor outcome. Whereas aromatase inhibitor therapy decreases AGR2 expression, tamoxifen acts as an agonist of AGR2 expression in ER-positive tumors, perhaps contributing to tamoxifen resistance. AGR2 is also overexpressed in a subset of ER-negative tumors. Furthermore, AGR2 expression is associated with the dissemination of metastatic breast cancer cells and can be used as a marker to identify circulating tumor cells and metastatic cells in sentinel lymph nodes. In conclusion, AGR2 is a promising drug target in breast cancer and may serve as a useful prognostic indicator as well as a marker of breast cancer metastasis.
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Norris AM, Gore A, Balboni A, Young A, Longnecker DS, Korc M. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 2012; 32:3867-76. [PMID: 22945649 PMCID: PMC3515713 DOI: 10.1038/onc.2012.394] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 07/11/2012] [Accepted: 07/16/2012] [Indexed: 12/14/2022]
Abstract
The mechanisms controlling expression of the putative oncogene AGR2 in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a TGF-β-responsive gene in human pancreatic cancer cells, whose down-regulation is SMAD4-dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is co-expressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-KrasG12D/Smad4lox/lox mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the up-regulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.
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Affiliation(s)
- A M Norris
- Department of Medicine, Dartmouth Medical School, Hanover, NH, USA
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The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway. Oncogene 2012; 32:1811-20. [PMID: 22665056 DOI: 10.1038/onc.2012.197] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is commonly described as a transcription factor, which regulates xenobiotic-metabolizing enzymes. Recent studies have suggested that the binding of ligands to the AhR also activates the Src kinase. In this manuscript, we show that the AhR, through the activation of Src, activates focal adhesion kinase (FAK) and promotes integrin clustering. These effects contribute to cell migration. Further, we show that the activation of the AhR increases the interaction of FAK with the metastatic marker, HEF1/NEDD9/CAS-L, and the expression of several integrins. Xenobiotic exposure, thus, may contribute to novel cell-migratory programs.
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Health and cellular impacts of air pollutants: from cytoprotection to cytotoxicity. Biochem Res Int 2012; 2012:493894. [PMID: 22550588 PMCID: PMC3328890 DOI: 10.1155/2012/493894] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 01/17/2012] [Accepted: 01/18/2012] [Indexed: 12/11/2022] Open
Abstract
Air pollution as one of the ravages of our modern societies is primarily linked to urban centers, industrial activities, or road traffic. These atmospheric pollutants have been incriminated in deleterious health effects by numerous epidemiological and in vitro studies. Environmental air pollutants are a heterogeneous mixture of particles suspended into a liquid and gaseous phase which trigger the disruption of redox homeostasis—known under the term of cellular oxidative stress—in relation with the establishment of inflammation and cell death via necrosis, apoptosis, or autophagy. Activation or repression of the apoptotic process as an adaptative response to xenobiotics might lead to either acute or chronic toxicity. The purpose of this paper is to highlight the central role of oxidative stress induced by air pollutants and to focus on the subsequent cellular impacts ranging from cytoprotection to cytotoxicity by decreasing or stimulating apoptosis, respectively.
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Chopra M, Schrenk D. Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-persistent pollutants affect programmed cell death. Crit Rev Toxicol 2011; 41:292-320. [PMID: 21323611 DOI: 10.3109/10408444.2010.524635] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Exogenous ligands of the aryl hydrocarbon receptor (AhR) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related substances are highly toxic pollutants ubiquitously present in the environment. They cause a variety of toxic effects to different organs and tissues. Among other effects, TCDD exposure to laboratory animals leads to thymus atrophy and immunosuppression on the one hand, and to tumor formation on the other. Apoptosis appears to be involved in both these toxic effects: AhR activation by TCDD was discussed to induce apoptosis of immune cells, leading to the depletion of thymocytes and ultimately immunosuppression. This mechanism could help to explain the highly immunotoxic actions of TCDD but it is nevertheless under debate whether this is the mode of action for immunosuppression by this class of chemical substances. In other cell types, especially liver cells, TCDD inhibits apoptosis induced by genotoxic treatment. In initiation-promotion studies, TCDD was shown to be a potent liver tumor promoter. Among other theories it was hypothesized that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis. The exact mechanisms of apoptosis inhibition by TCDD are not fully understood, but both in vivo and in vitro studies consistently showed an involvement of the tumor suppressor p53 in this effect. Various strings of evidence have been established linking apoptosis to the detrimental effects of exogenous activation of the AhR. Within this article, studies elucidating the effects of TCDD and related substances on apoptosis signaling, be it inducing or repressing, is to be reviewed.
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Affiliation(s)
- Martin Chopra
- Institute of Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany
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Polycyclic aromatic hydrocarbon components contribute to the mitochondria-antiapoptotic effect of fine particulate matter on human bronchial epithelial cells via the aryl hydrocarbon receptor. Part Fibre Toxicol 2010; 7:18. [PMID: 20663163 PMCID: PMC2914693 DOI: 10.1186/1743-8977-7-18] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Accepted: 07/21/2010] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Nowadays, effects of fine particulate matter (PM2.5) are well-documented and related to oxidative stress and pro-inflammatory response. Nevertheless, epidemiological studies show that PM2.5 exposure is correlated with an increase of pulmonary cancers and the remodeling of the airway epithelium involving the regulation of cell death processes. Here, we investigated the components of Parisian PM2.5 involved in either the induction or the inhibition of cell death quantified by different parameters of apoptosis and delineated the mechanism underlying this effect. RESULTS In this study, we showed that low levels of Parisian PM2.5 are not cytotoxic for three different cell lines and primary cultures of human bronchial epithelial cells. Conversely, a 4 hour-pretreatment with PM2.5 prevent mitochondria-driven apoptosis triggered by broad spectrum inducers (A23187, staurosporine and oligomycin) by reducing the mitochondrial transmembrane potential loss, the subsequent ROS production, phosphatidylserine externalization, plasma membrane permeabilization and typical morphological outcomes (cell size decrease, massive chromatin and nuclear condensation, formation of apoptotic bodies). The use of recombinant EGF and specific inhibitor led us to rule out the involvement of the classical EGFR signaling pathway as well as the proinflammatory cytokines secretion. Experiments performed with different compounds of PM2.5 suggest that endotoxins as well as carbon black do not participate to the antiapoptotic effect of PM2.5. Instead, the water-soluble fraction, washed particles and organic compounds such as polycyclic aromatic hydrocarbons (PAH) could mimic this antiapoptotic activity. Finally, the activation or silencing of the aryl hydrocarbon receptor (AhR) showed that it is involved into the molecular mechanism of the antiapoptotic effect of PM2.5 at the mitochondrial checkpoint of apoptosis. CONCLUSIONS The PM2.5-antiapoptotic effect in addition to the well-documented inflammatory response might explain the maintenance of a prolonged inflammation state induced after pollution exposure and might delay repair processes of injured tissues.
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