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1
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Burke S. Hypoxia, NSAIDs, and autism: A biocultural analysis of stressors in gametogenesis. Am J Hum Biol 2024; 36:e24042. [PMID: 38282542 DOI: 10.1002/ajhb.24042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/30/2024] Open
Abstract
Cultural and generational trends have increasingly favored "anti-inflammatory" action, innovating a new class of analgesic, non-steroidal anti-inflammatory drugs (NSAIDs) in the 20th century. The modern human body has been molded over evolutionary time and while acknowledging inflammation can be pathologically entwined, it also serves an important role in healthy folliculogenesis and ovulation, shaping cues that drive needed vascular change. This review argues that because of anti-inflammatory action, the cultural invention of NSAIDs represents a particular stressor on female reproductive-age bodies, interacting with natural, underlying variation and placing limits on healthy growth and development in the follicles, creating potential autism risk through hypoxia and mutagenic or epigenetic effects. Since testes are analogs to ovaries, the biological grounding extends naturally to spermatogenesis. This review suggests the introduction of over-the-counter NSAIDs in the 1980s failed to recognize the unique functioning of reproductive-age bodies, challenging the cyclical inflammation needed for healthy gamete development. NSAIDs are framed as one (notable) stressor in an anti-inflammatory era focused on taming the risks of inflammation in modern human life.
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Affiliation(s)
- Stacie Burke
- Department of Anthropology, University of Manitoba, Winnipeg, Manitoba, Canada
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2
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Rigazio CS, Mariz-Ponte N, Caballero EP, Penas FN, Goren NB, Santamaría MH, Corral RS. Involvement of glycoinositolphospholipid from Trypanosoma cruzi and macrophage migration inhibitory factor in proinflammatory mechanisms promoting cardiovascular injury mechanisms promoting cardiovascular inflammation tThe combined action of glycoinositolphospholipid from Trypanosoma cruzi and macrophage migration inhibitory factor increases proinflammatory mediator production by cardiomyocytes and vascular endothelial cells. Microb Pathog 2022; 173:105881. [DOI: 10.1016/j.micpath.2022.105881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/14/2022]
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Pujals M, Resar L, Villanueva J. HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location! Biomolecules 2021; 11:1334. [PMID: 34572547 PMCID: PMC8468999 DOI: 10.3390/biom11091334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/27/2021] [Accepted: 09/01/2021] [Indexed: 12/13/2022] Open
Abstract
The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene expression and downstream signaling pathways. However, the discovery of an extracellular HMGA1-RAGE autocrine loop in invasive triple-negative breast cancer (TNBC) cell lines implicates HMGA1 as a "moonlighting protein" with different functions depending upon cellular location. Here, we review the role of HMGA1, not only as a chromatin regulator in cancer and stem cells, but also as a potential secreted factor that drives tumor progression. Prior work found that HMGA1 is secreted from TNBC cell lines where it signals through the receptor for advanced glycation end products (RAGE) to foster phenotypes involved in tumor invasion and metastatic progression. Studies in primary TNBC tumors also suggest that HMGA1 secretion associates with distant metastasis in TNBC. Given the therapeutic potential to target extracellular proteins, further work to confirm this role in other contexts is warranted. Indeed, crosstalk between nuclear and secreted HMGA1 could change our understanding of tumor development and reveal novel therapeutic opportunities relevant to diverse human cancers overexpressing HMGA1.
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Affiliation(s)
- Mireia Pujals
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain;
| | - Linda Resar
- Department of Medicine, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Departments of Medicine (Hematology), Oncology, Pathology and Institute of Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Pathobiology, Cellular and Molecular Medicine and Human Genetics Graduate Programs, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Josep Villanueva
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain;
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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4
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Tutino VM, Zebraski HR, Rajabzadeh-Oghaz H, Waqas M, Jarvis JN, Bach K, Mokin M, Snyder KV, Siddiqui AH, Poppenberg KE. Identification of Circulating Gene Expression Signatures of Intracranial Aneurysm in Peripheral Blood Mononuclear Cells. Diagnostics (Basel) 2021; 11:1092. [PMID: 34203780 PMCID: PMC8232768 DOI: 10.3390/diagnostics11061092] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022] Open
Abstract
Peripheral blood mononuclear cells (PBMCs) play an important role in the inflammation that accompanies intracranial aneurysm (IA) pathophysiology. We hypothesized that PBMCs have different transcriptional profiles in patients harboring IAs as compared to IA-free controls, which could be the basis for potential blood-based biomarkers for the disease. To test this, we isolated PBMC RNA from whole blood of 52 subjects (24 with IA, 28 without) and performed next-generation RNA sequencing to obtain their transcriptomes. In a randomly assigned discovery cohort of n = 39 patients, we performed differential expression analysis to define an IA-associated signature of 54 genes (q < 0.05 and an absolute fold-change ≥ 1.3). In the withheld validation dataset, these genes could delineate patients with IAs from controls, as the majority of them still had the same direction of expression difference. Bioinformatics analyses by gene ontology enrichment analysis and Ingenuity Pathway Analysis (IPA) demonstrated enrichment of structural regulation processes, intracellular signaling function, regulation of ion transport, and cell adhesion. IPA analysis showed that these processes were likely coordinated through NF-kB, cytokine signaling, growth factors, and TNF activity. Correlation analysis with aneurysm size and risk assessment metrics showed that 4/54 genes were associated with rupture risk. These findings highlight the potential to develop predictive biomarkers from PBMCs to identify patients harboring IAs.
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Affiliation(s)
- Vincent M. Tutino
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, NY 14203, USA
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
- Department of Mechanical and Aerospace Engineering, University at Buffalo, Buffalo, NY 14228, USA
| | - Haley R. Zebraski
- Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14228, USA;
| | - Hamidreza Rajabzadeh-Oghaz
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
| | - Muhammad Waqas
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
| | - James N. Jarvis
- Department of Pediatrics, University at Buffalo, Buffalo, NY 14203, USA;
| | - Konrad Bach
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33620, USA; (K.B.); (M.M.)
| | - Maxim Mokin
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33620, USA; (K.B.); (M.M.)
| | - Kenneth V. Snyder
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
| | - Adnan H. Siddiqui
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
| | - Kerry E. Poppenberg
- Canon Stroke and Vascular Research Center, University at Buffalo, Buffalo, NY 14203, USA; (H.R.-O.); (M.W.); (K.V.S.); (A.H.S.); (K.E.P.)
- Department of Neurosurgery, University at Buffalo, Buffalo, NY 14203, USA
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Eligini S, Colli S, Habib A, Aldini G, Altomare A, Banfi C. Cyclooxygenase-2 Glycosylation Is Affected by Peroxynitrite in Endothelial Cells: Impact on Enzyme Activity and Degradation. Antioxidants (Basel) 2021; 10:496. [PMID: 33806920 PMCID: PMC8005028 DOI: 10.3390/antiox10030496] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/15/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
The exposure of human endothelial cells to 3-morpholinosydnonimine (SIN-1) induced the expression of cyclooxygenase-2 (COX-2) in a dose- and time-dependent manner. Interestingly, after a prolonged incubation (>8 h) several proteoforms were visualized by Western blot, corresponding to different states of glycosylation of the protein. This effect was specific for SIN-1 that generates peroxynitrite and it was not detected with other nitric oxide-donors. Metabolic labeling experiments using 35S or cycloheximide suggested that the formation of hypoglycosylated COX-2 was dependent on de novo synthesis of the protein rather than the deglycosylation of the native protein. Moreover, SIN-1 reduced the activity of the hexokinase, the enzyme responsible for the first step of glycolysis. The hypoglycosylated COX-2 induced by SIN-1 showed a reduced capacity to generate prostaglandins and the activity was only partially recovered after immunoprecipitation. Finally, hypoglycosylated COX-2 showed a more rapid rate of degradation compared to COX-2 induced by IL-1α and an alteration in the localization with an accumulation mainly detected in the nuclear membrane. Our results have important implication to understand the effect of peroxynitrite on COX-2 expression and activity, and they may help to identify new pharmacological tools direct to increase COX-2 degradation or to inhibit its activity.
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Affiliation(s)
- Sonia Eligini
- Centro Cardiologico Monzino I.R.C.C.S., 20138 Milan, Italy;
| | - Susanna Colli
- Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Aida Habib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon;
- INSERM-UMR1149, Centre de Recherche sur l’Inflammation, and Sorbonne Paris Cité, Laboratoire d’Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université de Paris, 75018 Paris, France
| | - Giancarlo Aldini
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, 20133 Milano, Italy; (G.A.); (A.A.)
| | - Alessandra Altomare
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, 20133 Milano, Italy; (G.A.); (A.A.)
| | - Cristina Banfi
- Centro Cardiologico Monzino I.R.C.C.S., 20138 Milan, Italy;
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Hypoxia-Inducible Factor 1A Upregulates HMGN5 by Increasing the Expression of GATA1 and Plays a Role in Osteosarcoma Metastasis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5630124. [PMID: 31930127 PMCID: PMC6942741 DOI: 10.1155/2019/5630124] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/10/2019] [Indexed: 11/17/2022]
Abstract
Osteosarcoma is one of the most common malignant tumors in children and adolescents and is characterized by early metastasis. High-mobility group N (HMGN) domains are involved in the development of several tumors. Our previous study found that HMGN5 is highly expressed in osteosarcoma tissues and knockdown of HMGN5 inhibits migration and invasion of U-2 OS and Saos-2 cells. A hypoxic environment is commonly found in solid tumors such as osteosarcoma and is likely to be associated with tumor metastasis, so we further explored the relationship between HMGN5 and the hypoxic environment. Hypoxia-inducible factor 1A (HIF1A) is an adaptive factor in the hypoxic environment. We found that HIF1A and HMGN5 were upregulated in osteosarcoma (OS) cells cultured in the hypoxic environment, and the results of overexpression and knockdown experiments showed that HIF1A upregulated the transcription factor GATA1 and further promoted the expression of HMGN5. In addition, MMP2 and MMP9 were subsequently upregulated through the c-jun pathway, and finally, this promoted the migration and invasion of OS cells. It is suggested that HMGN5 may be an important downstream factor for HIF1A to promote osteosarcoma metastasis. It has an important clinical significance for the selection of therapeutic targets for osteosarcoma.
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Li XJ, Huang FZ, Wan Y, Li YS, Zhang WK, Xi Y, Tian GH, Tang HB. Lipopolysaccharide Stimulated the Migration of NIH3T3 Cells Through a Positive Feedback Between β-Catenin and COX-2. Front Pharmacol 2018; 9:1487. [PMID: 30618773 PMCID: PMC6305731 DOI: 10.3389/fphar.2018.01487] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 12/04/2018] [Indexed: 02/03/2023] Open
Abstract
How β-catenin/COX-2 contribute to inflammation-induced fibroblasts migration remains poorly understood. Therefore, in this study, lipopolysaccharide (LPS) was used as a stimulus to accelerate the migration of NIH3T3 cells, which mimicked the tissue repair process. LPS treatment increased the cell migration in concentration-and time-dependent manner. And NS398, a COX-2 inhibitor, inhibited LPS-induced NIH3T3 cells migration. DKK-1, an antagonist of the Wnt/β-catenin signaling, also inhibited that migration. However, TWS119, an inducer of β-catenin via GSK-3β, increased the cell migration. LPS or TWS119 treatment increased COX-2, β-catenin, TGF-β1, and HMGB-1 expressions, and that could be attenuated by NS398 or DKK-1 addition. LPS induced the PGE2 production, and PGE2 increased the expression and nuclear translocation of β-catenin, while EP2 blocker, AH6809, alleviated those effects. TWS119 increased the luciferase activity in the COX-2 promoter. In conclusion, LPS stimulated the NIH3T3 fibroblasts migration through a positive feedback between β-catenin and COX-2, in which PGE2, EP2, TGF-β1, and HMGB-1 played as signal molecules.
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Affiliation(s)
- Xiao-Jun Li
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Feng-Zhen Huang
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yan Wan
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yu-Sang Li
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Wei Kevin Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yang Xi
- School of Medicine, Institute of Biochemistry and Molecular Biology, Ningbo University, Ningbo, China
| | - Gui-Hua Tian
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - He-Bin Tang
- Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China.,Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.,Research Institute of Huazhong University of Science and Technology, Shenzhen, China
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8
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Resar L, Chia L, Xian L. Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression. Cancer Res 2018; 78:1890-1897. [PMID: 29618461 DOI: 10.1158/0008-5472.can-17-3045] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/05/2017] [Accepted: 01/31/2018] [Indexed: 11/16/2022]
Abstract
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890-7. ©2018 AACR.
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Affiliation(s)
- Linda Resar
- Department of Medicine, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Departments of Oncology, Pathology and Institute of Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lionel Chia
- Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lingling Xian
- Department of Medicine, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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9
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Broadgate S, Kiire C, Halford S, Chong V. Diabetic macular oedema: under-represented in the genetic analysis of diabetic retinopathy. Acta Ophthalmol 2018; 96 Suppl A111:1-51. [PMID: 29682912 DOI: 10.1111/aos.13678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies.
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Affiliation(s)
- Suzanne Broadgate
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Christine Kiire
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
- Oxford Eye Hospital; John Radcliffe Hospital; Oxford University NHS Foundation Trust; Oxford UK
| | - Stephanie Halford
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Victor Chong
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
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Sumter TF, Xian L, Huso T, Koo M, Chang YT, Almasri TN, Chia L, Inglis C, Reid D, Resar LMS. The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development. Curr Mol Med 2016; 16:353-93. [PMID: 26980699 DOI: 10.2174/1566524016666160316152147] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 02/15/2016] [Accepted: 03/10/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND & OBJECTIVES Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 "transcriptome" is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer's disease and type-2 diabetes. CONCLUSION Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - L M S Resar
- Department of Medicine, Faculty of the Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, MD 21205-2109, USA.
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Chiefari E, Ventura V, Capula C, Randazzo G, Scorcia V, Fedele M, Arcidiacono B, Nevolo MT, Bilotta FL, Vitiello M, Palmieri C, Gulletta E, Fusco A, Foti D, Vero R, Brunetti A. A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression. Sci Rep 2016; 6:39429. [PMID: 27991577 PMCID: PMC5171873 DOI: 10.1038/srep39429] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 11/22/2016] [Indexed: 12/18/2022] Open
Abstract
Diabetic retinopathy (DR) is a major complication of diabetes mellitus, and is the leading cause of blindness in working-age people. Usually, DR progresses from the asymptomatic non-proliferative DR that does not significantly alter vision, to proliferative DR (PDR), which can result in aberrant retinal neovessel formation and blindness. The High-Mobility-Group A1 (HMGA1) protein is a transcriptional master regulator of numerous genes, including metabolic and inflammatory genes, which, by modulating the expression of angiogenic factors, may induce retinal neovascularization, a hallmark of PDR. Herein, we examined the relationship between HMGA1 rs139876191 variant and DR. Results revealed that patients with type 2 diabetes, who were carriers of the HMGA1 rs139876191 variant had a significantly lower risk of developing PDR, compared to non-carrier diabetic patients. From a mechanistic point of view, our findings indicated that, by adversely affecting HMGA1 protein expression and function, the HMGA1 rs139876191 variant played a key role in this protective mechanism by downregulating the expression of vascular endothelial growth factor A (VEGFA), a major activator of neovascularization in DR. These data provide new insights into the pathogenesis and progression of DR, and may offer opportunities for discovering novel biomarkers and therapeutic targets for diagnosis, prevention and treatment of PDR.
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Affiliation(s)
- Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Valeria Ventura
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Carmelo Capula
- Operative Unit of Endocrinology and Diabetes, Hospital Pugliese-Ciaccio, Catanzaro, Italy
| | - Giorgio Randazzo
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Vincenzo Scorcia
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Monica Fedele
- Institute of Experimental Endocrinology and Oncology, CNR, Napoli, Italy
| | - Biagio Arcidiacono
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Maria Teresa Nevolo
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | | | - Michela Vitiello
- Institute of Experimental Endocrinology and Oncology, CNR, Napoli, Italy
| | - Camillo Palmieri
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Elio Gulletta
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Alfredo Fusco
- Institute of Experimental Endocrinology and Oncology, CNR, Napoli, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Napoli, Italy
| | - Daniela Foti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Raffaella Vero
- Operative Unit of Endocrinology and Diabetes, Hospital Pugliese-Ciaccio, Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
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12
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Cheung CY. Vascular Endothelial Growth Factor Activation of Intramembranous Absorption: A Critical Pathway for Amniotic Fluid Volume Regulation. ACTA ACUST UNITED AC 2016; 11:63-74. [PMID: 14980307 DOI: 10.1016/j.jsgi.2003.09.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The purpose of this review is to propose a critical role for vascular endothelial growth factor (VEGF) in mediating the transfer of amniotic fluid from the amniotic compartment through the fetal membranes and fetal surface of the placenta into fetal blood. METHODS Experimental findings in humans and animal models on the action of VEGF in mediating fluid transfer are reviewed and interpreted in order to postulate a proposed mechanism for VEGF regulation of amniotic fluid absorption through the fetal membranes and placenta. RESULTS Recent scientific advances suggest that up-regulation of VEGF gene expression in the amnion and chorion is associated with increased transfer of amniotic fluid into fetal blood. The possible mechanisms of action for VEGF appear to involve regulation of intramembranous blood vessel proliferation and membrane transport via passive permeation as well as nonpassive transcytotic vesicular movement of fluid. CONCLUSION Currently evolving concepts suggest that amniotic fluid volume is regulated through modulation of the rate of intramembranous absorption of amniotic fluid by both passive and nonpassive mechanisms. The permeability factor VEGF appears to be a critical regulator of amniotic fluid transport in the fetal membranes.
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Affiliation(s)
- Cecilia Y Cheung
- Division of Perinatal Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, California 92093-0802, USA.
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Messineo S, Laria AE, Arcidiacono B, Chiefari E, Luque Huertas RM, Foti DP, Brunetti A. Cooperation between HMGA1 and HIF-1 Contributes to Hypoxia-Induced VEGF and Visfatin Gene Expression in 3T3-L1 Adipocytes. Front Endocrinol (Lausanne) 2016; 7:73. [PMID: 27445976 PMCID: PMC4921468 DOI: 10.3389/fendo.2016.00073] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/14/2016] [Indexed: 12/28/2022] Open
Abstract
The architectural transcription factor high-mobility group AT-hook 1 (HMGA1) is a chromatin regulator with implications in several biological processes, including tumorigenesis, inflammation, and metabolism. Previous studies have indicated a role for this factor in promoting the early stages of adipogenesis, while inhibiting adipocyte terminal differentiation, and decreasing fat mass. It has been demonstrated that hypoxia - through the hypoxia-inducible factor 1 (HIF-1) - plays a major role in triggering changes in the adipose tissue of the obese, leading to inhibition of adipocyte differentiation, adipose cell dysfunction, inflammation, insulin resistance, and type 2 diabetes. To examine the possible cooperation between HMGA1 and HIF-1, herein, we investigated the role of HMGA1 in the regulation of Visfatin and VEGF, two genes normally expressed in adipose cells, which are both responsive to hypoxia. We demonstrated that HMGA1 enhanced Visfatin and VEGF gene expression in human embryonic kidney (HEK) 293 cells in hypoxic conditions, whereas HMGA1 knockdown in differentiated 3T3-L1 adipocytes reduced these effects. Reporter gene analysis showed that Visfatin and VEGF transcriptional activity was increased by the addition of either HMGA1 or HIF-1 and even further by the combination of both factors. As demonstrated by chromatin immunoprecipitation in intact cells, HMGA1 directly interacted with the VEGF gene, and this interaction was enhanced in hypoxic conditions. Furthermore, as indicated by co-immunoprecipitation studies, HMGA1 and HIF-1 physically interacted with each other, supporting the notion that this association may corroborate a functional link between these factors. Therefore, our findings provide evidence for molecular cross-talk between HMGA1 and HIF-1, and this may be important for elucidating protein and gene networks relevant to obesity.
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Affiliation(s)
- Sebastiano Messineo
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Anna Elisa Laria
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Biagio Arcidiacono
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Raúl M. Luque Huertas
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía (HURS), CIBERobn and ceiA3, University of Córdoba, Córdoba, Spain
| | - Daniela P. Foti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
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Hopper RK, Moonen JRAJ, Diebold I, Cao A, Rhodes CJ, Tojais NF, Hennigs JK, Gu M, Wang L, Rabinovitch M. In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug. Circulation 2016; 133:1783-94. [PMID: 27045138 DOI: 10.1161/circulationaha.115.020617] [Citation(s) in RCA: 191] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 03/11/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH. METHODS AND RESULTS We documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell-specific loss of Bmpr2 showed similar gene and protein changes. CONCLUSIONS Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
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Affiliation(s)
- Rachel K Hopper
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Jan-Renier A J Moonen
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Isabel Diebold
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Aiqin Cao
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Christopher J Rhodes
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Nancy F Tojais
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Jan K Hennigs
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Mingxia Gu
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Lingli Wang
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.)
| | - Marlene Rabinovitch
- From Department of Pediatrics, the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA (R.K.H., J.-R.A.J.M., A.C., C.J.R., N.F.T., J.K.H., M.G., L.W., M.R.); Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia (R.K.H.); Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands (J.-R.A.J.M.).
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Keenan SW, Hill CA, Kandoth C, Buck LT, Warren DE. Transcriptomic Responses of the Heart and Brain to Anoxia in the Western Painted Turtle. PLoS One 2015; 10:e0131669. [PMID: 26147940 PMCID: PMC4493013 DOI: 10.1371/journal.pone.0131669] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 06/05/2015] [Indexed: 12/23/2022] Open
Abstract
Painted turtles are the most anoxia-tolerant tetrapods known, capable of surviving without oxygen for more than four months at 3°C and 30 hours at 20°C. To investigate the transcriptomic basis of this ability, we used RNA-seq to quantify mRNA expression in the painted turtle ventricle and telencephalon after 24 hours of anoxia at 19°C. Reads were obtained from 22,174 different genes, 13,236 of which were compared statistically between treatments for each tissue. Total tissue RNA contents decreased by 16% in telencephalon and 53% in ventricle. The telencephalon and ventricle showed ≥ 2x expression (increased expression) in 19 and 23 genes, respectively, while only four genes in ventricle showed ≤ 0.5x changes (decreased expression). When treatment effects were compared between anoxic and normoxic conditions in the two tissue types, 31 genes were increased (≥ 2x change) and 2 were decreased (≤ 0.5x change). Most of the effected genes were immediate early genes and transcription factors that regulate cellular growth and development; changes that would seem to promote transcriptional, translational, and metabolic arrest. No genes related to ion channels, synaptic transmission, cardiac contractility or excitation-contraction coupling changed. The generalized expression pattern in telencephalon and across tissues, but not in ventricle, correlated with the predicted metabolic cost of transcription, with the shortest genes and those with the fewest exons showing the largest increases in expression.
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Affiliation(s)
- Sarah W. Keenan
- Department of Biology, Saint Louis University, St. Louis, Missouri, United States of America
| | - Craig A. Hill
- Department of Biology, Saint Louis University, St. Louis, Missouri, United States of America
| | - Cyriac Kandoth
- The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Leslie T. Buck
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Daniel E. Warren
- Department of Biology, Saint Louis University, St. Louis, Missouri, United States of America
- * E-mail:
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Up-Regulation of the Biosynthesis and Release of Substance P through Wnt/β-Catenin Signaling Pathway in Rat Dorsal Root Ganglion Cells. PLoS One 2015; 10:e0129701. [PMID: 26054011 PMCID: PMC4459973 DOI: 10.1371/journal.pone.0129701] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 05/12/2015] [Indexed: 11/19/2022] Open
Abstract
To examine regulatory effects of β-catenin on the biosynthesis and release of substance P, a rat chronic constriction injury (CCI) model and a rat dorsal root ganglion (DRG) cell culture model were used in the present study. The CCI treatment significantly induced the overall expression of β-catenin (158 ± 6% of sham) in the ipsilateral L5 DRGs in comparison with the sham group (109 ± 4% of sham). The CCI-induced aberrant expression of β-catenin was significantly attenuated by oral administration of diclofenac (119 ± 6% of the sham value; 10 mg/kg). Importantly, aberrant nuclear accumulation of β-catenin in cultured DRG cells resulted in up-regulation of the PPT-A mRNA expression and the substance P release. The up-regulation of both the PPT-A mRNA expression and the substance P release by either a GSK-3β inhibitor TWS119 (10 μM) or a Wnt signaling agonist Wnt-3a (100 ng/ml) were significantly abolished by an inhibitor of cyclooxygenase-2 (COX-2; NS-398, 1 μM). Collectively, these data suggest that nociceptive input-activated β-catenin signaling plays an important role in regulating the biosynthesis and release of substance P, which may contribute to the inflammation responses related to chronic pain.
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Abstract
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the leading causes of blindness in adults. The impact of these conditions on the quality of life is increasing in significance with a rise in life expectancy. The role of hyperglycemia, oxidative stress and inflammatory responses in the development and/or progression of DR and AMD, and several other sight threatening ocular diseases, is well established. In proliferative retinopathy, signals sent by the retina for nourishment, triggers the growth of fragile and abnormal blood vessels. Changes in ocular pressure may lead to rupture of these blood vessels causing severe vision problems. Recent in vitro and preclinical studies demonstrate that certain phytochemicals possessing potent antioxidant and anti-inflammatory activity and ocular blood flow enhancing properties may be very useful in the treatment of, or as a prophylactic measure for, DR and AMD. Apart from these properties they have also been investigated for their anti-bacterial, hormonal, enzyme stimulation, and anti-angiogenic activities. The attractive aspect of these potential therapeutic candidates is that they can act on multiple pathways identified in the etiology of DR, AMD, cataract and other ocular diseases. However, results from clinical trials have been somewhat ambiguous, raising questions about the concentrations of these bioflavonoids achieved in the neural retina following oral administration. Unfortunately, as of date, an efficient noninvasive means to deliver therapeutic agents/candidates to the back-of-the eye is still not available. This review examines some of these promising natural agents and discusses the challenges encountered in delivering them to the posterior segment ocular tissues through the oral route.
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Gasparini G, De Gori M, Paonessa F, Chiefari E, Brunetti A, Galasso O. Functional relationship between high mobility group A1 (HMGA1) protein and insulin-like growth factor-binding protein 3 (IGFBP-3) in human chondrocytes. Arthritis Res Ther 2012; 14:R207. [PMID: 23036517 PMCID: PMC3580519 DOI: 10.1186/ar4045] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 10/04/2012] [Indexed: 11/10/2022] Open
Abstract
Introduction Insulin-like growth factor I (IGF-I) regulates articular cartilage homeostasis. During osteoarthritis (OA), the anabolic responses of chondrocytes to IGF-I are likely to be prevented by the enhanced production of IGF-binding proteins (IGFBPs), especially IGFBP-3. The aim of this study is to evaluate whether the architectural transcription factor high mobility group A1 (HMGA1) influences IGFBP-3 overexpression in vitro, in cultured chondrocytic cell lines, and ex vivo, in human osteoarthritic cartilage compared to healthy human cartilage controls. Methods Quantitative real-time reverse transcription-PCR (qRT-PCR) was performed to assess the relative transcript levels of HMGA1 and IGFBP-3 in vitro, in the human chondrocytic cell lines T/C-28a4 and C-28/I2. An electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and transient transfection assays were performed to investigate the HMGA1-IGFBP-3 gene interaction. Samples of articular cartilage were harvested from osteoarthritic patients and controls and analyzed by qRT-PCR for HMGA1 and IGFBP-3 mRNA levels. Results A parallelism between HMGA1 protein levels and IGFBP-3 gene expression has been observed in T/C-28a4 and C-28/I2 cells. The interaction of HMGA1 with the IGFBP-3 gene promoter has been demonstrated by EMSA and ChIP. In transient transfections, IGFBP-3 promoter activity increased in cells overexpressing HMGA1 and decreased in cells pretreated with siRNA detected against HMGA1. IGFBP-3 mRNA expression was higher in cartilage from patients with OA, where the increased expression of IGFBP-3 closely paralleled the increased expression of HMGA1 mRNA. Conclusions Our observations indicate that increased HMGA1 expression in human chondrocytes is associated with increased expression of IGFBP-3. It is tempting to speculate that, through the regulation of IGFBP3 expression, HMGA1 may act as a pathogenetic factor for OA.
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Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 2012; 92:967-1003. [PMID: 22811423 DOI: 10.1152/physrev.00030.2011] [Citation(s) in RCA: 478] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O(2)-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O(2) availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O(2) sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.
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Affiliation(s)
- Nanduri R Prabhakar
- Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, Illinois, USA.
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Harris RE, Beebe J, Alshafie GA. Reduction in cancer risk by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. J Exp Pharmacol 2012; 4:91-6. [PMID: 27186121 PMCID: PMC4863307 DOI: 10.2147/jep.s23826] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We conducted a series of epidemiologic studies to evaluate the chemopreventive effects of aspirin, ibuprofen, and selective cyxlooxygenase-2 (COX-2) inhibitors (coxibs) against cancers of the breast, colon, prostate, and lung. Composite results across all four cancer sites revealed that regular intake of 325 mg aspirin, 200 mg ibuprofen, or standard dosages of coxibs (200 mg celecoxib or 25 mg rofecoxib) produced risk reductions of 49%, 59%, and 64%, respectively. Use of coxibs for at least 2 years was associated with risk reductions of 71%, 70%, 55%, and 60% for breast cancer, colon cancer, prostate cancer and lung cancer, respectively. Effects of ibuprofen were similar to selective coxibs, and slightly stronger than aspirin. These observed effects are consistent with the relative COX-2 selectivity of ibuprofen, coxibs, and aspirin. Acetaminophen, an analgesic without COX-2 activity, had no effect. Overexpression of COX-2 and increased prostaglandin biosynthesis correlates with carcinogenesis and metastasis at most anatomic sites. These results indicate that regular intake of nonselective or selective COX-2 inhibiting agents protects against the development of major forms of cancer.
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Affiliation(s)
- Randall E Harris
- College of Medicine and College of Public Health, The Ohio State University, Columbus, Ohio, USA
| | - Joanne Beebe
- College of Medicine and College of Public Health, The Ohio State University, Columbus, Ohio, USA
| | - Galal A Alshafie
- College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
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Takeuchi I, Takaha N, Nakamura T, Hongo F, Mikami K, Kamoi K, Okihara K, Kawauchi A, Miki T. High mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independence in prostate cancer cells. Prostate 2012; 72:1124-32. [PMID: 22213442 DOI: 10.1002/pros.22460] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2011] [Accepted: 10/27/2011] [Indexed: 11/11/2022]
Abstract
BACKGROUND We previously reported that the level of high mobility group protein AT-hook 1 (HMGA1) is low in androgen-dependent prostate cancer (PCa) cells (LNCaP), but is high in androgen-independent PCa cells (DU145 and PC-3) and that HMGA1 is a strong candidate gene playing a potential role in the progression of PCa. These findings have prompted us to evaluate the effect of HMGA1 on developing androgen independency, which is associated with the progression of PCa. METHODS Expression of HMGA1 in PCa cells and mouse tissues was examined by Western blot. In order to examine the effect of HMGA1 on cell growth under androgen-deprived condition, we transfected HMGA1 into LNCaP cells, and siRNA into both DU145 and PC-3 cells, respectively. RESULTS Androgen-deprivation induced an increase in the level of HMGA1 in LNCaP cells in vitro and in vivo, but did not in normal prostate tissue. Overexpression of HMGA1 maintained the cell growth of LNCaP under androgen-deprived condition. Furthermore, knockdown of HMGA1 suppressed the cell growth of DU145 and PC-3. CONCLUSIONS These data suggest that elevated expression of HMGA1 is associated with the transition of PCa cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent PCa cells.
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Affiliation(s)
- Ichiro Takeuchi
- Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Kim SH, Park YY, Kim SW, Lee JS, Wang D, DuBois RN. ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression. Cancer Res 2011; 71:7010-20. [PMID: 21937683 DOI: 10.1158/0008-5472.can-11-1262] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prostaglandin E(2) (PGE(2)), the most abundant COX-2-derived prostaglandin found in colorectal cancer, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE(2) in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE(2) and hypoxia on enhancing angiopoietin-like protein 4 (ANGPTL4) expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE(2) induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE(2) receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by an antagonist inhibits PGE(2) induction of ANGPTL4 under hypoxic conditions. Importantly, overexpression of ANGPTL4 promotes cell proliferation and tumor growth in vitro and in vivo. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAP kinase and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease because we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers tested and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in colorectal carcinomas. Collectively, these findings suggest that PGE(2) plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.
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Affiliation(s)
- Sun-Hee Kim
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Moussavi Nik SH, Newman M, Lardelli M. The response of HMGA1 to changes in oxygen availability is evolutionarily conserved. Exp Cell Res 2011; 317:1503-12. [PMID: 21530505 DOI: 10.1016/j.yexcr.2011.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Revised: 04/05/2011] [Accepted: 04/10/2011] [Indexed: 10/18/2022]
Abstract
Zebrafish embryos have evolved to cope with hypoxia during development. This includes the ability to completely suspend embryo development for extended periods until normoxia is restored. However, only a limited number of studies have examined the gene regulatory responses of zebrafish embryos to hypoxia. The High Mobility Group A1 protein encoded by the mammalian gene HMGA1 is widely expressed during embryo development but not in adults. Its expression can be induced in adult neurons by hypoxia/oxidative stress and it is commonly reactivated in many types of cancer. We report the identification by phylogenetic and conserved synteny analyses of an HMGA1 orthologue in zebrafish, hmga1 (hmg-i/y) and analysis of sodium azide as a chemical agent for inducing hypoxia-like responses in zebrafish embryos including temporary suspension of development ("suspended animation"). Evidence was only found for the existence of the "a" isoform of HMGA1 in fish. The "b" and "c" isoforms were not detected. We show that zebrafish hmga1 is expressed in a manner similar to in mammals including its induction by hypoxia during hatching stage and in adult zebrafish brain. However, earlier during development, hypoxia causes a decrease in hmga1 transcript levels. By analysis of conservation of the HMGA1a isoform binding site in zebrafish psen2 gene transcripts, we predict that a zebrafish equivalent of the PS2V isoform of human PSEN2 is not formed and we support this by RT-PCR analyses. Thus, analysis of hmga1 function in zebrafish embryogenesis may be valuable for understanding its wider role in vertebrate development, cancer and cellular responses to hypoxia but not for analysis of the action of HMGA1 in PS2V formation.
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Affiliation(s)
- Seyyed Hani Moussavi Nik
- Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, Australia.
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25
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Semenza GL. Oxygen homeostasis. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2011; 2:336-361. [PMID: 20836033 DOI: 10.1002/wsbm.69] [Citation(s) in RCA: 257] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Metazoan life is dependent upon the utilization of O(2) for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF-1 activity is regulated and by which HIF-1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis.
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Affiliation(s)
- Gregg L Semenza
- Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA.,Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA.,McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA
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26
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Eilebrecht S, Brysbaert G, Wegert T, Urlaub H, Benecke BJ, Benecke A. 7SK small nuclear RNA directly affects HMGA1 function in transcription regulation. Nucleic Acids Res 2010; 39:2057-72. [PMID: 21087998 PMCID: PMC3064786 DOI: 10.1093/nar/gkq1153] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Non-coding (nc) RNAs are increasingly recognized to play important regulatory roles in eukaryotic gene expression. The highly abundant and essential 7SK ncRNA has been shown to negatively regulate RNA Polymerase II transcription by inactivating the positive transcription elongation factor b (P-TEFb) in cellular and Tat-dependent HIV transcription. Here, we identify a more general, P-TEFb-independent role of 7SK RNA in directly affecting the function of the architectural transcription factor and chromatin regulator HMGA1. An important regulatory role of 7SK RNA in HMGA1-dependent cell differentiation and proliferation regulation is uncovered with the identification of over 1500 7SK-responsive HMGA1 target genes. Elevated HMGA1 expression is observed in nearly every type of cancer making the use of a 7SK substructure in the inhibition of HMGA1 activity, as pioneered here, potentially useful in therapy. The 7SK-HMGA1 interaction not only adds an essential facet to the comprehension of transcriptional plasticity at the coupling of initiation and elongation, but also might provide a molecular link between HIV reprogramming of cellular gene expression-associated oncogenesis.
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Affiliation(s)
- Sebastian Eilebrecht
- Institut des Hautes Études Scientifiques & Centre National de la Recherche Scientifique USR3078, 35 route de Chartres, 91440 Bures sur Yvette, France
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Prandota J. Migraine Associated with Patent Foramen Ovale May Be Caused by Reactivation of Cerebral Toxoplasmosis Triggered by Arterial Blood Oxygen Desaturation. Int J Neurosci 2010; 120:81-7. [DOI: 10.3109/00207450903458647] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
High mobility group A1 (HMGA1) is highly expressed during embryogenesis and in poorly differentiated cancers, and high levels portend a poor prognosis in some tumors. HMGA1 induces oncogenic transformation in cultured cells and causes aggressive cancers in transgenic mice, whereas blocking it interferes with transformation in experimental models. These findings suggest a pivotal role for HMGA1 in cancer. This review focuses on two recently described HMGA1 transcriptional targets that mediate inflammatory signals and drive malignant transformation because they could serve as biomarkers or therapeutic targets. Further elucidation of HMGA1 function in transformation promises to have a major impact on our war on cancer.
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Affiliation(s)
- Linda M S Resar
- The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2109., USA.
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29
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Manabe T, Katayama T, Tohyama M. HMGA1a recognition candidate DNA sequences in humans. PLoS One 2009; 4:e8004. [PMID: 19956671 PMCID: PMC2777381 DOI: 10.1371/journal.pone.0008004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Accepted: 10/30/2009] [Indexed: 12/17/2022] Open
Abstract
High mobility group protein A1a (HMGA1a) acts as an architectural transcription factor and influences a diverse array of normal biological processes. It binds AT-rich sequences, and previous reports have demonstrated HMGA1a binding to the authentic promoters of various genes. However, the precise sequences that HMGA1a binds to remain to be clarified. Therefore, in this study, we searched for the sequences with the highest affinity for human HMGA1a using an existing SELEX method, and then compared the identified sequences with known human promoter sequences. Based on our results, we propose the sequences “-(G/A)-G-(A/T)-(A/T)-A-T-T-T-” as HMGA1a-binding candidate sequences. Furthermore, these candidate sequences bound native human HMGA1a from SK-N-SH cells. When candidate sequences were analyzed by performing FASTAs against all known human promoter sequences, 500–900 sequences were hit by each one. Some of the extracted genes have already been proven or suggested as HMGA1a-binding promoters. The candidate sequences presented here represent important information for research into the various roles of HMGA1a, including cell differentiation, death, growth, proliferation, and the pathogenesis of cancer.
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Affiliation(s)
- Takayuki Manabe
- Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.
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30
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Hang X, Li P, Li Z, Qu W, Yu Y, Li H, Shen Z, Zheng H, Gao Y, Wu Y, Deng M, Sun Z, Zhang C. Transcription and splicing regulation in human umbilical vein endothelial cells under hypoxic stress conditions by exon array. BMC Genomics 2009; 10:126. [PMID: 19320972 PMCID: PMC2678155 DOI: 10.1186/1471-2164-10-126] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2008] [Accepted: 03/25/2009] [Indexed: 12/22/2022] Open
Abstract
Background The balance between endothelial cell survival and apoptosis during stress is an important cellular process for vessel integrity and vascular homeostasis, and it is also pivotal in angiogenesis during the development of many vascular diseases. However, the underlying molecular mechanisms remain largely unknown. Although both transcription and alternative splicing are important in regulating gene expression in endothelial cells under stress, the regulatory mechanisms underlying this state and their interactions have not yet been studied on a genome-wide basis. Results Human umbilical vein endothelial cells (HUVECs) were treated with cobalt chloride (CoCl2) both to mimic hypoxia and to induce cell apoptosis and alternative splicing responses. Cell apoptosis rate analysis indicated that HUVECs exposed to 300 μM CoCl2 for 24 hrs were initially counterbalancing apoptosis with cell survival. We therefore used the Affymetrix exon array system to determine genome-wide transcript- and exon-level differential expression. Other than 1583 differentially expressed transcripts, 342 alternatively spliced exons were detected and classified by different splicing types. Sixteen alternatively spliced exons were validated by RT-PCR. Furthermore, direct evidence for the ongoing balance between HUVEC survival and apoptosis was provided by Gene Ontology (GO) and protein function, as well as protein domain and pathway enrichment analyses of the differentially expressed transcripts. Importantly, a novel molecular module, in which the heat shock protein (HSP) families play a significant role, was found to be activated under mimicked hypoxia conditions. In addition, 46% of the transcripts containing stress-modulated exons were differentially expressed, indicating the possibility of combinatorial regulation of transcription and splicing. Conclusion The exon array system effectively profiles gene expression and splicing on the genome-wide scale. Based on this approach, our data suggest that transcription and splicing not only regulate gene expression, but also carry out combinational regulation of the balance between survival and apoptosis of HUVECs under mimicked hypoxia conditions. Since cell survival following the apoptotic challenge is pivotal in angiogenesis during the development of many vascular diseases, our results may advance the knowledge of multilevel gene regulation in endothelial cells under physiological and pathological conditions.
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Affiliation(s)
- Xingyi Hang
- Beijing Institute of Radiation Medicine, State Key Laboratory of Proteomics, Beijing, PR China.
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31
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Chang KY, Shen MR, Lee MY, Wang WL, Su WC, Chang WC, Chen BK. Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1{beta} signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma. J Biol Chem 2009; 284:9908-16. [PMID: 19203995 DOI: 10.1074/jbc.m806210200] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hypoxia-inducible factor (HIF) accumulates when tumors grow under hypoxic conditions. The genesis of tumors, however, usually involves normoxic conditions. In this study, we were interested in examining the potential role of aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF-1beta in tumor growth under normoxic conditions, specifically when cells are treated with epidermal growth factor (EGF), which is known to affect the gene expression of tumor growth-related protein COX-2 (cyclooxygenase-2). The results showed that EGF receptor inhibitor, AG1478, abolished EGF-induced nuclear accumulation of ARNT as well as the expression of COX-2. ARNT small interfering RNA inhibited the promoter activity, mRNA level, and protein expression of COX-2 in cells treated with EGF. In contrast, CoCl(2)-induced HIF-1alpha exhibited no effect on COX-2 expression. EGF also stimulated the formation of the ARNT.c-Jun complex as well as the complex binding to the COX-2 promoter. ARNT small interfering RNAs blocked EGF-activated cell migration. Moreover, COX-2 and ARNT were cohorts present distinctively in clinical specimens of human cervical squamous cell carcinoma and were almost nondetectable in adjacent normal or noncancerous cervical tissues. Our results revealed that ARNT plays an important role in EGF-regulated COX-2 gene expression and may thus be related to either a cause or a consequence of tumorigenesis in cervical cancer.
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Affiliation(s)
- Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan 701, Taiwan
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32
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Saed GM, Al-Hendy A, Salama SA, Diamond MP. Adenovirus-mediated expression of cyclooxygenase-2 antisense reverse abnormal genetic profile of human adhesion fibroblasts. Fertil Steril 2008; 89:1455-60. [PMID: 17624339 DOI: 10.1016/j.fertnstert.2007.04.061] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Revised: 04/09/2007] [Accepted: 04/09/2007] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To determine the effects of blocking the translation of cyclooxygenase-2 (COX-2) mRNA on the mRNA levels of type I collagen, type III collagen, fibronectin, and transforming growth factor-beta (TGF-beta1) in fibroblasts obtained from normal peritoneal and adhesion tissues. DESIGN Prospective experimental study. SETTING University medical center. PATIENT(S) Fibroblasts established from peritoneal and adhesion tissue of the same patients. INTERVENTION(S) Adenovirus with COX-2 treatment of the primary cultured fibroblasts. MAIN OUTCOME MEASURE(S) Fibroblasts of normal peritoneal and adhesion tissues were isolated from the same patients. Adhesion and normal peritoneal fibroblasts were transfected with an adenovirus COX-2 mRNA in sense or antisense orientation. RNA was extracted from each treatment and subjected to real time reverse transcriptase-polymerase chain reaction to quantify change in mRNA levels of type I collagen, type III collagen, fibronectin, and TGF-beta1. RESULT(S) Type I collagen, type III collagen, fibronectin, and TGF-beta1 mRNAs were present in both normal peritoneal and adhesion fibroblasts with significantly higher levels in adhesion fibroblasts. Normal fibroblasts transfected with the COX-2 sense virus exhibited an elevated mRNA level in those molecules that reached the mRNA levels seen for adhesion fibroblasts. There were no effects seen on the mRNA levels in those molecules when adhesion fibroblasts were transfected with COX-2 sense virus. Normal fibroblasts transfected with COX-2 antisense virus exhibited no difference in mRNA levels in those molecules as compared with untransfected controls. In contrast, adhesion fibroblasts transfected with COX-2 antisense exhibited markedly reduced mRNA levels in those molecules to levels that were seen in normal peritoneal fibroblasts. CONCLUSION(S) Our data suggest that inhibition of COX-2 may reduce the development of postoperative adhesions by preventing the formation of the adhesion phenotype.
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Affiliation(s)
- Ghassan M Saed
- Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
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Abstract
The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation. Here, we focus on the role of the HMGA proteins in human neoplastic diseases, the mechanisms by which they contribute to carcinogenesis, and therapeutic strategies based on targeting HMGA proteins.
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Affiliation(s)
- Alfredo Fusco
- Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via Pansini, 5, 80131, Naples, Italy.
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Abstract
Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that aberrant induction of COX-2 and up-regulation of the prostaglandin cascade play a significant role in carcinogenesis, and reciprocally, blockade of the process has strong potential for cancer prevention and therapy. Supporting evidence includes the following: [1] expression of constitutive COX-2-catalyzed prostaglandin biosynthesis is induced by most cancer-causing agents including tobacco smoke and its components (polycylic aromatic amines, heterocyclic amines, nitrosamines), essential polyunsaturated fatty acids (unconjugated linoleic acid), mitogens, growth factors, proinflammatory cytokines, microbial agents, tumor promoters, and other epigenetic factors, [2] COX-2 expression is a characteristic feature of all premalignant neoplasms, [3] COX-2 expression is a characteristic feature of all malignant neoplasms, and expression intensifies with stage at detection and cancer progression and metastasis, [4] all essential features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis, and immunosuppression) are linked to COX-2-driven prostaglandin (PGE-2) biosynthesis, [5] animal studies show that COX-2 up-regulation (in the absence of genetic mutations) is sufficient to stimulate the transformation of normal cells to invasive cancer and metastatic disease, [6] non-selective COX-2 inhibitors, such as aspirin and ibuprofen, reduce the risk of human cancer and precancerous lesions, and [7] selective COX-2 inhibitors, such as celecoxib, reduce the risk of human cancer and precancerous lesions at all anatomic sites thus far investigated. Results confirming that COX-2 blockade is effective for both cancer prevention and therapy have been tempered by observations that some COX2 inhibitors pose a risk to the cardiovascular system, and more studies are needed in order to determine if certain of these drugs can be taken at dosages that prevent cancer without increasing cardiovascular risk. It is emphasized that the "inflammogenesis model of cancer" is not mutually exclusive and may in fact be synergistic with the accumulation of somatic mutations in tumor suppressor genes and oncogenes or epigenetic factors in the development of cancer.
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Affiliation(s)
- Randall E Harris
- College of Medicine and School of Public Health, Center of Molecular Epidemiology and Environmental Health, The Ohio State University Medical Center, 310 West 10th Avenue, Columbus, Ohio 43210-1240, USA
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35
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Tesfaye A, Di Cello F, Hillion J, Ronnett BM, Elbahloul O, Ashfaq R, Dhara S, Prochownik E, Tworkoski K, Reeves R, Roden R, Ellenson LH, Huso DL, Resar LMS. The High-Mobility Group A1 Gene Up-Regulates Cyclooxygenase 2 Expression in Uterine Tumorigenesis. Cancer Res 2007; 67:3998-4004. [PMID: 17483309 DOI: 10.1158/0008-5472.can-05-1684] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Uterine cancer is the most common cancer of the female genital tract and is the fourth most frequent cause of cancer death in women in the U.S. Despite the high prevalence of uterine cancers, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. Moreover, there are limited mouse models to study these malignancies. We generated transgenic mice with high-mobility group A1 gene (HMGA1a) expression targeted to uterine tissue and all female mice developed tumors by 9 months of age. Histopathologically, the tumors resemble human uterine adenosarcoma and are transplantable. To determine whether these findings are relevant to human disease, we evaluated primary human uterine neoplasms and found that HMGA1a mRNA and protein levels are increased in most high-grade neoplasms but not in normal uterine tissue, benign tumors, or most low-grade neoplasms. We also found that HMGA1a up-regulates cyclooxygenase 2 (COX-2) expression in transgenic tumors. Moreover, both HMGA1a and COX-2 expression are up-regulated in high-grade human leiomyosarcomas. Using chromatin immunoprecipitation, HMGA1a binds directly to the COX-2 promoter in human uterine cancer cells in vivo and activates its expression in transfection experiments. We also show that blocking either HMGA1a or COX-2 in high-grade human uterine cancer cells blocks anchorage-independent cell growth in methylcellulose. These findings show that HMGA1a functions as an oncogene when overexpressed in the uterus and contributes to the pathogenesis of human uterine cancer by activating COX-2 expression. Although a larger study is needed to confirm these results, HMGA1a may be a useful marker for aggressive human uterine cancers.
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Affiliation(s)
- Abeba Tesfaye
- Hematology Division, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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Chapple KS, Parry DJ, McKenzie S, MacLennan KA, Jones P, Scott DJA. Cyclooxygenase-2 expression and its association with increased angiogenesis in human abdominal aortic aneurysms. Ann Vasc Surg 2007; 21:61-6. [PMID: 17349338 DOI: 10.1016/j.avsg.2006.10.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2006] [Revised: 09/05/2006] [Accepted: 10/19/2006] [Indexed: 11/23/2022]
Abstract
Although the mechanism whereby non-steroidal anti-inflammatory drugs may reduce abdominal aortic aneurysm (AAA) development is unknown, one potential route is via inhibition of the cyclooxygenase (COX) enzyme. Despite the fact that evidence from animal models suggests a role for the COX-2 isoform in promotion of AAA development, only very limited data exist on COX-2 expression in human AAAs. Semiquantitative immunohistochemistry for COX-2 was performed on a series of formalin-fixed, paraffin-embedded human AAAs (n = 49). Associated clinicopathological data, including the degree of inflammatory cell infiltration and neorevascularization, were obtained. COX-2 protein was detected in 46 of 49 (94%) human AAAs. Expression of COX-2 protein varied widely between AAAs. COX-2 protein localized to cells in the inflammatory infiltrate with a morphology characteristic of macrophages. COX-2 expression increased with the extent of inflammatory cell infiltration (P < 0.001) and with the degree of AAA neorevascularization (P < 0.001). Logistic regression analysis identified neorevascularization (P < 0.001) as the only significant independent predictor of COX-2 positivity in human AAAs. COX-2 protein is present at increased levels in the majority of human AAAs and is expressed by mononuclear cells in the inflammatory cell infiltrate. Promotion of angiogenesis by COX-2 may play a role in AAA development.
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Affiliation(s)
- K S Chapple
- Academic Unit of Vascular Surgery, University of Leeds, St. James's University Hospital, Leeds, UK.
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37
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Schweppe RE, Cheung TH, Ahn NG. Global gene expression analysis of ERK5 and ERK1/2 signaling reveals a role for HIF-1 in ERK5-mediated responses. J Biol Chem 2006; 281:20993-21003. [PMID: 16735500 DOI: 10.1074/jbc.m604208200] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
ERK5 is a recently characterized MAPK, which is most similar to the well studied ERK1/2 subfamily but uses distinct mechanisms to elicit responses. To understand the specificity of signaling through ERK5 versus ERK1/2, we examined global gene expression changes in response to each pathway. Microarray measurements in retinal pigment epithelial cells revealed 36 genes regulated by ERK5, all which were novel targets for this pathway. 39 genes were regulated by ERK1/2, which included 11 known genes. Of these genes, 19 were regulated by both pathways. Inspection of the 17 genes uniquely regulated by ERK5 revealed that 14 genes (82%) were previously associated with hypoxia via regulation by HIF-1. In contrast, 16 genes (84%) regulated by either ERK5 or ERK1/2 were implicated in hypoxia, most through mechanisms independent of HIF-1. Of the 20 genes regulated by ERK1/2, only 9 were implicated in hypoxia and were not well characterized hypoxia targets. Thus, unlike ERK5, a mechanistic link between ERK1/2 and HIF-1/HRE could not be established on the basis of gene regulation. Activation of both pathways enhanced transcription from a hypoxia-response element and increased HIF-1alpha protein expression. In contrast, ERK5 but not ERK1/2 elevated transcription through GAL4-HIF-1. Most interestingly, ERK5 is not significantly activated by hypoxia in retinal pigment epithelial cells, indicating that ERK5 regulation of these genes is relevant in normoxia rather than hypoxia. Thus, ERK5 and ERK1/2 differ in their mechanisms of gene regulation, and indicate that ERK5 may control hypoxia-responsive genes by a mechanism independent of HIF-1alpha expression control.
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Affiliation(s)
- Rebecca E Schweppe
- Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309
| | - Tom Hiu Cheung
- Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309
| | - Natalie G Ahn
- Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309; Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309.
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38
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Csiki I, Yanagisawa K, Haruki N, Nadaf S, Morrow JD, Johnson DH, Carbone DP. Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1alpha in non-small cell lung cancer. Cancer Res 2006; 66:143-50. [PMID: 16397226 DOI: 10.1158/0008-5472.can-05-1357] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIF-1) transcription factor and is a critical step in tumor growth. Cyclooxygenase-2 (COX-2) is commonly overexpressed in non-small cell lung cancer (NSCLC). In this study, we sought to determine the role of HIF-1 in the induction of COX-2 expression during hypoxia. Through sequence comparison of hypoxia-responsive genes, COX-2 promoter deletion analysis, and site-directed mutagenesis, we identified a hypoxia-responsive element within the COX-2 promoter that interacts with HIF-1alpha and underlies the mechanism of hypoxic activation of COX-2 in lung cancer cells. Proteomic analysis of NSCLC identified thioredoxin-1 as a redox protein overexpressed in NSCLC correlated with poor prognosis. We also show that thioredoxin-1 stabilizes HIF-1alpha to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.
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MESH Headings
- Carcinoma, Non-Small-Cell Lung/enzymology
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Hypoxia
- Cell Line, Tumor
- Cyclooxygenase 2/biosynthesis
- Cyclooxygenase 2/genetics
- Enzyme Induction
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/pharmacology
- Hypoxia-Inducible Factor 1, alpha Subunit/physiology
- Lung Neoplasms/enzymology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Promoter Regions, Genetic
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Thioredoxins/biosynthesis
- Thioredoxins/genetics
- Transcription, Genetic
- Transcriptional Activation
- Transfection
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Affiliation(s)
- Ildiko Csiki
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, USA
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Giannini G, Cerignoli F, Mellone M, Massimi I, Ambrosi C, Rinaldi C, Gulino A. Molecular mechanism of HMGA1 deregulation in human neuroblastoma. Cancer Lett 2005; 228:97-104. [PMID: 15923078 DOI: 10.1016/j.canlet.2005.01.045] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2004] [Accepted: 01/12/2005] [Indexed: 11/21/2022]
Abstract
Very soon after their original identification in HeLa cells in 1983, HMGA proteins appeared as interesting cancer-related molecules. Indeed, they were immediately noted as a sub-class of High Mobility Group proteins induced in fibroblast or epithelial cells transformed with sarcoma viruses. After more than 20 years, the association between HMGA protein expressions and cellular transformation has been largely confirmed and HMGA are among the most widely expressed cancer-associated proteins. Nevertheless, their functional contribution to tumour development and progression is far from being completely understood. Furthermore, although HMGA1 expression has been reported to be inducible by a number of factors and circumstances, the question of how their expression is deregulated in cancer is even less clear and somehow has been ignored from most researchers. An active AP1 site is the only characterized element of the HMGA1 human promoter, that remains a rather complicated and unexplored source of information to answer this question. Following the indication that c-Myc might bind and activate the mouse HMGA1 gene promoter, we have demonstrated that HMGA1 is a new target for MYCN in human neuroblastomas. In this report, we overview part of the current information on HMGA1 and focus our attention on the analysis of its human promoter.
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Affiliation(s)
- Giuseppe Giannini
- Department of Experimental Medicine and Pathology, Department of Pediatrics, University La Sapienza, Policlinico Umberto 1, Viale Regina Elena, 324, 00161 Rome, Italy.
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40
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Chang ZG, Yang LY, Wang W, Peng JX, Huang GW, Tao YM, Ding X. Determination of high mobility group A1 (HMGA1) expression in hepatocellular carcinoma: a potential prognostic marker. Dig Dis Sci 2005; 50:1764-70. [PMID: 16187170 DOI: 10.1007/s10620-005-2934-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2004] [Accepted: 02/24/2005] [Indexed: 01/04/2023]
Abstract
Our objective was to investigate the expression of HMGA1 mRNA and protein in hepatocellular carcinoma (HCC) and the correlation between its expression and clinical pathological characteristics and prognosis. HMGA1 expression was determined at both the mRNA level and the protein level in 30 HCC tissues and their corresponding paracancer liver tissues (PCLTs) and 2 normal liver tissues by RT-PCR and IHC. Follow-up study was done on the 30 patients involved in this research. HMGA1 mRNA was detected in nine cases of HCC tissues and two PCLTs, for a positivity rate of 30% and 6.7%, respectively (P < 0.05), whereas no HMGA1 mRNA expression was found in normal liver tissues. Clinicopathological analysis revealed that HMGA1 mRNA expression was significantly correlated with Edmondson's grade (P < 0.05). HMGA1 protein was detected in four HCC tissues by IHC and located mainly in the nuclei; no positive staining was found in PCLTs. Follow-up study showed that HMGA1 mRNA-positive patients had a higher risk of recurrence/metastasis and a shorter survival than negative cases (P < 0.05). Our findings indicate that HMGA1 may be involved in the carcinogenesis and invasiveness of HCC and the determination of HMGA1 can be of great value in predicting the prognosis of patients with HCC.
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Affiliation(s)
- Zhi-Gang Chang
- Liver Cancer Laboratory and Department of General Surgery, Xiangya Hospital, Central South University, Hunan, PR China
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41
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Bogatcheva NV, Sergeeva MG, Dudek SM, Verin AD. Arachidonic acid cascade in endothelial pathobiology. Microvasc Res 2005; 69:107-27. [PMID: 15896353 DOI: 10.1016/j.mvr.2005.01.007] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2004] [Revised: 01/21/2005] [Accepted: 01/26/2005] [Indexed: 01/26/2023]
Abstract
Arachidonic acid (AA) and its metabolites (eicosanoids) represent powerful mediators, used by organisms to induce and suppress inflammation as a part of the innate response to disturbances. Several cell types participate in the synthesis and release of AA metabolites, while many cell types represent the targets for eicosanoid action. Endothelial cells (EC), forming a semi-permeable barrier between the interior space of blood vessels and underlying tissues, are of particular importance for the development of inflammation, since endothelium controls such diverse processes as vascular tone, homeostasis, adhesion of platelets and leukocytes to the vascular wall, and permeability of the vascular wall for cells and fluids. Proliferation and migration of endothelial cells contribute significantly to new vessel development (angiogenesis). This review discusses endothelial-specific synthesis and action of arachidonic acid derivatives with a particular focus on the mechanisms of signal transduction and associated intracellular protein targets.
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Affiliation(s)
- Natalia V Bogatcheva
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA
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Kranenburg O, Gebbink MFBG, Voest EE. Stimulation of angiogenesis by Ras proteins. Biochim Biophys Acta Rev Cancer 2004; 1654:23-37. [PMID: 14984765 DOI: 10.1016/j.bbcan.2003.09.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2003] [Accepted: 09/03/2003] [Indexed: 12/13/2022]
Abstract
Cells that have acquired a proliferative advantage form islets of hyperplasia during the initial stages of tumor development. Like normal cells, they require oxygen and nutrients to survive and proliferate. The centre of the islets is characterized by low oxygen pressure and low pH, conditions that stimulate the sprouting of new capillaries from nearby vascular beds. It is now well established that neovascularisation (angiogenesis) of the hyperplasias is essential for further development of the tumor. The family of ras oncogenes promotes the initiation of tumor growth by stimulating tumor cell proliferation, but also ensures tumor progression by stimulating tumor-associated angiogenesis. Oncogenic Ras proteins stimulate a number of effector pathways that culminate in the transcriptional activation of genes that control angiogenesis. Moreover, Ras signaling leads to stabilization of the produced mRNAs and, possibly, to enhanced initiation of their translation. In this review we describe the mechanisms that underlie Ras regulation of vascular endothelial growth factor (VEGF), cyclooxygenases (COX-1/-2), thrombospondins (TSP-1/-2), urokinase plasminogen activator (uPA) and matrix metalloproteases-2 and -9 (MMP-2/-9). As a result of these Ras-regulated changes in gene expression, the tumor cells cause stimulation of endothelial cells in nearby vascular beds (directly via VEGF, and indirectly via COX-produced prostaglandins) and promote remodeling of the extracellular matrix (by lowering TSP and increasing uPA/MMPs). The latter effect makes growth factors available for endothelial cell activation and migration. In addition, tumor cell-activated stromal cells also contribute to the stimulation of angiogenesis by further enhancing the production and secretion of pro-angiogenic factors into the tumor stroma.
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Affiliation(s)
- Onno Kranenburg
- Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
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Yamashita K, Imaizumi T, Hatakeyama M, Tamo W, Kimura D, Kumagai M, Yoshida H, Satoh K. Effect of hypoxia on the expression of fractalkine in human endothelial cells. TOHOKU J EXP MED 2004; 200:187-94. [PMID: 14580149 DOI: 10.1620/tjem.200.187] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
CX3CL1/fractalkine is a chemokine with a unique CX3C motif. Hypoxia mediates the expression of various genes, such as vascular endothelial growth factor (VEGF), cyclooxygenase-2, and plasminogen-activator inhibitor-1, in vascular endothelial cells. We studied the effect of hypoxia on the expression of fractalkine induced by interferon-gamma (IFN-gamma) in endothelial cells. Human umbilical vein endothelial cells were cultured, and the stimulation of the cells with IFN-gamma was found to induce the expression of fractalkine. Hypoxia inhibited the expression of fractalkine mRNA and protein by IFN-gamma, and this effect was observed with concomitant increase in VEGF expression. Desferrioxamine, an iron chelator that mimics hypoxia in vitro, also inhibited the fractalkine production induced by IFN-gamma. Hypoxia did not affect the degradation of fractalkine mRNA. The inhibition of fractalkine expression by hypoxia was reversed on returning the cultures to reoxygenation condition. Inhibition of IFN-induced fractalkine expression by hypoxia was not affected by the presence of a radical scavenger, N-acetyl-L-cysteine, and the involvement of reactive oxygen species may be excluded. Inhibition of fractalkine expression by hypoxia may be involved in the pathophysiology of ischemic diseases.
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Affiliation(s)
- Koji Yamashita
- Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
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Müller R. Crosstalk of oncogenic and prostanoid signaling pathways. J Cancer Res Clin Oncol 2004; 130:429-44. [PMID: 15205946 DOI: 10.1007/s00432-004-0570-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2004] [Accepted: 03/16/2004] [Indexed: 12/21/2022]
Affiliation(s)
- Rolf Müller
- Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
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Ogawa H, Rafiee P, Fisher PJ, Johnson NA, Otterson MF, Binion DG. Butyrate modulates gene and protein expression in human intestinal endothelial cells. Biochem Biophys Res Commun 2003; 309:512-9. [PMID: 12963019 DOI: 10.1016/j.bbrc.2003.08.026] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We hypothesized that sodium butyrate, a product of enteric bacterial fermentation, modulates gene expression in gut microvascular endothelium which plays a central role in mucosal immunity. We examined sodium butyrate's effect on LPS-induced gene and protein expression in primary cultures of human intestinal microvascular endothelial cells. cDNA array analysis revealed that sodium butyrate augmented ICAM-1 mRNA expression, while it inhibited IL-6 and COX-2 expression in response to LPS stimulation. These results were confirmed at the protein level. Prostaglandin E2 production by LPS was also strongly inhibited by butyrate. The pattern of altered gene expression by butyrate was reproduced by the histone deacetylase inhibitor tricostatin A, suggesting that the regulatory mechanism of butyrate on HIMEC gene expression involves histone deacetylase inhibition. IkappaBalpha degradation and NF-kappaB activation were unaffected by butyrate. In addition to effects on epithelium, sodium butyrate modulates the innate mucosal immune response towards LPS through effects on microvascular endothelial function.
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Affiliation(s)
- Hitoshi Ogawa
- Department of Medicine, Digestive Disease Center, Free Radical Research Center, Froedtert Memorial Lutheran Hospital, Milwaukee Veterans Administration Medical Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Bacterial lipopolysaccharide induces retinoic acid-inducible gene-I in vascular endothelial cells. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s0531-5131(03)00121-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Colgan SP, Taylor CT, Narravula S, Synnestvedt K, Blume ED. Endothelial COX-2 induction by hypoxia liberates 6-keto-PGF1 alpha, a potent epithelial secretagogue. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 507:107-12. [PMID: 12664572 DOI: 10.1007/978-1-4615-0193-0_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Affiliation(s)
- Sean P Colgan
- Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, MA
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Abstract
BACKGROUND Prostaglandins, synthesized by cyclo-oxygenase (COX), regulate renal hemodynamics and also epithelial water and solute transport. Developmental changes occur in COX-2 mRNA expression and its response to lipopolysaccharide stimulation in rats. We examined age-related changes in COX mRNA expression induced by hypoxia in the renal cortex and medulla of developing rats. METHODS Total RNA was extracted from 1- and 4-week-old male Wistar rats exposed to one or 4 h of hypoxia (8% O2). Cyclo-oxygenase mRNA was quantitatively analyzed using a real-time polymerase chain reaction with dual-labeled fluorogenic probes. RESULTS Expression of COX-1 mRNA did not change in response to hypoxia in the cortex or medulla in either infantile or adult rats. In infantile rats, COX-2 mRNA expression was not induced by one or 4 h of hypoxia. In adults, 1- and 4-h exposures to hypoxia induced COX-2 mRNA in the renal cortex, and 1-h of exposure induced COX-2 mRNA in the medulla. CONCLUSIONS Response of expression of COX-2 mRNA in rats exposed to acute hypoxia show age-related variability treated by acute hypoxia. Cyclo-oxygenase-2 might not play a major role in the hypoxic infantile rat kidney.
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Affiliation(s)
- Tetsushi Ogawa
- Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
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Yang X, Sheares KKK, Davie N, Upton PD, Taylor GW, Horsley J, Wharton J, Morrell NW. Hypoxic induction of cox-2 regulates proliferation of human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 2002; 27:688-96. [PMID: 12444028 DOI: 10.1165/rcmb.2002-0067oc] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Therefore, we examined the effect of hypoxia on growth of pulmonary artery smooth muscle cells (PASMCs) from human distal pulmonary arteries. Initial studies identified that serum-induced proliferation of explant-derived PASMCs was inhibited under hypoxic conditions (3-4 kPa in medium). However, selection of hypoxia-stimulated cells was achieved by culturing cells at low density under conditions of prolonged hypoxia (1-2 wk). In hypoxia-inhibited and -stimulated cells, Western blotting revealed hypoxic induction of cyclooxygenase (COX)-2, which was dependent on the activation of p38(MAPK), but not COX-1, inducible nitric oxide synthase (iNOS), or hemoxygenase-1 (HO-1). Hypoxic induction of COX-2 was also observed in the media of pulmonary arteries in lung organ culture. Hypoxia induced a 4- to 5-fold increase (P < 0.001) in prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and 6-keto-PGF(1alpha) release from PASMCs. Hypoxic inhibition of proliferation was attenuated by incubation with indomethacin (10 micro M), or the COX-2 antagonist, NS398 (10 micro M), but not by the COX-1 antagonist, valeryl salicylate (0.5 mM). In conclusion, we have isolated cells from human peripheral pulmonary arteries that are either inhibited or stimulated by culture under hypoxic conditions. In both cell types hypoxia modulates cell proliferation by induction of COX-2 and production of antiproliferative prostaglandins. Induction of COX-2 may contribute to the inhibition of hypoxia-induced pulmonary vascular remodeling.
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Affiliation(s)
- Xudong Yang
- Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospitals, Cambridge, UK
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Abstract
Hypoxia is sensed by all mammalian cells and elicits a variety of adaptive and pathophysiological responses at the molecular and cellular level. For the pulmonary vasculature, hypoxia causes increased vasoconstriction and vessel-wall remodeling. These responses are mediated by complex intracellular cascades leading to altered gene expression and cell-cell interaction. Hypoxia transiently increases the transcriptional rate of the heme oxygenase-1 (HO-1) gene, resulting in increased production of carbon monoxide (CO) and bilirubin. CO has vasodilatory and antiinflammatory properties in the vasculature, whereas bilirubin is an antioxidant. Both enzymatic products could thus modulate the hypoxic cellular response. Accumulating data suggest that CO inhibits the hypoxic induction of genes encoding vasoconstrictors and smooth muscle cell mitogens in the early hypoxic phase. During chronic hypoxia, low CO levels tilt the balance toward increased production of growth factors and vasoconstrictors that promote vessel-wall remodeling. Mice null in the HO-1 gene manifest decreased tolerance to hypoxia with right ventricular dilatation and infarction, whereas targeted lung overexpression of HO-1 prevents hypoxia-induced inflammatory responses and protects against the development of pulmonary hypertension. Such observations point to CO as a critical modulator of the body's adaptive responses to hypoxia.
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Affiliation(s)
- Stella Kourembanas
- Department of Medicine, Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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