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Torang A, Kirov AB, Lammers V, Cameron K, Wouters VM, Jackstadt RF, Lannagan TRM, de Jong JH, Koster J, Sansom O, Medema JP. Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability. Nat Commun 2025; 16:264. [PMID: 39747069 PMCID: PMC11696116 DOI: 10.1038/s41467-024-55574-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 12/13/2024] [Indexed: 01/04/2025] Open
Abstract
Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition.
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Affiliation(s)
- Arezo Torang
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Aleksandar B Kirov
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Veerle Lammers
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Kate Cameron
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Valérie M Wouters
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Rene F Jackstadt
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Heidelberg, Germany Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
| | | | - Joan H de Jong
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Jan Koster
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Owen Sansom
- Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
- Oncode Institute, Amsterdam, the Netherlands.
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Mestrovic A, Perkovic N, Bozic D, Kumric M, Vilovic M, Bozic J. Precision Medicine in Inflammatory Bowel Disease: A Spotlight on Emerging Molecular Biomarkers. Biomedicines 2024; 12:1520. [PMID: 39062093 PMCID: PMC11274502 DOI: 10.3390/biomedicines12071520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/30/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
Inflammatory bowel diseases (IBD) remain challenging in terms of understanding their causes and in terms of diagnosing, treating, and monitoring patients. Modern diagnosis combines biomarkers, imaging, and endoscopic methods. Common biomarkers like CRP and fecal calprotectin, while invaluable tools, have limitations and are not entirely specific to IBD. The limitations of existing markers and the invasiveness of endoscopic procedures highlight the need to discover and implement new markers. With an ideal biomarker, we could predict the risk of disease development, as well as the possibility of response to a particular therapy, which would be significant in elucidating the pathogenesis of the disease. Recent research in the fields of machine learning, proteomics, epigenetics, and gut microbiota provides further insight into the pathogenesis of the disease and is also revealing new biomarkers. New markers, such as BAFF, PGE-MUM, oncostatin M, microRNA panels, αvβ6 antibody, and S100A12 from stool, are increasingly being identified, with αvβ6 antibody and oncostatin M being potentially close to being presented into clinical practice. However, the specificity of certain markers still remains problematic. Furthermore, the use of expensive and less accessible technology for detecting new markers, such as microRNAs, represents a limitation for widespread use in clinical practice. Nevertheless, the need for non-invasive, comprehensive markers is becoming increasingly important regarding the complexity of treatment and overall management of IBD.
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Affiliation(s)
- Antonio Mestrovic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Nikola Perkovic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Dorotea Bozic
- Department of Gastroenterology, University Hospital of Split, Spinciceva 2, 21000 Split, Croatia; (A.M.); (N.P.); (D.B.)
| | - Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
| | - Marino Vilovic
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia;
- Laboratory for Cardiometabolic Research, University of Split School of Medicine, Soltanska 2A, 21000 Split, Croatia
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Bhasin N, Dabra P, Senavirathna L, Pan S, Chen R. Inhibition of TRAP1 Accelerates the DNA Damage Response, Activation of the Heat Shock Response and Metabolic Reprogramming in Colon Cancer Cells. FRONT BIOSCI-LANDMRK 2023; 28:227. [PMID: 37796715 PMCID: PMC10727129 DOI: 10.31083/j.fbl2809227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/29/2023] [Accepted: 08/24/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the major causes of cancer-related mortality worldwide. The tumor microenvironment plays a significant role in CRC development, progression and metastasis. Oxidative stress in the colon is a major etiological factor impacting tumor progression. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial member of the heat shock protein 90 (HSP90) family that is involved in modulating apoptosis in colon cancer cells under oxidative stress. We undertook this study to provide mechanistic insight into the role of TRAP1 under oxidative stress in colon cells. METHODS We first assessed the The Cancer Genome Atlas (TCGA) CRC gene expression dataset to evaluate the expression of TRAP1 and its association with oxidative stress and disease progression. We then treated colon HCT116 cells with hydrogen peroxide to induce oxidative stress and with the TRAP1 inhibitor gamitrinib-triphenylphosphonium (GTPP) to inhibit TRAP1. We examined the cellular proteomic landscape using liquid chromatography tandem mass spectrometry (LC-MS/MS) in this context compared to controls. We further examined the impact of treatment on DNA damage and cell survival. RESULTS TRAP1 expression under oxidative stress is associated with the disease outcomes of colorectal cancer. TRAP1 inhibition under oxidative stress induced metabolic reprogramming and heat shock factor 1 (HSF1)-dependent transactivation. In addition, we also observed enhanced induction of DNA damage and cell death in the cells under oxidative stress and TRAP1 inhibition in comparison to single treatments and the nontreatment control. CONCLUSIONS These findings provide new insights into TRAP1-driven metabolic reprogramming in response to oxidative stress.
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Affiliation(s)
- Nobel Bhasin
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Prerna Dabra
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, University of Texas at Houston Health Science Center, Houston, TX, United States
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, University of Texas at Houston Health Science Center, Houston, TX, United States
| | - Ru Chen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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4
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Fabian O, Bajer L, Drastich P, Harant K, Sticova E, Daskova N, Modos I, Tichanek F, Cahova M. A Current State of Proteomics in Adult and Pediatric Inflammatory Bowel Diseases: A Systematic Search and Review. Int J Mol Sci 2023; 24:ijms24119386. [PMID: 37298338 DOI: 10.3390/ijms24119386] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are systemic immune-mediated conditions with predilection for the gastrointestinal tract and include Crohn's disease and ulcerative colitis. Despite the advances in the fields of basic and applied research, the etiopathogenesis remains largely unknown. As a result, only one third of the patients achieve endoscopic remission. A substantial portion of the patients also develop severe clinical complications or neoplasia. The need for novel biomarkers that can enhance diagnostic accuracy, more precisely reflect disease activity, and predict a complicated disease course, thus, remains high. Genomic and transcriptomic studies contributed substantially to our understanding of the immunopathological pathways involved in disease initiation and progression. However, eventual genomic alterations do not necessarily translate into the final clinical picture. Proteomics may represent a missing link between the genome, transcriptome, and phenotypical presentation of the disease. Based on the analysis of a large spectrum of proteins in tissues, it seems to be a promising method for the identification of new biomarkers. This systematic search and review summarize the current state of proteomics in human IBD. It comments on the utility of proteomics in research, describes the basic proteomic techniques, and provides an up-to-date overview of available studies in both adult and pediatric IBD.
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Affiliation(s)
- Ondrej Fabian
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
- Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University and Thomayer Hospital, 140 59 Prague, Czech Republic
| | - Lukas Bajer
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
- Institute of Microbiology, Czech Academy of Sciences, 142 20 Prague, Czech Republic
| | - Pavel Drastich
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
| | - Karel Harant
- Proteomics Core Facility, Faculty of Science, Charles University, 252 50 Vestec, Czech Republic
| | - Eva Sticova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
- Department of Pathology, Royal Vinohrady Teaching Hospital, Srobarova 1150/50, 100 00 Prague, Czech Republic
| | - Nikola Daskova
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
| | - Istvan Modos
- Department of Informatics, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
| | - Filip Tichanek
- Department of Informatics, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
| | - Monika Cahova
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic
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5
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Cicio A, Serio R, Zizzo MG. Anti-Inflammatory Potential of Brassicaceae-Derived Phytochemicals: In Vitro and In Vivo Evidence for a Putative Role in the Prevention and Treatment of IBD. Nutrients 2022; 15:nu15010031. [PMID: 36615689 PMCID: PMC9824272 DOI: 10.3390/nu15010031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of intestinal disorders, of unknown etiology, characterized by chronic inflammation within the gut. They are gradually becoming critical because of the increasing incidence worldwide and improved diagnosis. Due to the important side effects observed during conventional therapy, natural bioactive components are now under intense investigation for the prevention and treatment of chronic illnesses. The Brassicaceae family comprises vegetables widely consumed all over the world. In recent decades, a growing body of literature has reported that extracts from the Brassicaceae family and their purified constituents have anti-inflammatory properties, which has generated interest from both the scientific community and clinicians. In this review, data from the literature are scrutinized and concisely presented demonstrating that Brassicaceae may have anti-IBD potential. The excellent biological activities of Brassicacea are widely attributable to their ability to regulate the levels of inflammatory and oxidant mediators, as well as their capacity for immunomodulatory regulation, maintenance of intestinal barrier integrity and intestinal flora balance. Possible future applications of bioactive-derived compounds from Brassicaceae for promoting intestinal health should be investigated.
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Affiliation(s)
- Adele Cicio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, ed 16, 90128 Palermo, Italy
| | - Rosa Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, ed 16, 90128 Palermo, Italy
| | - Maria Grazia Zizzo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, ed 16, 90128 Palermo, Italy
- ATeN (Advanced Technologies Network) Center, Viale delle Scienze, University of Palermo, 90128 Palermo, Italy
- Correspondence:
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Tsai HY, Bronner MP, March JK, Valentine JF, Shroyer NF, Lai LA, Brentnall TA, Pan S, Chen R. Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer. Cancer Lett 2022; 549:215915. [PMID: 36113636 PMCID: PMC11262000 DOI: 10.1016/j.canlet.2022.215915] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 09/02/2022] [Accepted: 09/08/2022] [Indexed: 01/12/2023]
Abstract
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.
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Affiliation(s)
- Hong-Yuan Tsai
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
| | - Mary P Bronner
- Department of Pathology, University of Utah, Salt Lake City, UT, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Jordon K March
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - John F Valentine
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Noah F Shroyer
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Lisa A Lai
- Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Sheng Pan
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ru Chen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
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Senavirathna L, Ma C, Chen R, Pan S. Spectral Library-Based Single-Cell Proteomics Resolves Cellular Heterogeneity. Cells 2022; 11:cells11152450. [PMID: 35954294 PMCID: PMC9368228 DOI: 10.3390/cells11152450] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/29/2022] [Accepted: 08/04/2022] [Indexed: 02/07/2023] Open
Abstract
Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant challenges remain in analyzing an extremely small amount of proteins collected from a single cell, as a proteome-wide amplification of proteins is not currently feasible. Here, we report an integrated spectral library-based single-cell proteomics (SLB-SCP) platform that is ultrasensitive and well suited for a large-scale analysis. To overcome the low MS/MS signal intensity intrinsically associated with a single-cell analysis, this approach takes an alternative approach by extracting a breadth of information that specifically defines the physicochemical characteristics of a peptide from MS1 spectra, including monoisotopic mass, isotopic distribution, and retention time (hydrophobicity), and uses a spectral library for proteomic identification. This conceptually unique MS platform, coupled with the DIRECT sample preparation method, enabled identification of more than 2000 proteins in a single cell to distinguish different proteome landscapes associated with cellular types and heterogeneity. We characterized individual normal and cancerous pancreatic ductal cells (HPDE and PANC-1, respectively) and demonstrated the substantial difference in the proteomes between HPDE and PANC-1 at the single-cell level. A significant upregulation of multiple protein networks in cancer hallmarks was identified in the PANC-1 cells, functionally discriminating the PANC-1 cells from the HPDE cells. This integrated platform can be built on high-resolution MS and widely accepted proteomic software, making it possible for community-wide applications.
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Affiliation(s)
- Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Cheng Ma
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ru Chen
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Correspondence:
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8
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Chen HM, MacDonald JA. Molecular Network Analyses Implicate Death-Associated Protein Kinase 3 (DAPK3) as a Key Factor in Colitis-Associated Dysplasia Progression. Inflamm Bowel Dis 2022; 28:1485-1496. [PMID: 35604388 PMCID: PMC9527615 DOI: 10.1093/ibd/izac098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a progressive disorder that elevates the risk of colon cancer development through a colitis-dysplasia-carcinoma sequence. Gene expression profiling of colitis-associated lesions obtained from patients with varied extents of UC can be mined to define molecular panels associated with colon cancer development. METHODS Differential gene expression profiles of 3 UC clinical subtypes and healthy controls were developed for the GSE47908 microarray data set of healthy controls, left-sided colitis, pancolitis, and colitis-associated dysplasia (CAD) using limma R. RESULTS A gene ontology enrichment analysis of differentially expressed genes (DEGs) revealed a shift in the transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein [YAP]) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. A molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed 1 pairwise line, or edge, that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase member of this network. Death-associated protein kinase 3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls that flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. CONCLUSION In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.
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Affiliation(s)
- Huey-Miin Chen
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Justin A MacDonald
- Address correspondence to: Justin A. MacDonald, PhD, Department of Biochemistry & Molecular Biology, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6 ()
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Baldan-Martin M, Chaparro M, Gisbert JP. Tissue Proteomic Approaches to Understand the Pathogenesis of Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1184-1200. [PMID: 33529308 DOI: 10.1093/ibd/izaa352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) has become a global disease encompassing a group of progressive disorders characterized by recurrent chronic inflammation of the gut with variable disease courses and complications. Despite recent advances in the knowledge of IBD pathophysiology, the elucidation of its etiopathology and progression is far from fully understood, requiring complex and multiple approaches. Therefore, limited clinical progress in diagnosis, assessment of disease activity, and optimal therapeutic regimens have been made over the past few decades. This review explores recent advances and challenges in tissue proteomics with an emphasis on biomarker discovery and better understanding of the molecular mechanisms underlying IBD pathogenesis. Future multi-omic studies are required for the comprehensive molecular characterization of disease biology in real time with a future impact on early detection, disease monitoring, and prediction of the clinical outcome.
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Affiliation(s)
- Montserrat Baldan-Martin
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
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10
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Cocetta V, Governa P, Borgonetti V, Tinazzi M, Peron G, Catanzaro D, Berretta M, Biagi M, Manetti F, Dall'Acqua S, Montopoli M. Cannabidiol Isolated From Cannabis sativa L. Protects Intestinal Barrier From In Vitro Inflammation and Oxidative Stress. Front Pharmacol 2021; 12:641210. [PMID: 33995048 PMCID: PMC8115937 DOI: 10.3389/fphar.2021.641210] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 04/08/2021] [Indexed: 12/11/2022] Open
Abstract
The relevance and incidence of intestinal bowel diseases (IBD) have been increasing over the last 50 years and the current therapies are characterized by severe side effects, making essential the development of new strategies that combine efficacy and safety in the management of human IBD. Herbal products are highly considered in research aimed at discovering new approaches for IBD therapy and, among others, Cannabis sativa L. has been traditionally used for centuries as an analgesic and anti-inflammatory remedy also in different gastrointestinal disorders. This study aims to investigate the effects of different C. sativa isolated compounds in an in vitro model of intestinal epithelium. The ability of treatments to modulate markers of intestinal dysfunctions was tested on Caco-2 intestinal cell monolayers. Our results, obtained by evaluation of ROS production, TEER and paracellular permeability measurements and tight junctions evaluation show Cannabidiol as the most promising compound against intestinal inflammatory condition. Cannabidiol is able to inhibit ROS production and restore epithelial permeability during inflammatory and oxidative stress conditions, suggesting its possible application as adjuvant in IBD management.
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Affiliation(s)
- Veronica Cocetta
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Paolo Governa
- Department of Biotechnology, Chemistry and Pharmacy Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Vittoria Borgonetti
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy
| | - Mattia Tinazzi
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Gregorio Peron
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Daniela Catanzaro
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Marco Biagi
- Department of Physical Sciences, Earth and Environment, University of Siena, Siena, Italy
| | - Fabrizio Manetti
- Department of Biotechnology, Chemistry and Pharmacy Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Stefano Dall'Acqua
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | - Monica Montopoli
- Department of Pharmaceutical Sciences, University of Padova, Padova, Italy.,Veneto Institute of Molecular Medicine, VIMM, Padova, Italy
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Abstract
Colorectal cancer (CRC) is characterized by genetic-environmental interplay leading to diffuse changes in the entire colonic mucosa (field carcinogenesis or field of injury) and to a pro-neoplastic genetic/epigenetic/physiological milieu. The clinical consequences are increased risk of synchronous and metachronous neoplasia. Factors such as genetics, race, ethnicity, age, and socioeconomic status are thought to influence neoplasia development. Here, we explore the potential improvement to CRC screening through exploiting field carcinogenesis, with particular focus on racial disparities and chemoprevention strategies. Also, we discuss future directions for field carcinogenesis/risk stratification using molecular and novel biophotonic techniques for personalized CRC screening.
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Minakshi P, Kumar R, Ghosh M, Brar B, Barnela M, Lakhani P. Application of Polymeric Nano-Materials in Management of Inflammatory Bowel Disease. Curr Top Med Chem 2021; 20:982-1008. [PMID: 32196449 DOI: 10.2174/1568026620666200320113322] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/25/2020] [Accepted: 02/24/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory Bowel Disease (IBD) is an umbrella term used to describe disorders that involve Crohn's disease (CD), ulcerative colitis (UC) and pouchitis. The disease occurrence is more prevalent in the working group population which not only hampers the well being of an individual but also has negative economical impact on society. The current drug regime used therapy is very costly owing to the chronic nature of the disease leading to several side effects. The condition gets more aggravated due to the lower concentration of drug at the desired site. Therefore, in the present scenario, a therapy is needed which can maximize efficacy, adhere to quality of life, minimize toxicity and doses, be helpful in maintaining and stimulating physical growth of mucosa with minimum disease complications. In this aspect, nanotechnology intervention is one promising field as it can act as a carrier to reduce toxicity, doses and frequency which in turn help in faster recovery. Moreover, nanomedicine and nanodiagnostic techniques will further open a new window for treatment in understanding pathogenesis along with better diagnosis which is poorly understood till now. Therefore the present review is more focused on recent advancements in IBD in the application of nanotechnology.
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Affiliation(s)
- Prasad Minakshi
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125001, Haryana, India
| | - Rajesh Kumar
- Department of Veterinary Physiology & Biochemistry, LUVAS, Hisar-125 004, India
| | - Mayukh Ghosh
- Department of Veterinary Physiology and Biochemistry, RGSC, Banaras Hindu University, Mirzapur (UP) - 231001, India
| | - Basanti Brar
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125001, Haryana, India
| | - Manju Barnela
- Department of Nano & Biotechnology, Guru Jambheshwar University, Hisar-125001, Haryana, India
| | - Preeti Lakhani
- Department of Veterinary Physiology & Biochemistry, LUVAS, Hisar-125 004, India
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13
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Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement. Clin Transl Gastroenterol 2020; 10:e00105. [PMID: 31789935 PMCID: PMC6970556 DOI: 10.14309/ctg.0000000000000105] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES: Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. METHODS: We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. RESULTS: UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). DISCUSSION: Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.
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Ahmad G, Chami B, Liu Y, Schroder AL, San Gabriel PT, Gao A, Fong G, Wang X, Witting PK. The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis. Front Pharmacol 2020; 11:556020. [PMID: 33041796 PMCID: PMC7522858 DOI: 10.3389/fphar.2020.556020] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
Chronic inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including increased risk malignancies. The current study aimed to target neutrophil-myeloperoxidase, a key contributor to the pathogenesis of IBD, through the use of AZD3241that inhibits extracellular myeloperoxidase. Experimental colitis was induced in C57BL/6 male mice by 2% dextran sodium sulfate in drinking water ad libitum over 9 days. Mice received either normal drinking water and peanut butter (control), 2% DSS in drinking water and peanut butter or 2% DSS in drinking water and AZD3241 (30 mg/kg) dispersed in peanut butter daily for 9 days. Administered AZD3241 attenuated body weight loss (10% p<0.05) and improved clinical score (9 fold p<0.05; a score comprising the time-dependent assessment of stool consistency and extent of rectal bleeding), loss of colonic crypts (p<0.001), preserved surface epithelium (p<0.001) and enhanced expression of the transcription factor Nrf-2 (regulator of antioxidants) and enhanced expression of the downstream antioxidant response element haeoxygenase-1 (HO-1) in the colon tissue. Also, the concentration of fecal hemoglobin and the myeloperoxidase specific oxidative damage biomarker 3-chlorotyrosine in the colon were significantly decreased in the presence of AZD3241. This latter result was consistent with AZD3241 inhibiting MPO activity in vitro. Overall, AZD3241 ameliorated the course and severity of experimental colitis through ameliorating MPO derived tissue damage and could be considered a potential therapeutic option, subject to further validation in chronic IBD models.
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Affiliation(s)
- Gulfam Ahmad
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Belal Chami
- Discipline of Oral Pathology, Faculty of Medicine and Health, School of Dentistry, The University of Sydney, Sydney, NSW, Australia
| | - Yuyang Liu
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Angie L Schroder
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Patrick T San Gabriel
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Antony Gao
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Genevieve Fong
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - XiaoSuo Wang
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Paul K Witting
- Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
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15
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Merli AM, Vieujean S, Massot C, Blétard N, Quesada Calvo F, Baiwir D, Mazzucchelli G, Servais L, Wéra O, Oury C, de Leval L, Sempoux C, Manzini R, Bluemel S, Scharl M, Rogler G, De Pauw E, Coimbra Marques C, Colard A, Vijverman A, Delvenne P, Louis E, Meuwis MA. Solute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis. J Crohns Colitis 2020; 15:jjaa168. [PMID: 32920643 DOI: 10.1093/ecco-jcc/jjaa168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. METHODS A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. RESULTS Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed "loss of gradient" reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 - 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. CONCLUSIONS We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.
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Affiliation(s)
- Angela-Maria Merli
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
| | - Sophie Vieujean
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Charlotte Massot
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Noella Blétard
- Pathological Anatomy and Cytology, University Hospital CHU of Liège, Liège, Belgium
| | | | | | | | - Laurence Servais
- Laboratory of Cardiology, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Odile Wéra
- Laboratory of Cardiology, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Cécile Oury
- Laboratory of Cardiology, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - Laurence de Leval
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Christine Sempoux
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Roberto Manzini
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Sena Bluemel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Edwin De Pauw
- Laboratory of Mass Spectrometry, University of Liège, Liège, Belgium
| | - C Coimbra Marques
- Abdominal Surgery Department, University Hospital CHU of Liège, Liège, Belgium
| | - Arnaud Colard
- Department of Gastroenterology, CHC Clinique Saint-Joseph, Liège, Belgium
| | - Anne Vijverman
- Department of Gastroenterology, CHR Citadelle, Liège, Belgium
| | - Philippe Delvenne
- Pathological Anatomy and Cytology, University Hospital CHU of Liège, Liège, Belgium
| | - Edouard Louis
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Equally contributed to this work
| | - Marie-Alice Meuwis
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Equally contributed to this work
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Moura FA, Goulart MOF, Campos SBG, da Paz Martins AS. The Close Interplay of Nitro-Oxidative Stress, Advanced Glycation end Products and Inflammation in Inflammatory Bowel Diseases. Curr Med Chem 2020; 27:2059-2076. [PMID: 30182837 DOI: 10.2174/0929867325666180904115633] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 07/29/2018] [Accepted: 08/11/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Inflammatory Bowel Disease (IBD) exhibits no defined aetiology. However, factors such as genetic and nitro-oxidative stress are associated with chronic inflammation and IBD progression to Colorectal Cancer (CRC). The present review discusses the association of nitro-oxidative stress, inflammation and Advanced Glycation End products (AGE) and their corresponding receptor (RAGE) in IBD and examines the connection between these factors and nuclear factors, such as Nuclear Factor Kappa B (NF-κB), factorerythroid 2-related factor-2 (Nrf2), and p53 Mutant (p53M). METHODS We searched the PubMed, ScienceDirect and Web of Science databases using a combination of the following terms: IBD, CRC, oxidative stress, inflammation, NF-κB, Nrf2, p53M, AGE and RAGE. RESULTS Oxidative stress and inflammation activated two cellular pathways, the nuclear expression of pro-inflammatory, pro-oxidant and pro-oncogenic genes based on NF-κB and p53M, which is associated with NF-κB activation, Deoxyribonucleic acid (DNA) damage and the expression of pro-oncogenic genes. Nrf2 stimulates the nuclear expression of enzymatic and non-enzymatic antioxidant systems and anti-inflammatory genes, and is inhibited by chronic oxidative stress, NF-κB and p53M. AGE/RAGE are involved in inflammation progression because RAGE polymorphisms and increased RAGE levels are found in IBD patients. Alterations of these pathways in combination with oxidative damage are responsible for IBD symptoms and the progression to CRC. CONCLUSION IBD is an inflammatory and nitro-oxidative stress-based bowel disease. Achieving a molecular understanding of the biochemical events and their complicated interactions will impact basic and applied research, animal models, and clinical trials.
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Affiliation(s)
- Fabiana Andréa Moura
- Faculdade de Nutrição/Universidade Federal de Alagoas (FANUT/UFAL), Campus A. C. Simões, Avenida Lourival Melo Mota, s/n, Tabuleiro dos Martins, 57072-970 Maceió, Alagoas, Brazil
| | | | - Samara Bonfim Gomes Campos
- Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Universidade Federal de Alagoas (UFAL), 57072-970 Maceió, Alagoas, Brazil
| | - Amylly Sanuelly da Paz Martins
- Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Universidade Federal de Alagoas (UFAL), 57072-970 Maceió, Alagoas, Brazil
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Rolfe A, Yao S, Nguyen TV, Omoto K, Colombo F, Virrankoski M, Vaillancourt FH, Yu L, Cook A, Reynolds D, Ioannidis S, Zhu P, Larsen NA, Bolduc DM. Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1. ACS Med Chem Lett 2020; 11:1305-1309. [PMID: 32551016 DOI: 10.1021/acsmedchemlett.0c00145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/21/2020] [Indexed: 12/24/2022] Open
Abstract
Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (25), a potent allosteric inhibitor of CPS1 (IC50 = 66 nM).
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Affiliation(s)
- Alan Rolfe
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Shihua Yao
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Toung-Vi Nguyen
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Kiyoyuki Omoto
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Federico Colombo
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Milena Virrankoski
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Frédéric H. Vaillancourt
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Lihua Yu
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Andrew Cook
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Dominic Reynolds
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Stephanos Ioannidis
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Ping Zhu
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - Nicholas A. Larsen
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
| | - David M. Bolduc
- H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States
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18
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Yao S, Nguyen TV, Rolfe A, Agrawal AA, Ke J, Peng S, Colombo F, Yu S, Bouchard P, Wu J, Huang KC, Bao X, Omoto K, Selvaraj A, Yu L, Ioannidis S, Vaillancourt FH, Zhu P, Larsen NA, Bolduc DM. Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket. Cell Chem Biol 2020; 27:259-268.e5. [PMID: 32017919 DOI: 10.1016/j.chembiol.2020.01.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/09/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.
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Affiliation(s)
- Shihua Yao
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Tuong-Vi Nguyen
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Alan Rolfe
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Anant A Agrawal
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Jiyuan Ke
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Shouyong Peng
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Federico Colombo
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Sean Yu
- RMI Laboratories LLC, 418 Industrial Drive, North Wales, PA 19454, USA
| | - Patricia Bouchard
- NMX Research and Solutions, Inc., 500 Cartier Boulevard W., Laval, Quebec H7V 5B7, Canada
| | - Jiayi Wu
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Kuan-Chun Huang
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Xingfeng Bao
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Kiyoyuki Omoto
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Anand Selvaraj
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Lihua Yu
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | | | | | - Ping Zhu
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Nicholas A Larsen
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - David M Bolduc
- H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA.
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Low END, Mokhtar NM, Wong Z, Raja Ali RA. Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways. J Crohns Colitis 2019; 13:755-763. [PMID: 30954025 PMCID: PMC6535502 DOI: 10.1093/ecco-jcc/jjz002] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Patients with ulcerative colitis [UC] with long disease duration have a higher risk of developing colitis-associated cancer [CAC] compared with patients with short-duration UC. The aim of this study was to identify transcriptomic differences associated with the duration of UC disease. METHODS We conducted transcriptome profiling on 32 colonic biopsies [11 long-duration UC, ≥20 years; and 21 short-duration UC, ≤5 years] using Affymetrix Human Transcriptome Array 2.0. Differentially expressed genes [fold change > 1.5, p < 0.05] and alternative splicing events [splicing index > 1.5, p < 0.05] were determined using the Transcriptome Analysis Console. KOBAS 3.0 and DAVID 6.8 were used for KEGG and GO analysis. Selected genes from microarray analysis were validated using qPCR. RESULTS There were 640 differentially expressed genes between both groups. The top ten upregulated genes were HMGCS2, UGT2A3 isoforms, B4GALNT2, MEP1B, GUCA2B, ADH1C, OTOP2, SLC9A3, and LYPD8; the top ten downregulated genes were PI3, DUOX2, VNN1, SLC6A14, GREM1, MMP1, CXCL1, TNIP3, TFF1, and LCN2. Among the 123 altered KEGG pathways, the most significant were metabolic pathways; fatty acid degradation; valine, leucine, and isoleucine degradation; the peroxisome proliferator-activated receptor signalling pathway; and bile secretion, which were previously linked with CAC. Analysis showed that 3560 genes exhibited differential alternative splicing between long- and short-duration UC. Among them, 374 were differentially expressed, underscoring the intrinsic relationship between altered gene expression and alternative splicing. CONCLUSIONS Long-duration UC patients have altered gene expressions, pathways, and alternative splicing events as compared with short-duration UC patients, and these could be further validated to improve our understanding of the pathogenesis of CAC.
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Affiliation(s)
- Eden Ngah Den Low
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Zhiqin Wong
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia,Corresponding author: Professor Dr Raja Affendi Raja Ali, MD, FRCP, Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: 603-9145-6094; Fax: 603-9145-6679;
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20
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Gisbert JP, Chaparro M. Clinical Usefulness of Proteomics in Inflammatory Bowel Disease: A Comprehensive Review. J Crohns Colitis 2019; 13:374-384. [PMID: 30307487 DOI: 10.1093/ecco-jcc/jjy158] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The protein domain is probably the most ubiquitously affected in disease, response and recovery, and therefore proteomics holds special promise for biomarker discovery in general, and particularly in inflammatory bowel disease [IBD], i.e. ulcerative colitis and Crohn's disease. Tremendous progress has been made over the past decade in the development and refinement of proteomics technologies. These advances provide opportunities for a long-anticipated personalized medicine approach to the treatment of IBD. The present review examines the current state of IBD proteomics research and its usefulness in clinical practice. We performed a systematic bibliographic search to identify studies investigating the use of proteomics in patients with IBD, and we then summarized the current 'state of the art' in the applications of proteomic technologies in the study of IBD. In particular, in the present review we provide: [1] a brief introduction to proteomics in health and disease; [2] a review of the different stages from biomarker discovery to clinical application; and [3] a comprehensive review of the clinical usefulness and application of proteomics in IBD, including: [a] screening to differentiate IBD from healthy controls; [b] differentiating Crohn's disease from ulcerative colitis; [c] prediction of the behaviour or the IBD course; [d] prediction of IBD response to biological treatment; and [e] monitoring response to treatment. We also review the importance of the type of sample-blood vs intestinal tissue-for the study of proteomics in IBD patients. Finally, we emphasize the current limitations of proteomic studies in IBD.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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Assadsangabi A, Evans CA, Corfe BM, Lobo A. Application of Proteomics to Inflammatory Bowel Disease Research: Current Status and Future Perspectives. Gastroenterol Res Pract 2019; 2019:1426954. [PMID: 30774653 PMCID: PMC6350533 DOI: 10.1155/2019/1426954] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/08/2018] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing/remitting inflammatory illness of the gastrointestinal tract of unknown aetiology. Despite recent advances in decoding the pathophysiology of IBD, many questions regarding disease pathogenesis remain. Genome-wide association studies (GWAS) and knockout mouse models have significantly advanced our understanding of genetic susceptibility loci and inflammatory pathways involved in IBD pathogenesis. Despite their important contribution to a better delineation of the disease process in IBD, these genetic findings have had little clinical impact to date. This is because the presence of a given gene mutation does not automatically correspond to changes in its expression or final metabolic or structural effect(s). Furthermore, the existence of these gene susceptibility loci in the normal population suggests other driving prerequisites for the disease manifestation. Proteins can be considered the main functional units as almost all intracellular physiological functions as well as intercellular interactions are dependent on them. Proteomics provides methods for the large-scale study of the proteins encoded by the genome of an organism or a cell, to directly investigate the proteins and pathways involved. Understanding the proteome composition and alterations yields insights into IBD pathogenesis as well as identifying potential biomarkers of disease activity, mucosal healing, and cancer progression. This review describes the state of the art in the field with respect to the study of IBD and the potential for translation from biomarker discovery to clinical application.
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Affiliation(s)
- Arash Assadsangabi
- Gastroenterology Unit, Salford Royal Hospital, Salford, UK
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology and Insigneo Institute, University of Sheffield, Sheffield, UK
| | - Caroline A. Evans
- Department of Chemical and Biological Engineering, University of Sheffield, Sheffield, UK
| | - Bernard M. Corfe
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology and Insigneo Institute, University of Sheffield, Sheffield, UK
| | - Alan Lobo
- Gastroenterology Unit, Salford Royal Hospital, Salford, UK
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Abstract
Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC intermediates that are required to accommodate cellular needs. Interestingly, the expression of UC enzymes is altered in cancer, revealing a revolutionary mechanism to maximize nitrogen incorporation into biomass. In this Review, we discuss the metabolic benefits underlying UC deregulation in cancer and the relevance of these alterations for cancer diagnosis and therapy.
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Affiliation(s)
- Rom Keshet
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Peter Szlosarek
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK
- Barts Health NHS Trust, St Bartholomew's Hospital, London, UK
| | - Arkaitz Carracedo
- CIC bioGUNE, Bizkaia, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
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Baker KT, Salk JJ, Brentnall TA, Risques RA. Precancer in ulcerative colitis: the role of the field effect and its clinical implications. Carcinogenesis 2018; 39:11-20. [PMID: 29087436 PMCID: PMC6248676 DOI: 10.1093/carcin/bgx117] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 09/22/2017] [Accepted: 10/26/2017] [Indexed: 12/13/2022] Open
Abstract
Cumulative evidence indicates that a significant proportion of cancer evolution may occur before the development of histological abnormalities. While recent improvements in DNA sequencing technology have begun to reveal the presence of these early preneoplastic clones, the concept of 'premalignant field' was already introduced by Slaughter more than half a century ago. Also referred to as 'field effect', 'field defect' or 'field cancerization', these terms describe the phenomenon by which molecular alterations develop in normal-appearing tissue and expand to form premalignant patches with the potential to progress to dysplasia and cancer. Field effects have been well-characterized in ulcerative colitis, an inflammatory bowel disease that increases the risk of colorectal cancer. The study of the molecular alterations that define these fields is informative of mechanisms of tumor initiation and progression and has provided potential targets for early cancer detection. Herein, we summarize the current knowledge about the molecular alterations that comprise the field effect in ulcerative colitis and the clinical utility of these fields for cancer screening and prevention.
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Affiliation(s)
- Kathryn T Baker
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Jesse J Salk
- Division of Hematology and Oncology, Department of Medicine, University of
Washington, Seattle, WA, USA
- TwinStrand Biosciences Seattle, WA, USA
| | - Teresa A Brentnall
- Division of Gasteroenterology, Department of Medicine, University of
Washington, Seattle, WA, USA
| | - Rosa Ana Risques
- To whom correspondence should be addressed. Tel: +206-616-4976; Fax:
+206-543-1140;
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Colorectal Cancer Blood-Based Biomarkers. Gastroenterol Res Pract 2017; 2017:2195361. [PMID: 29147109 PMCID: PMC5632863 DOI: 10.1155/2017/2195361] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/16/2017] [Accepted: 09/13/2017] [Indexed: 12/26/2022] Open
Abstract
Mortality and morbidity associated with colorectal cancer (CRC) are increasing globally, partly due to lack of early detection of the disease. The screening is usually performed with colonoscopy, which is invasive and unpleasant, discouraging participation in the screening. As a source of noninvasive and easily accessible biomarkers, liquid biopsies are emerging. Blood-based biomarkers have the potential as diagnostic and prognostic tool in CRC. Early stage detection of CRC with high sensitivity and specificity would likely lead to higher participation in the screening test. It would also improve the prognosis of the disease and improve the recurrence risk. In this review, we summarize the potential biomarkers for early detection and monitoring of CRC.
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25
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Inflammatory Bowel Diseases. GASTROINTESTINAL TISSUE 2017. [DOI: 10.1016/b978-0-12-805377-5.00007-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen R, Lai LA, Brentnall TA, Pan S. Biomarkers for colitis-associated colorectal cancer. World J Gastroenterol 2016; 22:7882-7891. [PMID: 27672285 PMCID: PMC5028804 DOI: 10.3748/wjg.v22.i35.7882] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/30/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with extensive ulcerative colitis (UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques - including cutting-edge OMICS technologies - recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
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Chan PPY, Wasinger VC, Leong RW. Current application of proteomics in biomarker discovery for inflammatory bowel disease. World J Gastrointest Pathophysiol 2016; 7:27-37. [PMID: 26909226 PMCID: PMC4753187 DOI: 10.4291/wjgp.v7.i1.27] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/13/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
Recently, the field of proteomics has rapidly expanded in its application towards clinical research with objectives ranging from elucidating disease pathogenesis to discovering clinical biomarkers. As proteins govern and/or reflect underlying cellular processes, the study of proteomics provides an attractive avenue for research as it allows for the rapid identification of protein profiles in a biological sample. Inflammatory bowel disease (IBD) encompasses several heterogeneous and chronic conditions of the gastrointestinal tract. Proteomic technology provides a powerful means of addressing major challenges in IBD today, especially for identifying biomarkers to improve its diagnosis and management. This review will examine the current state of IBD proteomics research and its use in biomarker research. Furthermore, we also discuss the challenges of translating proteomic research into clinically relevant tools. The potential application of this growing field is enormous and is likely to provide significant insights towards improving our future understanding and management of IBD.
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Antioxidant therapy for treatment of inflammatory bowel disease: Does it work? Redox Biol 2015; 6:617-639. [PMID: 26520808 PMCID: PMC4637335 DOI: 10.1016/j.redox.2015.10.006] [Citation(s) in RCA: 266] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/18/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.
Major biomarkers used for evaluation of antioxidant therapy were MPO, TBARS/MDA and glutathione levels. Challenges were identified for the yet poor use of antioxidant therapy in IBD. This review stimulates the investigation of alternative and efficacious antioxidant therapies.
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Corfe BM, Majumdar D, Assadsangabi A, Marsh AMR, Cross SS, Connolly JB, Evans CA, Lobo AJ. Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer. BMJ Open Gastroenterol 2015; 2:e000024. [PMID: 26462276 PMCID: PMC4599170 DOI: 10.1136/bmjgast-2014-000024] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 12/21/2014] [Accepted: 01/04/2015] [Indexed: 01/08/2023] Open
Abstract
Background Keratins are intermediate filament (IF) proteins, which form part of the epithelial cytoskeleton and which have been implicated pathology of inflammatory bowel diseases (IBD). Methods In this study biopsies were obtained from IBD patients grouped by disease duration and subtype into eight categories based on cancer risk and inflammatory status: quiescent recent onset (<5 years) UC (ROUC); UC with primary sclerosing cholangitis; quiescent long-standing pancolitis (20–40 years) (LSPC); active colitis and non-inflamed proximal colonic mucosa; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR); control group without pathology. Alterations in IF protein composition across the groups were determined by quantitative proteomics. Key protein changes were validated by western immunoblotting and immunohistochemical analysis. Result Acute inflammation resulted in reduced K8, K18, K19 and VIM (all p<0.05) compared to controls and non inflamed mucosa; reduced levels of if– associated proteins were also seen in DT and DR. Increased levels of keratins in LSPC was noted relative to controls or ROUC (K8, K18, K19 and VIM, p<0.05). Multiple K8 forms were noted on immunoblotting, with K8 phosphorylation reduced in progressive disease along with an increase in VIM:K8 ratio. K8 levels and phosphorylation are reduced in acute inflammation but appear restored or elevated in subjects with clinical and endoscopic remission (LSPC) but not apparent in subjects with elevated risk of cancer. Conclusions These data suggest that keratin regulation in remission may influence subsequent cancer risk.
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Affiliation(s)
- Bernard M Corfe
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology , University of Sheffield, The Medical School , Sheffield , UK ; Insigneo Institute for in silico Medicine, University of Sheffield , Sheffield , UK
| | - Debabrata Majumdar
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology , University of Sheffield, The Medical School , Sheffield , UK ; Gastroenterology Unit , Royal Hallamshire Hospital , Sheffield , UK
| | - Arash Assadsangabi
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology , University of Sheffield, The Medical School , Sheffield , UK ; Gastroenterology Unit , Royal Hallamshire Hospital , Sheffield , UK
| | - Alexandra M R Marsh
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology , University of Sheffield, The Medical School , Sheffield , UK ; Gastroenterology Unit , Royal Hallamshire Hospital , Sheffield , UK
| | - Simon S Cross
- Academic Unit of Pathology, Department of Neuroscience, Faculty of Medicine, Dentistry & Health , University of Sheffield , Sheffield , UK
| | | | - Caroline A Evans
- Biological and Systems Engineering Group, Department of Chemical and Biological Engineering , ChELSI Institute, University of Sheffield , Sheffield , UK
| | - Alan J Lobo
- Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology , University of Sheffield, The Medical School , Sheffield , UK ; Gastroenterology Unit , Royal Hallamshire Hospital , Sheffield , UK
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Kaur J, Kaur G. An insight into the role of citrus bioactives in modulation of colon cancer. J Funct Foods 2015. [DOI: 10.1016/j.jff.2014.12.043] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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Chen R, Pan S, Lai K, Lai LA, Crispin DA, Bronner MP, Brentnall TA. Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer. World J Gastroenterol 2014; 20:17037-17048. [PMID: 25493016 PMCID: PMC4258572 DOI: 10.3748/wjg.v20.i45.17037] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/21/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer.
METHODS: Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer. Immunohistochemical analysis was used to evaluate TRAP1 expression on tissue microarrays containing colonic tissues from 42 UC progressors (patients with cancer or dysplasia) and 38 non-progressors (dysplasia/cancer free patients). Statistical analyses of the TRAP1 immunohistochemistry staining were performed using GraphPad Prism. Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test. Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.
RESULTS: TRAP1 was up-regulated in the colon tissues from UC progressors, but not in the colon tissues from UC non-progressors. Moreover, up-regulation of TRAP1 preceded the neoplastic changes: it was present in both the dysplastic and non-dysplastic tissues of UC progressors. When TRAP1 staining in rectal tissue was used as a diagnostic marker, it could distinguish progressors from non-progressors with 59% sensitivity and 80% specificity. Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues, which could be related to the increased oxidation present in the colonic mucosa from UC progressors. We then investigated the cellular proteome changes underlying oxidative stress, and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.
CONCLUSION: These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1, which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis. TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.
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Multi-omics analysis of inflammatory bowel disease. Immunol Lett 2014; 162:62-8. [PMID: 25131220 DOI: 10.1016/j.imlet.2014.07.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 06/21/2014] [Accepted: 07/29/2014] [Indexed: 12/16/2022]
Abstract
Crohn's disease and ulcerative colitis, known together as inflammatory bowel disease (IBD), are severe autoimmune disorders now causing gut inflammation and ulceration, among other symptoms, in up to 1 in 250 people worldwide. Incidence and prevalence of IBD have been increasing dramatically over the past several decades, although the causes for this increase are still unknown. IBD has both a complex genotype and a complex phenotype, and although it has received substantial attention from the medical research community over recent years, much of the etiology remains unexplained. Genome-wide association studies have identified a rich genetic signature of disease risk in patients with IBD, consisting of at least 163 genetic loci. Many of these loci contain genes directly involved in microbial handling, indicating that the genetic architecture of the disease has been driven by host-microbe interactions. In addition, systematic shifts in gut microbiome structure (enterotype) and function have been observed in patients with IBD. Furthermore, both the host genotype and enterotype are associated with aspects of the disease phenotype, including location of the disease. This provides strong evidence of interactions between host genotype and enterotype; however, there is a lack of published multi-omics data from IBD patients, and a lack of bioinformatics tools for modeling such systems. In this article we discuss, from a computational biologist's point of view, the potential benefits of and the challenges involved in designing and analyzing such multi-omics studies of IBD.
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Luo Y, Wang L, Wang J. Developing proteomics-based biomarkers for colorectal neoplasms for clinical practice: opportunities and challenges. Proteomics Clin Appl 2014; 7:30-41. [PMID: 23255431 DOI: 10.1002/prca.201200071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 10/30/2012] [Accepted: 11/20/2012] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) arises from the normal colon epithelium through the accumulation of genetic mutations and epigenetic alterations that are associated with progression along the histological adenoma-adenocarcinoma sequence. Elucidating the molecular alterations underlying disease progression will not only provide insight into the behavior of the tumors, but also could lead to the discovery of useful biomarkers for diagnosis, monitoring treatment responsiveness, or predicting disease outcomes. In the past a few years, there have been several evaluating differentially expressed protein biomarkers by employing proteomics technologies coupled with mass spectrometry. In the current review, we will briefly summarize the results from selected recent studies using tissue or serum samples from CRC patients in the past 5 years and discuss the opportunities and challenges in translating these findings from the research setting to clinical practice.
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Affiliation(s)
- Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
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Pham TV, Piersma SR, Oudgenoeg G, Jimenez CR. Label-free mass spectrometry-based proteomics for biomarker discovery and validation. Expert Rev Mol Diagn 2014; 12:343-59. [DOI: 10.1586/erm.12.31] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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May DH, Navarro SL, Ruczinski I, Hogan J, Ogata Y, Schwarz Y, Levy L, Holzman T, McIntosh MW, Lampe JW. Metabolomic profiling of urine: response to a randomised, controlled feeding study of select fruits and vegetables, and application to an observational study. Br J Nutr 2013; 110:1760-70. [PMID: 23657156 PMCID: PMC3818452 DOI: 10.1017/s000711451300127x] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Metabolomic profiles were used to characterise the effects of consuming a high-phytochemical diet compared with a diet devoid of fruits and vegetables (F&V) in a randomised trial and cross-sectional study. In the trial, 8 h fasting urine from healthy men (n 5) and women (n 5) was collected after a 2-week randomised, controlled trial of two diet periods: a diet rich in cruciferous vegetables, citrus and soya (F&V), and a fruit- and vegetable-free (basal) diet. Among the ions found to differentiate the diets, 176 were putatively annotated with compound identifications, with forty-six supported by MS/MS fragment evidence. Metabolites more abundant in the F&V diet included markers of the dietary intervention (e.g. crucifers, citrus and soya), fatty acids and niacin metabolites. Ions more abundant in the basal diet included riboflavin, several acylcarnitines and amino acid metabolites. In the cross-sectional study, we compared the participants based on the tertiles of crucifers, citrus and soya from 3 d food records (n 36) and FFQ (n 57); intake was separately divided into the tertiles of total fruit and vegetable intake for FFQ. As a group, ions individually differential between the experimental diets differentiated the observational study participants. However, only four ions were significant individually, differentiating the third v. first tertile of crucifer, citrus and soya intake based on 3 d food records. One of these ions was putatively annotated: proline betaine, a marker of citrus consumption. There were no ions significantly distinguishing tertiles by FFQ. The metabolomic assessment of controlled dietary interventions provides a more accurate and stronger characterisation of the diet than observational data.
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Affiliation(s)
- Damon H. May
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Sandi L. Navarro
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Ingo Ruczinski
- Johns Hopkins Bloomberg School of Public Health, Department of Biostatistics
| | - Jason Hogan
- Fred Hutchinson Cancer Research Center, Proteomics Facility
| | - Yuko Ogata
- Fred Hutchinson Cancer Research Center, Proteomics Facility
| | - Yvonne Schwarz
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Lisa Levy
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Ted Holzman
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Martin W. McIntosh
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
| | - Johanna W. Lampe
- Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, 98109
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Targeting sphingosine kinase 1 (SphK1) and apoptosis by colon-specific delivery formula of resveratrol in treatment of experimental ulcerative colitis in rats. Eur J Pharmacol 2013; 718:145-53. [PMID: 24055189 DOI: 10.1016/j.ejphar.2013.08.040] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Revised: 07/17/2013] [Accepted: 08/30/2013] [Indexed: 12/17/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) that has an elevated risk of developing into colon cancer. In trials to develop new therapeutic alternatives for UC, it is important to fulfill modifying effects on pathogenic targets and to reach the colon in a high concentration. Thus, the current work has investigated a colon-specific delivery formula of resveratrol in targeting sphingosine kinase 1 (SphK1) and apoptotic pathways to control pathogenesis and its progression to any expected neoplasm. This work was conducted on 40 Wister albino rats equally divided into 4 groups where group I served as the normal control group. The untreated oxazolone-induced colitis in group II exhibited significant increase in SphK1 activity as well as activity of both myeloperoxidase (MPO) and caspase-3 with concomitant mild DNA fragmentation in colonic tissue. Colonic SphK1 activity showed significant positive correlation with the disease activity index (DAI) and histopathological score in this group. Comparable with treatment by the native resveratrol formula, nRes (group III), treatment by the colon-specific delivery resveratrol formula, cRes (group IV) caused significant decrease in the activity of SphK1 and MPO with massive DNA fragmentation in colonic tissue and non significant change in caspase-3 activity. The lowest DAI and histopathological score have been recorded in the group treated by the colon-specific delivery resveratrol formula. In conclusion, the anti-inflammatory and apoptotic effects of resveratrol could be attributed to its inhibitory effect on sphingosine kinase 1 (SphK1) providing a useful therapeutic tool to break the link between inflammation and carcinogenesis risk in ulcerative colitis.
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Ussakli CH, Ebaee A, Binkley J, Brentnall TA, Emond MJ, Rabinovitch PS, Risques RA. Mitochondria and tumor progression in ulcerative colitis. J Natl Cancer Inst 2013; 105:1239-48. [PMID: 23852949 DOI: 10.1093/jnci/djt167] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis. METHODS Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C oxidase (COX), a component of the electron transport chain, and were quantified by multispectral imaging. For six additional progressors, nondysplastic and dysplastic biopsies were stained for COX and additional mitochondrial proteins including PGC1α, the master regulator of mitochondrial biogenesis. Mitochondrial DNA (mtDNA) copy number was determined by quantitative polymerase chain reaction. Generalized estimating equations with two-sided tests were used to account for correlation of measurements within individuals. RESULTS Nondysplastic biopsies of UC progressors showed statistically significant COX loss compared with UC nonprogressors by generalized estimating equation (-18.5 units, 95% confidence interval = -12.1 to -24.9; P < .001). COX intensity progressively decreased with proximity to dysplasia and was the lowest in adjacent to dysplasia and dysplastic epithelium. Surprisingly, COX intensity was statistically significantly increased in cancers. This bimodal pattern was observed for other mitochondrial proteins, including PGC1α, and was confirmed by mtDNA copy number. CONCLUSIONS Mitochondrial loss precedes the development of dysplasia, and it could be used to detect and potentially predict cancer. Cancer cells restore mitochondria, suggesting that mitochondria are needed for further proliferation. This bimodal pattern might be driven by transcriptional regulation of mitochondrial biogenesis by PGC1α.
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Pan S, Brentnall TA, Kelly K, Chen R. Tissue proteomics in pancreatic cancer study: discovery, emerging technologies, and challenges. Proteomics 2013; 13:710-21. [PMID: 23125171 DOI: 10.1002/pmic.201200319] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 10/01/2012] [Accepted: 10/05/2012] [Indexed: 12/22/2022]
Abstract
Pancreatic cancer is a highly lethal disease that is difficult to diagnose and treat. The advances in proteomics technology, especially quantitative proteomics, have stimulated a great interest in applying this technology for pancreatic cancer study. A variety of tissue proteomics approaches have been applied to investigate pancreatic cancer and the associated diseases. These studies were carried out with various goals, aiming to better understand the molecular mechanisms underlying pancreatic tumorigenesis, to improve therapeutic treatment and to identify cancer associated protein signatures, signaling events as well as interactions between cancer cells and tumor microenvironment. Here, we provide an overview on the tissue proteomics studies of pancreatic cancer reported in the past few years in light of discovery and technology development.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
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Han NY, Kim EH, Choi J, Lee H, Hahm KB. Quantitative proteomic approaches in biomarker discovery of inflammatory bowel disease. J Dig Dis 2012; 13:497-503. [PMID: 22988922 DOI: 10.1111/j.1751-2980.2012.00625.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Proteomics offers considerable opportunities for either enhancing our biological understanding or discovering biomarkers, blood and biopsied specimen-based proteomic approaches, provide reproducible and quantitative tools that can complement clinical assessments and aid clinicians in the diagnosis and treatment of inflammatory bowel disease (IBD). Sometimes a differential diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) and the prediction of treatment response can be deduced by finding meaningful biomarkers, for which the central platform for proteomics is tandem mass spectrometry (MS/MS). A range of workflows are available for protein (or peptide) separation prior to MS/MS as well as bioinformatics analysis to achieve protein identification, for which two-dimensional electrophoresis (2-DE) and subsequent mass spectrometry (MS), liquid chromatography-MS, difference gel electrophoresis following 2-DE, isobaric tags for relative and absolute quantification (iTRAQ), stable isotope labeling by amino acids and label-free quantification are under development. In this article, the current status and perspective of these advanced proteomic technologies are introduced, with examples of recent biomarkers focused on the diagnosis, treatment response, prognosis of IBD, and even colitis-associated carcinogenesis in both animal models and human patients.
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Affiliation(s)
- Na-Young Han
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
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Pan S, Chen R, Stevens T, Bronner MP, May D, Tamura Y, McIntosh MW, Brentnall TA. Proteomics portrait of archival lesions of chronic pancreatitis. PLoS One 2011; 6:e27574. [PMID: 22132114 PMCID: PMC3223181 DOI: 10.1371/journal.pone.0027574] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 10/19/2011] [Indexed: 12/11/2022] Open
Abstract
Chronic pancreatitis is a chronic inflammatory disorder of the pancreas. The etiology is multi-fold, but all lead to progressive scarring and loss of pancreatic function. Early diagnosis is difficult; and the understanding of the molecular events that underlie this progressive disease is limited. In this study, we investigated differential proteins associated with mild and severe chronic pancreatitis in comparison with normal pancreas and pancreatic cancer. Paraffin-embedded formalin-fixed tissues from five well-characterized specimens each of normal pancreas (NL), mild chronic pancreatitis (MCP), severe chronic pancreatitis (SCP) and pancreatic ductal adenocarcinoma (PDAC) were subjected to proteomic analysis using a “label-free” comparative approach. Our results show that the numbers of differential proteins increase substantially with the disease severity, from mild to severe chronic pancreatitis, while the number of dysregulated proteins is highest in pancreatic adenocarcinoma. Important functional groups and biological processes associated with chronic pancreatitis and cancer include acinar cell secretory proteins, pancreatic fibrosis/stellate cell activation, glycoproteins, and inflammatory proteins. Three differential proteins were selected for verification by immunohistochemistry, including collagen 14A1, lumican and versican. Further canonical pathway analysis revealed that acute phase response signal, prothrombin activation pathway, and pancreatic fibrosis/pancreatic stellate cell activation pathway were the most significant pathways involved in chronic pancreatitis, while pathways relating to metabolism were the most significant pathways in pancreatic adenocarcinoma. Our study reveals a group of differentially expressed proteins and the related pathways that may shed light on the pathogenesis of chronic pancreatitis and the common molecular events associated with chronic pancreatitis and pancreatic adenocarcinoma.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- * E-mail: (SP); (TB)
| | - Ru Chen
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Mary P. Bronner
- Department of Anatomic Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Damon May
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, Washington, United States of America
| | - Yasuko Tamura
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Martin W. McIntosh
- Fred Hutchinson Cancer Research Center, Molecular Diagnostics Program, Seattle, Washington, United States of America
| | - Teresa A. Brentnall
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- * E-mail: (SP); (TB)
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