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Chang K, Jiang L, Sun Y, Li H. Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update. Mol Diagn Ther 2022; 26:397-409. [PMID: 35732878 DOI: 10.1007/s40291-022-00593-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE The effect of E-cadherin on colorectal cancer is still controversial. In order to clarify the effect of E-cadherin on the prognosis and clinicopathological features of colorectal cancer, a meta-analysis was conducted. METHODS PubMed, Embase and Cochrane Library were used to collect all relevant literature published before November 2021, and the corresponding data was extracted to analyze the correlation between the expression of E-cadherin and the prognosis and clinicopathological features of colorectal cancer. In addition, the Gene Expression Profiling Interactive Analysis (GEPIA) was used to validate our results. RESULTS Fifty-two studies, including 9591 patients, were included in this meta-analysis. According to the meta-analysis, low expression of E-cadherin was significantly associated with shorter overall survival (OS) (hazard ratio [HR] 2.09, 95% confidence interval [CI]1.67-2.62; Z = 6.42, p = 0.000) and disease-free survival (DFS) (HR 2.03, 95% CI 1.71-2.42; Z = 7.95, p = 0.000). In addition, low expression of E-cadherin resulted in higher risk of low differentiation (odds ratio [OR] 0.35, 95% CI 0.25-0.50; p = 0.000), high risk of distant metastasis (OR 0.45, 95% CI 0.35-0.58; p = 0.000), high risk of vascular invasion (OR 0.61, 95% CI 0.45-0.83; p = 0.002), higher risk of lymph node metastasis (OR 0.54, 95% CI 0.42-0.69; p = 0.000), high risk of lymphatic invasion (OR 0.56, 95% CI 0.40-0.80; p = 0.001), high risk of deep infiltration (OR 0.63, 95% CI 0.50-0.80; p = 0.000), later TNM stage (OR 0.60, 95% CI 0.46-0.78; p = 0.000) and late Dukes' stage (OR 0.35,95% CI 0.25-0.49; p = 0.000), but wasn't associated with tumor size (OR 0.90, 95% CI 0.71-1.15; p = 0.406).The results of GEPIA showed that E-cadherin mRNA expression in colorectal cancer tumor tissues and normal tissues had no difference, and had no effect on OS and DFS. CONCLUSION Although not supported by GEPIA, our meta-analysis provided abundant data to suggest that low expression of E-cadherin is associated with poor prognosis in colorectal cancer patients and is an important factor influencing adverse clinicopathological features. Therefore, E-cadherin may be used to predict the prognosis of colorectal cancer and provide guidance for clinical treatment.
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Affiliation(s)
- Kaibin Chang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Lei Jiang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Yifeng Sun
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - He Li
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China.
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Reszegi A, Tátrai P, Regős E, Kovalszky I, Baghy K. Syndecan-1 in liver pathophysiology. Am J Physiol Cell Physiol 2022; 323:C289-C294. [PMID: 35704700 DOI: 10.1152/ajpcell.00039.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Syndecan-1 is a heparan sulfate/chondroitin sulfate proteoglycan (PG) of the cell surface and the extracellular matrix, which regulates a broad spectrum of physiological and pathological processes such as cell proliferation, migration, inflammation, matrix remodeling, wound healing, or tumorigenesis. Syndecan-1 represents the major PG of the liver, expressed by hepatocytes and cholangiocytes, and its elevated expression is a characteristic feature of liver diseases. The highest syndecan-1 expression is found in liver cirrhosis and in hepatocellular carcinoma (HCC) developed in cirrhotic livers. In addition, as being a hepatitis C receptor, hepatitis C virus (HCV) infected livers produce extremely large amounts of syndecan-1. The serum levels of the cleaved (shedded) extracellular domain has clinical significance, as its increased concentration reflects on poor prognosis in cirrhosis as well as in cancer. In vivo experiments confirmed that syndecan-1 protects against early stages of fibrogenesis mainly by enhanced clearance of transforming growth factor beta (TGFβ1) and thrombospondin-1 via circulation, and against hepatocarcinogenesis by interfering with several signaling pathways and enhancing cell cycle blockade. In addition, syndecan-1 is capable to hinder lipid metabolism and ribosomal biogenesis in induced cancer models.. These observations together with its participation in the uptake of viruses (e.g. HCV, SARS-CoV-2) indicate that syndecan-1 is a central player in liver pathologies.
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Affiliation(s)
- Andrea Reszegi
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary
| | | | - Eszter Regős
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Kornelia Baghy
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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A Novel Immune-Related Prognostic Signature Predicting Survival in Patients with Pancreatic Adenocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:8909631. [PMID: 35342420 PMCID: PMC8956421 DOI: 10.1155/2022/8909631] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 11/03/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) carries the lowest survival rate of all major organ cancers, which is of dismal prognosis and high mortality rate. Thus, the present study attempted to identify a few novel prognostic biomarkers and establish an immune-related prognostic signature which could predict the prognosis of PAAD. Four prognostic immune-related genes (IRGs) including S100A6, S100A10, S100A16, and SDC1 were screened by differentially expressed gene (DEG) identification and weighted gene coexpression network analysis (WGCNA). Subsequent analysis proved the high expression of these IRGs in PAAD tissues, suggested by TCGA-PAAD data, merged microarray-acquired dataset (MMD), GEPIA, and Oncomine webtool. By using MMD and TCGA-PAAD data, S100A6 (MMD: AUC = 0.897; TCGA: AUC = 0.843), S100A10 (MMD: AUC = 0.880; TCGA: AUC = 0.780), S100A16 (MMD: AUC = 0.878; TCGA: AUC = 0.838), and SDC1 (MMD: AUC = 0.885; TCGA: AUC = 0.812) exhibited excellent diagnostic efficiency for PAAD. By conducting connectivity map (CMap) analysis, we concluded that three molecule drugs (sulpiride, famotidine, and nalidixic acid) might have worked in the treatment of PAAD. Then, an immune-related prognostic index was constructed, which was validated as an independent prognostic factor for PAAD patients (P=0.004). We further constructed a nomogram by using this immune-related signature and age, the prognostic value of which was validated by using concordance index (C-index = 0.780) and area under curve (AUC = 0.909). Moreover, the immune-related prognostic signature was associated with response to anti-PD-1/L1 immunotherapy. To sum up, four IRGs were screened out and verified to be novel immune-related prognostic biomarkers in PAAD. Besides, sulpiride, famotidine, and nalidixic acid might be potential choices in the treatment of PAAD. An immune-related signature was established to show great potential for prognosis prediction for PAAD, independently, which might guide more effective immunotherapy strategies. A nomogram is further established by using this immune-related prognostic index, which might contribute to more effective prognosis prediction in PAAD patients.
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4
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Ning S, Chao HJ, Li S, Zhou R, Zou L, Zhang X, Liu J, Yan D, Duan M. The auto-inhibition mechanism of transcription factor Ets-1 induced by phosphorylation on the intrinsically disordered region. Comput Struct Biotechnol J 2022; 20:1132-1141. [PMID: 35317227 PMCID: PMC8902471 DOI: 10.1016/j.csbj.2022.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/20/2022] [Accepted: 02/26/2022] [Indexed: 12/01/2022] Open
Abstract
As the most abundant post-translation modifications (PTMs), the phosphorylation usually occurred on the intrinsically disordered regions (IDRs). The regulation on the structures and interactions of IDRs induced by phosphorylation is critical to the function performing. The eukaryotic transcription factor 1 (Ets-1) is a member of transcription factor family, which participates in many important biological processes. The DNA-binding ability of Ets-1 is auto-inhibited by a disordered serine-rich region (SRR) on the Ets-1. The inhibition ability of SRR is greatly enhanced by the phosphorylation of the serine on the SRR. Nevertheless, the molecular mechanisms of the phosphorylation regulation on the structure and activity of Ets-1 are still unclear and under debates. By using both of the molecular simulations and biochemical experiments, we studied the molecule mechanism of phosphorylation regulation on the auto-inhibition of the Ets-1. The reasons of stabilization of Ets-1 core by phosphorylation on SRR region were elucidated. More important, the free energy landscapes (FEL) show that both of the steric hindrance and allosteric regulation are responsible for the DNA-binding inhibitory induced by phosphorylation, but the steric effects contribute greater than the allosteric regulation. The phosphorylation not only enhances the electrostatic interactions to facilitate the steric impedance, but also promotes the formation of hydrophobic residue clusters, which provide major driven force for the allosteric regulation. The structural basis of auto-inhibition of Ets-1 induced by the phosphorylation revealed in this study would great help the developing of inhibitor for the cancer therapy.
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Key Words
- BE, Biased-exchange
- CD, Circular dichroism
- CS, Chemical shift
- DCC, Dynamic correlation coefficient
- EMSA, Electrophoretic mobility shift assay
- FEL, Free energy landscape
- HRC, Hydrophobic residue clusters
- IDRs, Intrinsically disordered regions
- IM, Inhibitory module
- PT-WTE, Parallel tempering Well-Tempered Ensemble
- PTMs, Post-translation modifications
- RMSE, Root-mean-square error
- SRR, Serine-rich region
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Affiliation(s)
- Shangbo Ning
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, People’s Republic of China
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, People’s Republic of China
| | - Hong-Jun Chao
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, People’s Republic of China
| | - Shuangli Li
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
| | - Rui Zhou
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
| | - Lei Zou
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, People’s Republic of China
| | - Xu Zhang
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
| | - Jun Liu
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, People’s Republic of China
| | - Dazhong Yan
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, People’s Republic of China
| | - Mojie Duan
- National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, Hubei, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
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Syndecan-1 (CD138), Carcinomas and EMT. Int J Mol Sci 2021; 22:ijms22084227. [PMID: 33921767 PMCID: PMC8072910 DOI: 10.3390/ijms22084227] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/14/2021] [Indexed: 12/16/2022] Open
Abstract
Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principal family of transmembrane proteoglycans is the syndecans, of which there are four in mammals. Syndecan-1 is mostly restricted to epithelia, and bears heparan sulfate chains that are capable of interacting with a large array of polypeptides, including extracellular matrix components and potent mediators of proliferation, adhesion and migration. For this reason, it has been studied extensively with respect to carcinomas and tumor progression. Frequently, but not always, syndecan-1 levels decrease as tumor grade, stage and invasiveness and dedifferentiation increase. This parallels experiments that show depletion of syndecan-1 can be accompanied by loss of cadherin-mediated adhesion. However, in some tumors, levels of syndecan-1 increase, but the characterization of its distribution is relevant. There can be loss of membrane staining, but acquisition of cytoplasmic and/or nuclear staining that is abnormal. Moreover, the appearance of syndecan-1 in the tumor stroma, either associated with its cellular component or the collagenous matrix, is nearly always a sign of poor prognosis. Given its relevance to myeloma progression, syndecan-1-directed antibody—toxin conjugates are being tested in clinical and preclinical trials, and may have future relevance to some carcinomas.
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Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1. Biomolecules 2020; 10:biom10101356. [PMID: 32977498 PMCID: PMC7598270 DOI: 10.3390/biom10101356] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023] Open
Abstract
Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.
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Coscia F, Doll S, Bech JM, Schweizer L, Mund A, Lengyel E, Lindebjerg J, Madsen GI, Moreira JM, Mann M. A streamlined mass spectrometry-based proteomics workflow for large-scale FFPE tissue analysis. J Pathol 2020; 251:100-112. [PMID: 32154592 DOI: 10.1002/path.5420] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 12/15/2022]
Abstract
Formalin fixation and paraffin-embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis, and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)-based proteomics has so far proven challenging. Herein we describe a MS-based proteomic workflow for quantitative profiling of large FFPE tissue cohorts directly from histopathology glass slides. We demonstrate broad applicability of the workflow to clinical pathology specimens and variable sample amounts, including low-input cancer tissue isolated by laser microdissection. Using state-of-the-art data dependent acquisition (DDA) and data independent acquisition (DIA) MS workflows, we consistently quantify a large part of the proteome in 100 min single-run analyses. In an adenoma cohort comprising more than 100 samples, total workup took less than a day. We observed a moderate trend towards lower protein identification in long-term stored samples (>15 years), but clustering into distinct proteomic subtypes was independent of archival time. Our results underscore the great promise of FFPE tissues for patient phenotyping using unbiased proteomics and they prove the feasibility of analyzing large tissue cohorts in a robust, timely, and streamlined manner. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Fabian Coscia
- Clinical Proteomics Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Sophia Doll
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Jacob Mathias Bech
- Section for Molecular Disease Biology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lisa Schweizer
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Andreas Mund
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Ernst Lengyel
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA
| | - Jan Lindebjerg
- Lillebaelt Hospital, Vejle Hospital, Department of Pathology, Vejle, Denmark
| | | | - José Ma Moreira
- Section for Molecular Disease Biology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Matthias Mann
- Clinical Proteomics Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
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Teixeira FCOB, Götte M. Involvement of Syndecan-1 and Heparanase in Cancer and Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:97-135. [PMID: 32274708 DOI: 10.1007/978-3-030-34521-1_4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The cell surface heparan sulfate proteoglycan Syndecan-1 acts as an important co-receptor for receptor tyrosine kinases and chemokine receptors, and as an adhesion receptor for structural glycoproteins of the extracellular matrix. It serves as a substrate for heparanase, an endo-β-glucuronidase that degrades specific domains of heparan sulfate carbohydrate chains and thereby alters the functional status of the proteoglycan and of Syndecan-1-bound ligands. Syndecan-1 and heparanase show multiple levels of functional interactions, resulting in mutual regulation of their expression, processing, and activity. These interactions are of particular relevance in the context of inflammation and malignant disease. Studies in animal models have revealed a mechanistic role of Syndecan-1 and heparanase in the regulation of contact allergies, kidney inflammation, multiple sclerosis, inflammatory bowel disease, and inflammation-associated tumorigenesis. Moreover, functional interactions between Syndecan-1 and heparanase modulate virtually all steps of tumor progression as defined in the Hallmarks of Cancer. Due to their prognostic value in cancer, and their mechanistic involvement in tumor progression, Syndecan-1 and heparanase have emerged as important drug targets. Data in preclinical models and preclinical phase I/II studies have already yielded promising results that provide a translational perspective.
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Affiliation(s)
- Felipe C O B Teixeira
- Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
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Kumar Katakam S, Tria V, Sim WC, Yip GW, Molgora S, Karnavas T, Elghonaimy EA, Pelucchi P, Piscitelli E, Ibrahim SA, Zucchi I, Reinbold R, Greve B, Götte M. The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase-Wnt signaling axis. FEBS J 2020; 288:486-506. [PMID: 32367652 DOI: 10.1111/febs.15356] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 04/23/2020] [Accepted: 05/01/2020] [Indexed: 12/21/2022]
Abstract
In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of β1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. DATABASES: The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.
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Affiliation(s)
| | - Valeria Tria
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | - Wey-Cheng Sim
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Stefano Molgora
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | - Theodoros Karnavas
- Chromatin Dynamics Unit, Vita Salute San Raffaele University and Research Institute, Milan, Italy.,Department of Neurosurgery, NYU Langone Medical Center, New York, NY, USA
| | - Eslam A Elghonaimy
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Paride Pelucchi
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | - Eleonora Piscitelli
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | | | - Ileana Zucchi
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | - Rolland Reinbold
- Istituto di Technologie Biomediche Consiglio Nazionale dell Ricerche, ITB-CNR, Segrate-Milano, Italy
| | - Burkhard Greve
- Department of Radiotherapy - Radiooncology, University Hospital Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Germany
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10
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Prevalence of Syndecan-1 (CD138) Expression in Different Kinds of Human Tumors and Normal Tissues. DISEASE MARKERS 2019; 2019:4928315. [PMID: 31976021 PMCID: PMC6954471 DOI: 10.1155/2019/4928315] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/07/2019] [Indexed: 12/28/2022]
Abstract
Syndecan-1 (CD138) is a transmembrane proteoglycan known to be expressed in various normal and malignant tissues. It is of interest because of a possible prognostic role of differential expression in tumors and its role as a target for indatuximab, a monoclonal antibody coupled with a cytotoxic agent. To comprehensively analyze CD138 in normal and neoplastic tissues, we used tissue microarrays (TMAs) for analyzing immunohistochemically detectable CD138 expression in 2,518 tissue samples from 85 different tumor entities and 76 different normal tissue types. The data showed that CD138 expression is abundant in tumors. At least an occasional weak CD138 immunostaining could be detected in 71 of 82 (87%) different tumor types, and 58 entities (71%) had at least one tumor with a strong positivity. In normal tissues, a particularly strong expression was found in normal squamous epithelium of various organs, goblet and columnar cells of the gastrointestinal tract, and in hepatocytes. The highly standardized analysis of most human cancer types resulted in a ranking order of tumors according to the frequency and levels of CD138 expression. CD138 immunostaining was highest in squamous cell carcinomas such as from the esophagus (100%), cervix uteri (79.5%), lung (85.7%), vagina (89.7%) or vulva (73.3%), and in invasive urothelial cancer (76.2%). In adenocarcinomas, CD138 was also high in lung (82.9%) and colorectal cancer (85.3%) but often lower in pancreas (73.3%), stomach (54.2% in intestinal type), or prostate carcinomas (16.3%). CD138 expression was usually low or absent in germ cell tumors, sarcomas, endocrine tumors including thyroid cancer, and neuroendocrine tumors. In summary, the preferential expression in squamous cell carcinomas of various sites makes these cancers prime targets for anti-CD138 treatments once these might become available. Abundant expression in many different normal tissues might pose obstacles to exploiting CD138 as a therapeutic target, however.
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11
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Liao S, Liu C, Zhu G, Wang K, Yang Y, Wang C. Relationship between SDC1 and cadherin signalling activation in cancer. Pathol Res Pract 2019; 216:152756. [PMID: 31810587 DOI: 10.1016/j.prp.2019.152756] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/31/2019] [Accepted: 11/17/2019] [Indexed: 12/17/2022]
Abstract
E-cadherin and SDC1 are markers of epithelial-to-mesenchymal transition (EMT) that can be used to assess tumour prognosis. SDC1 has different effects in various types of cancers. On the one hand, reduced expression of SDC1 can leads to advantage stages of some cancers, such as gastric and colorectal cancer. On the other hand, SDC1 overexpression can also promote the growth and proliferation of cancer cells in pancreatic and breast cancer. However, the function of SDC1 is influenced and regulated by many factors. Exfoliated extracellular domain HS chain can mediate the function of SDC1 and play an important role in the occurrence and development of cancer. SDC1 binds to various ligands and influences the growth and reproduction of cancer cells via the activation of Wnt, the long isoform of FLICE-inhibitory protein (FLIP long), vascular endothelial growth factor receptor (VEGFR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and MAPK/c-Jun N-terminal kinase (JNK) and other pathways. Cadherins occur in several types, but this review focuses on classical cadherins. N-cadherin and P-cadherin are activated during tumour development, whereas E-cadherin is a tumour suppressor. The cellular signalling pathways involved in classical cadherins, such as Wnt and VEGFR pathways, are also related to SDC1. The activation of E-cadherin caused by SDC1 knockdown has also been observed. Despite this evidence, no articles regarding the relationship of SDC1 and cadherin activation have been published. This review summarises the expressions of these two molecules in different cancers and analyses their possible relationship to provide insights into future cancer research and clinical treatment.
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Affiliation(s)
- Shiyao Liao
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116011, China
| | - Chang Liu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116011, China; Clinical Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Guiying Zhu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116011, China
| | - Kai Wang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116011, China
| | - Ying Yang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116011, China
| | - Changmiao Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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Regős E, Karászi K, Reszegi A, Kiss A, Schaff Z, Baghy K, Kovalszky I. Syndecan-1 in Liver Diseases. Pathol Oncol Res 2019; 26:813-819. [PMID: 30826971 PMCID: PMC7242248 DOI: 10.1007/s12253-019-00617-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 02/15/2019] [Indexed: 12/14/2022]
Abstract
Liver diseases such as liver cirrhosis, primary and metastatic liver cancers are still a major medical challenge. Syndecan-1 is one of the most important proteoglycans in the liver. Syndecan-1 is normally expressed on the surfaces of hepatocytes and cholangiocytes. Due to liver diseases the amount of syndecan-1 increases in the liver. Despite the emerging data of the biological function of syndecan-1, the clinical usefulness of this proteoglycan is still unknown. In our study we correlated syndecan-1 expression to clinico-pathological data. We found that syndecan-1 proved to be a good marker for hepatitis C virus based hepatocellular carcinoma and increased with liver dysfunction.
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Affiliation(s)
- Eszter Regős
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői Street 26, Budapest, 1085, Hungary
| | - Katalin Karászi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői Street 26, Budapest, 1085, Hungary
| | - Andrea Reszegi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői Street 26, Budapest, 1085, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Üllői street 93, Budapest, 1091, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Üllői street 93, Budapest, 1091, Hungary
| | - Kornélia Baghy
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői Street 26, Budapest, 1085, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői Street 26, Budapest, 1085, Hungary.
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Pisamai S, Rungsipipat A, Kalpravidh C, Suriyaphol G. Gene expression profiles of cell adhesion molecules, matrix metalloproteinases and their tissue inhibitors in canine oral tumors. Res Vet Sci 2017; 113:94-100. [DOI: 10.1016/j.rvsc.2017.09.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 08/06/2017] [Accepted: 09/07/2017] [Indexed: 12/15/2022]
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Jaiswal AK, Sadasivam M, Hamad ARA. Syndecan-1-coating of interleukin-17-producing natural killer T cells provides a specific method for their visualization and analysis. World J Diabetes 2017; 8:130-134. [PMID: 28465789 PMCID: PMC5394732 DOI: 10.4239/wjd.v8.i4.130] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/27/2017] [Accepted: 02/20/2017] [Indexed: 02/05/2023] Open
Abstract
Natural killer T cells (NKT cells) are innate-like T cells that acquire effector functions while developing in the thymus, polarize into three distinct functional subsets viz. NKT1, NKT2 and NKT17 cells that produce interferon (IFN)-γ, interleukin (IL)-4 and IL-17, respectively. However, there has been no unique surface markers that define each subsets, forcing investigators to use intracellular staining of transcription factors and cytokines in combination of surface markers to distinguish among these subsets. Intracellular staining, however, causes apoptosis and prevents subsequent utilization of NKT cells in functional in vitro and in vivo assays that require viable cells. This limitation has significantly impeded understanding the specific properties of each subset and their interactions with each other. Therefore, there has been fervent efforts to find a specific markers for each NKT cell subset. We have recently identified that syndecan-1 (SDC-1; CD138) as a specific surface marker of NKT17 cells. This discovery now allows visualization of NKT17 in situ and study of their peripheral tissue distribution, characteristics of their TCR and viable sorting for in vitro and in vivo analysis. In addition, it lays the ground working for investigating significance of SDC-1 expression on this particular subset in regulating their roles in host defense and glucose metabolism.
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Wei HT, Guo EN, Dong BG, Chen LS. Prognostic and clinical significance of syndecan-1 in colorectal cancer: a meta-analysis. BMC Gastroenterol 2015; 15:152. [PMID: 26518017 PMCID: PMC4628393 DOI: 10.1186/s12876-015-0383-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 10/21/2015] [Indexed: 12/31/2022] Open
Abstract
Background Syndecan-1 plays a vital role in the suppression, transformation, and migration of several cancer types, including colorectal cancer (CRC). However, the prognostic and clinical significance of syndecan-1 in CRC remains conflicting. Therefore, we performed a meta-analysis to clarify this relationship. Methods A comprehensive literature search for relevant studies published up to December 2014 was performed using PubMed, EMBASE, and Ovid library database. The odds ratio (OR) and pooled hazard ratio (HR) with their 95 % confidence intervals (CI) were used to estimate the effects. Results Ten studies with 888 CRC patients were selected for evaluation. The results showed that syndecan-1 expression was lower in CRC tissue than in normal colorectal tissue (OR = 0.02, 95 % CI = 0.00–0.09), and lower in the advanced stage than in the early stage (OR = 2.24, 95 % CI = 1.14 − 4.42). Additionally, syndecan-1 expression was higher in well and moderately differentiated CRC than in poorly differentiated CRC (OR = 2.91, 95 % CI = 1.21–6.98); no significant difference was found in patients with or without lymph node metastasis (OR = 0.91, 95 % CI = 0.34–2.43) and distant metastasis (OR = 0.89, 95 % CI = 0.19-4.21). The pooled results showed that syndecan-1 expression was not associated with survival in CRC patients (HR = 0.93, 95 % CI = 0.86–1.01). Conclusion This meta-analysis indicated that loss of syndecan-1 expression is associated with CRC development, histological differentiation, and clinical stage, but not with lymph node metastasis and distant metastasis. In addition, these findings fail to support the prognostic significance of syndecan-1 in CRC.
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Affiliation(s)
- Hao-Tang Wei
- Department of Colorectal & Anal Surgery, the First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6, Nanning, 530021, China
| | - Er-Na Guo
- Institute of International Education, Guangxi Medical University, Nanning, 530021, China
| | - Bao-Guo Dong
- Department of gastrointestinal surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, 530031, China
| | - Li-Sheng Chen
- Department of Colorectal & Anal Surgery, the First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6, Nanning, 530021, China.
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Dittmer J. The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol 2015; 35:20-38. [PMID: 26392377 DOI: 10.1016/j.semcancer.2015.09.010] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/16/2015] [Accepted: 09/16/2015] [Indexed: 12/12/2022]
Abstract
Ets1 belongs to the large family of the ETS domain family of transcription factors and is involved in cancer progression. In most carcinomas, Ets1 expression is linked to poor survival. In breast cancer, Ets1 is primarily expressed in the triple-negative subtype, which is associated with unfavorable prognosis. Ets1 contributes to the acquisition of cancer cell invasiveness, to EMT (epithelial-to-mesenchymal transition), to the development of drug resistance and neo-angiogenesis. The aim of this review is to summarize the current knowledge on the functions of Ets1 in carcinoma progression and on the mechanisms that regulate Ets1 activity in cancer.
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Affiliation(s)
- Jürgen Dittmer
- Clinic for Gynecology, Martin Luther University Halle-Wittenberg, Germany.
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Syndecan-1 in Cancer: Implications for Cell Signaling, Differentiation, and Prognostication. DISEASE MARKERS 2015; 2015:796052. [PMID: 26420915 PMCID: PMC4569789 DOI: 10.1155/2015/796052] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/16/2015] [Indexed: 11/17/2022]
Abstract
Syndecan-1, a cell surface heparan sulfate proteoglycan, is critically involved in the differentiation and prognosis of various tumors. In this review, we highlight the synthesis, cellular interactions, and the signalling pathways regulated by syndecan-1. The basal syndecan-1 level is also crucial for understanding the sequential changes involving malignant transformation, tumor progression, and advanced or disseminated cancer stages. Moreover, we focus on the cellular localization of this proteoglycan as cell membrane anchored and/or shed, soluble syndecan-1 with stromal or nuclear accumulation and how this may carry different, highly tissue specific prognostic information for individual tumor types.
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Suhovskih AV, Aidagulova SV, Kashuba VI, Grigorieva EV. Proteoglycans as potential microenvironmental biomarkers for colon cancer. Cell Tissue Res 2015; 361:833-44. [PMID: 25715761 DOI: 10.1007/s00441-015-2141-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 01/28/2015] [Indexed: 12/18/2022]
Abstract
Glycosylation changes occur widely in colon tumours, suggesting glycosylated molecules as potential biomarkers for colon cancer diagnostics. In this study, proteoglycans (PGs) expression levels and their transcriptional patterns are investigated in human colon tumours in vivo and carcinoma cells in vitro. According to RT-PCR analysis, normal and cancer colon tissues expressed a specific set of PGs (syndecan-1, perlecan, decorin, biglycan, versican, NG2/CSPG4, serglycin, lumican, CD44), while the expression of glypican-1, brevican and aggrecan was almost undetectable. Overall transcriptional activity of the PGs in normal and cancer tissues was similar, although expression patterns were different. Expression of decorin and perlecan was down-regulated 2-fold in colon tumours, while biglycan and versican expression was significantly up-regulated (6-fold and 3-fold, respectively). Expression of collagen1A1 was also increased 6-fold in colon tumours. However, conventional HCT-116 colon carcinoma and AG2 colon cancer-initiating cells did not express biglycan and decorin and were versican-positive and -negative, respectively, demonstrating an extracellular origin of the PGs in cancer tissue. Selective expression of heparan sulfate (HS) proteoglycans syndecan-1 and perlecan in the AG2 colon cancer-initiating cell line suggests these PGs as potential biomarkers for cancer stem cells. Overall transcriptional activity of the HS biosynthetic system was similar in normal and cancer tissues, although significant up-regulation of extracellular sulfatases SULF1/2 argues for a possible distortion of HS sulfation patterns in colon tumours. Taken together, the obtained results suggest versican, biglycan, collagen1A1 and SULF1/2 expression as potential microenvironmental biomarkers and/or targets for colon cancer diagnostics and treatment.
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Affiliation(s)
- Anastasia V Suhovskih
- Institute of Molecular Biology and Biophysics SB RAMS, Timakova str 2, Novosibirsk, 630117, Russia
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Li C, Wang Z, Chen Y, Zhou M, Zhang H, Chen R, Shi F, Wang C, Rui Z. Transcriptional silencing of ETS-1 abrogates epithelial-mesenchymal transition resulting in reduced motility of pancreatic cancer cells. Oncol Rep 2014; 33:559-65. [PMID: 25421630 PMCID: PMC4306275 DOI: 10.3892/or.2014.3613] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 10/30/2014] [Indexed: 11/23/2022] Open
Abstract
v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays crucial roles in a spectrum of malignancies. ETS-1 has gained attention in cancer research for its importance in cell migration, invasion and proliferation. In the present study, we focused on the effect of ETS-1 on epithelial-mesenchymal transition (EMT), which is characterized by reduced E-cadherin expression and increased N-cadherin expression. We found that ETS-1 mRNA expression was positively correlated with N-cadherin and negatively correlated with E-cadherin mRNA expression in five pancreatic cancer cell lines. To elucidate the functionality of ETS-1 on EMT in pancreatic cancer cells, we constructed a green fluorescent protein (GFP)-expressing plasmid carrying ETS-1 short hairpin RNA (shRNA), and transfected Panc-1 cells with the plasmid. We detected reduced N-cadherin and vascular endothelial growth factor yet higher E-cadherin expression in the ETS-1-silenced cells compared with the control group. In addition, we observed reduced cell migration and increased adhesion in these cells. Our data showed that ETS-1 actively functioned as a regulator of EMT in Panc-1 cells, and provide additional evidence supporting a fundamental role for ETS-1 in metastatic pancreatic cancer cells. These results suggest that analysis of ETS-1 expression levels may provide an avenue for evaluating prognosis in pancreatic cancer.
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Affiliation(s)
- Chunyan Li
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhonghan Wang
- Department of Internal Medicine, Nanjing Government Hospital, Nanjing, Jiangsu 210009, P.R. China
| | - Yan Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Min Zhou
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Haijun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Fangfang Shi
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Cailian Wang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zongdao Rui
- Department of General Surgery, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Peng C, Gao H, Niu Z, Wang B, Tan Z, Niu W, Liu E, Wang J, Sun J, Shahbaz M, Agrez M, Niu J. Integrin αvβ6 and transcriptional factor Ets-1 act as prognostic indicators in colorectal cancer. Cell Biosci 2014; 4:53. [PMID: 25264483 PMCID: PMC4175281 DOI: 10.1186/2045-3701-4-53] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 08/18/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Both transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins' correlation and their clinical significance in colorectal cancerous tissues. RESULTS The specimens were arranged into microarray using the immunohistochemistry method to investigate the expression of integrin αvβ6 and transcriptional factor Ets-1 in these tissues. Among the 158 tissue specimens, 36.07% were positive for αvβ6 expression, and 57.59% were positive for Ets-1 expression. There were obvious statistical differences existed regarding differentiation, N stage, M stage and TNM stage between αvβ6 and Ets-1 positively and negatively expressing tumors. The correlation analysis confirmed the expression of αvβ6 and Ets-1 were positively correlated in colorectal cancer. The Kaplan-Meier survival analysis showed that patients who were both αvβ6 and Ets-1 positive relapsed earlier than those who were both αvβ6 and Ets-1 negative; and the former group had much shorter survival time than the latter. And Cox model indicated that αvβ6 and Ets-1 were the independent prognostic factors (RR = 2.175, P = 0.012 and RR = 3.903, P < 0.001). CONCLUSIONS The expression of αvβ6 and Ets-1 were positively correlated, and their expression degrees were associated with the differentiation, N stage, M stage and TNM stage of the tumors. Hence, the combination of αvβ6 and Ets-1 can be used as a prognostic marker in colorectal cancer, especially for the early stage.
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Affiliation(s)
- Cheng Peng
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Huijie Gao
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Zhengchuan Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Ben Wang
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Zhen Tan
- />Health Science College, The State University of New York -Stony Brook University, Stony Brook, NY USA
| | - Weibo Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Enyu Liu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Jiayong Wang
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Jiuzheng Sun
- />Department of General Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong China
| | - Muhammad Shahbaz
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
| | - Michael Agrez
- />Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research Institute, John Hunter Hospital and Faculty of Medicine and Health Sciences, The University of Newcastle, Callaghan, NSW Australia
| | - Jun Niu
- />Department of Hepatobiliary Surgery, QiLu Hospital, Shandong University, Jinan, Shandong China
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Xu XL, Ling ZQ, Chen SZ, Li B, Ji WH, Mao WM. The impact of E-cadherin expression on the prognosis of esophageal cancer: a meta-analysis. Dis Esophagus 2014; 27:79-86. [PMID: 23317312 DOI: 10.1111/dote.12024] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
E-cadherin is a 120-KD transmembrane calcium-dependent cell adhesion protein that has been demonstrated drownregulated in a large amount of invasive tumors. However, its effect on the prognosis of esophageal cancer (EC) remains controversial. All the relevant English articles that reported survival data or clinicopathological parameters were enrolled in this meta-analysis. A total of 24 studies, including 2691 cases, were included in this study. Twelve studies containing 1669 cases were enrolled to synthesize with hazard ratio (HR) and its 95% confidence interval (CI). The pooled HR for all 12 studies enrolled in this meta-analysis was 1.33 (95% CI 1.16-1.52; z = 3.99, P = 0.00). When the study measured by enzyme-linked immunosorbent assay is excluded, the pooled HR-evaluated E-cadherin to reduce the expression in EC, and in esophageal squamous cell carcinoma was 1.39 (95% CI 1.22-1.58; z = 5.08, P = 0.00) and 1.38 (95% CI 1.21-1.56; z = 4.87, P = 0.00), respectively. The risk of reduced E-cadherin expression on poor differentiation degree was 1.636 (95% CI 1.33-2.02). The pooled odds ratio of reduced E-cadherin expression on deeper tumor invasion, lymph node metastasis, and higher clinical stage were 2.63 (95% CI 1.75-3.94), 1.77 (95% CI 1.06 -2.97), and 3.39 (95% CI 1.85-6.23). Reduced E-cadherin expression detected by immunohistochemistry could be a valid prognostic marker in patients with EC, especially in patients with esophageal squamous cell carcinoma. Reduced E-cadherin expression is significantly associated with poorer differentiation degree.
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Affiliation(s)
- X-L Xu
- Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou, China
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Szatmári T, Dobra K. The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors. Front Oncol 2013; 3:310. [PMID: 24392351 PMCID: PMC3867677 DOI: 10.3389/fonc.2013.00310] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 12/04/2013] [Indexed: 12/23/2022] Open
Abstract
Proteoglycans (PGs) and in particular the syndecans are involved in the differentiation process across the epithelial-mesenchymal axis, principally through their ability to bind growth factors and modulate their downstream signaling. Malignant tumors have individual proteoglycan profiles, which are closely associated with their differentiation and biological behavior, mesenchymal tumors showing a different profile from that of epithelial tumors. Syndecan-1 is the main syndecan of epithelial malignancies, whereas in sarcomas its expression level is generally low, in accordance with their mesenchymal phenotype and highly malignant behavior. This proteoglycan is often overexpressed in adenocarcinoma cells, whereas mesothelioma and fibrosarcoma cells express syndecan-2 and syndecan-4 more abundantly. Increased expression of syndecan-1 in mesenchymal tumors changes the tumor cell morphology to an epithelioid direction whereas downregulation results in a change in shape from polygonal to spindle-like morphology. Although syndecan-1 plays major roles on the cell-surface, there are also intracellular functions, which are not very well studied. On the functional level, syndecan-1 affects mesenchymal tumor cell proliferation, adhesion, migration and motility, and the effect varies with the different domains of the core protein. Syndecan-1 may exert stimulatory or inhibitory effects, depending on the concentration of various mitogens, enzymes, and signaling molecules, the ratio between the shed and membrane-associated syndecan-1 and histological grade of the tumour. Growth factor signaling seems to be delicately controlled by regulatory loops involving the syndecan expression levels and their sulfation patterns. Overexpression of syndecan-1 modulates the biosynthesis and sulfation of heparan sulfate and it also affects the expression of other PGs. On transcriptomic level, syndecan-1 modulation results in profound effects on genes involved in regulation of cell growth.
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Affiliation(s)
- Tünde Szatmári
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
| | - Katalin Dobra
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
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He X, Chen Z, Jia M, Zhao X. Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis. PLoS One 2013; 8:e70858. [PMID: 23923027 PMCID: PMC3726621 DOI: 10.1371/journal.pone.0070858] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/24/2013] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive. METHODOLOGY Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value. PRINCIPAL FINDINGS A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63-3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13-3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95-1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45-2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21-0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32-0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22-0.91, Z = 3.43, P = 0.001), respectively. CONCLUSIONS This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.
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Affiliation(s)
- Xin He
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhigang Chen
- Department of Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Minyue Jia
- Department of Endocrinology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoying Zhao
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Choi S, Kang DH, Oh ES. Targeting syndecans: a promising strategy for the treatment of cancer. Expert Opin Ther Targets 2013; 17:695-705. [DOI: 10.1517/14728222.2013.773313] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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25
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Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci 2013; 70:3375-90. [PMID: 23288305 DOI: 10.1007/s00018-012-1243-7] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 11/20/2012] [Accepted: 12/11/2012] [Indexed: 10/27/2022]
Abstract
The Ets1 transcription factor is a member of the Ets gene family and is highly conserved throughout evolution. Ets1 is known to regulate a number of important biological processes in normal cells and in tumors. In particular, Ets1 has been associated with regulation of immune cell function and with an aggressive behavior in tumors that express it at high levels. Here we review and summarize the general features of Ets1 and describe its roles in immunity and autoimmunity, with a focus on its roles in B lymphocytes. We also review evidence that suggests that Ets1 may play a role in malignant transformation of hematopoietic malignancies including B cell malignancies.
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26
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Szatmári T, Mundt F, Heidari-Hamedani G, Zong F, Ferolla E, Alexeyenko A, Hjerpe A, Dobra K. Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells. PLoS One 2012; 7:e48091. [PMID: 23144729 PMCID: PMC3483307 DOI: 10.1371/journal.pone.0048091] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 09/19/2012] [Indexed: 11/19/2022] Open
Abstract
Malignant pleural mesothelioma is a highly malignant tumor, originating from mesothelial cells of the serous cavities. In mesothelioma the expression of syndecan-1 correlates to epithelioid morphology and inhibition of growth and migration. Our previous data suggest a complex role of syndecan-1 in mesothelioma cell proliferation although the exact underlying molecular mechanisms are not completely elucidated. The aim of this study is therefore to disclose critical genes and pathways affected by syndecan-1 in mesothelioma; in order to better understand its importance for tumor cell growth and proliferation. We modulated the expression of syndecan-1 in a human mesothelioma cell line via both overexpression and silencing, and followed the transcriptomic responses with microarray analysis. To project the transcriptome analysis on the full-dimensional picture of cellular regulation, we applied pathway analysis using Ingenuity Pathway Analysis (IPA) and a novel method of network enrichment analysis (NEA) which elucidated signaling relations between differentially expressed genes and pathways acting via various molecular mechanisms. Syndecan-1 overexpression had profound effects on genes involved in regulation of cell growth, cell cycle progression, adhesion, migration and extracellular matrix organization. In particular, expression of several growth factors, interleukins, and enzymes of importance for heparan sulfate sulfation pattern, extracellular matrix proteins and proteoglycans were significantly altered. Syndecan-1 silencing had less powerful effect on the transcriptome compared to overexpression, which can be explained by the already low initial syndecan-1 level of these cells. Nevertheless, 14 genes showed response to both up- and downregulation of syndecan-1. The "cytokine - cytokine-receptor interaction", the TGF-β, EGF, VEGF and ERK/MAPK pathways were enriched in both experimental settings. Most strikingly, nearly all analyzed pathways related to cell cycle were enriched after syndecan-1 silencing and depleted after syndecan-1 overexpression. Syndecan-1 regulates proliferation in a highly complex way, although the exact contribution of the altered pathways necessitates further functional studies.
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Affiliation(s)
- Tünde Szatmári
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
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27
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Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells. PLoS One 2012. [PMID: 23144729 DOI: 10.1371/journal.pone.0048091pone-d-12-14424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Malignant pleural mesothelioma is a highly malignant tumor, originating from mesothelial cells of the serous cavities. In mesothelioma the expression of syndecan-1 correlates to epithelioid morphology and inhibition of growth and migration. Our previous data suggest a complex role of syndecan-1 in mesothelioma cell proliferation although the exact underlying molecular mechanisms are not completely elucidated. The aim of this study is therefore to disclose critical genes and pathways affected by syndecan-1 in mesothelioma; in order to better understand its importance for tumor cell growth and proliferation. We modulated the expression of syndecan-1 in a human mesothelioma cell line via both overexpression and silencing, and followed the transcriptomic responses with microarray analysis. To project the transcriptome analysis on the full-dimensional picture of cellular regulation, we applied pathway analysis using Ingenuity Pathway Analysis (IPA) and a novel method of network enrichment analysis (NEA) which elucidated signaling relations between differentially expressed genes and pathways acting via various molecular mechanisms. Syndecan-1 overexpression had profound effects on genes involved in regulation of cell growth, cell cycle progression, adhesion, migration and extracellular matrix organization. In particular, expression of several growth factors, interleukins, and enzymes of importance for heparan sulfate sulfation pattern, extracellular matrix proteins and proteoglycans were significantly altered. Syndecan-1 silencing had less powerful effect on the transcriptome compared to overexpression, which can be explained by the already low initial syndecan-1 level of these cells. Nevertheless, 14 genes showed response to both up- and downregulation of syndecan-1. The "cytokine - cytokine-receptor interaction", the TGF-β, EGF, VEGF and ERK/MAPK pathways were enriched in both experimental settings. Most strikingly, nearly all analyzed pathways related to cell cycle were enriched after syndecan-1 silencing and depleted after syndecan-1 overexpression. Syndecan-1 regulates proliferation in a highly complex way, although the exact contribution of the altered pathways necessitates further functional studies.
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28
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Ahearn TU, Shaukat A, Flanders WD, Rutherford RE, Bostick RM. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prev Res (Phila) 2012; 5:1247-56. [PMID: 22964475 DOI: 10.1158/1940-6207.capr-12-0292] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months (N = 92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D(3)-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (Φh APC) increased 21% (P = 0.01), β-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the Φh APC/β-catenin ratio (APC/β-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group Φh APC increased 10% (P = 0.12), β-catenin decreased 15% (P = 0.08), and the APC/β-catenin score increased 41% (P = 0.01). In the calcium/vitamin D(3)-supplemented group, β-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/β-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.
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Affiliation(s)
- Thomas U Ahearn
- Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
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Ahearn TU, Shaukat A, Flanders WD, Seabrook ME, Bostick RM. Markers of the APC/β-catenin signaling pathway as potential treatable, preneoplastic biomarkers of risk for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev 2012; 21:969-79. [PMID: 22539608 DOI: 10.1158/1055-9965.epi-12-0126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Malfunctioning of the adenomatous polyposis coli (APC)/β-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/β-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. METHODS We evaluated APC, β-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires. RESULTS In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total β-catenin expression (APC/β-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, β-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/β-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D(3) concentrations ≥ 27 ng/mL]. CONCLUSIONS These preliminary data suggest that the combined expression of APC and β-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms. IMPACT Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms.
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Affiliation(s)
- Thomas U Ahearn
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
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