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Deng EZ, Marino GB, Clarke DJB, Diamant I, Resnick AC, Ma W, Wang P, Ma'ayan A. Multiomics2Targets identifies targets from cancer cohorts profiled with transcriptomics, proteomics, and phosphoproteomics. CELL REPORTS METHODS 2024; 4:100839. [PMID: 39127042 PMCID: PMC11384097 DOI: 10.1016/j.crmeth.2024.100839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/06/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024]
Abstract
The availability of data from profiling of cancer patients with multiomics is rapidly increasing. However, integrative analysis of such data for personalized target identification is not trivial. Multiomics2Targets is a platform that enables users to upload transcriptomics, proteomics, and phosphoproteomics data matrices collected from the same cohort of cancer patients. After uploading the data, Multiomics2Targets produces a report that resembles a research publication. The uploaded matrices are processed, analyzed, and visualized using the tools Enrichr, KEA3, ChEA3, Expression2Kinases, and TargetRanger to identify and prioritize proteins, genes, and transcripts as potential targets. Figures and tables, as well as descriptions of the methods and results, are automatically generated. Reports include an abstract, introduction, methods, results, discussion, conclusions, and references and are exportable as citable PDFs and Jupyter Notebooks. Multiomics2Targets is applied to analyze version 3 of the Clinical Proteomic Tumor Analysis Consortium (CPTAC3) pan-cancer cohort, identifying potential targets for each CPTAC3 cancer subtype. Multiomics2Targets is available from https://multiomics2targets.maayanlab.cloud/.
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Affiliation(s)
- Eden Z Deng
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Giacomo B Marino
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Daniel J B Clarke
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Ido Diamant
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
| | - Adam C Resnick
- Center for Data Driven Discovery in Biomedicine, Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Weiping Ma
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA
| | - Pei Wang
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA
| | - Avi Ma'ayan
- Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
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Oldak L, Lukaszewski Z, Leśniewska A, Goławski K, Laudański P, Gorodkiewicz E. Development of an SPRi Test for the Quantitative Detection of Cadherin 12 in Human Plasma and Peritoneal Fluid. Int J Mol Sci 2023; 24:16894. [PMID: 38069216 PMCID: PMC10706750 DOI: 10.3390/ijms242316894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
A new method for the determination of cadherin 12 (CDH12)-an adhesive protein that has a significant impact on the development, growth, and movement of cancer cells-was developed and validated. The method is based on a biosensor using surface plasmon resonance imaging (SPRi) detection. A quartz crystal microbalance was used to analyze the characteristics of the formation of successive layers of the biosensor, from the linker monolayer to the final capture of CDH12 from solution. The association equilibrium constant (KA = 1.66 × 1011 dm3 mol-1) and the dissociation equilibrium constant (KD = 7.52 × 10-12 mol dm-3) of the anti-CDH12 antibody-CDH12 protein complex were determined. The determined analytical parameters, namely the values determining the accuracy, precision, and repeatability of the method, do not exceed the permissible 20% deviations specified by the aforementioned institutions. The proposed method is also selective with respect to possible potential interferents, occurring in up to 100-fold excess concentration relative to the CDH12 concentration. The determined Limit of Quantification (LOQ = 4.92 pg mL-1) indicates the possibility of performing quantitative analysis in human plasma or peritoneal fluid without the need to concentrate the samples; however, particular attention should be paid to their storage conditions, as the analyte does not exhibit high stability. The Passing-Bablok regression model revealed good agreement between the reference method and the SPRi biosensor, with ρSpearman values of 0.961 and 0.925.
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Affiliation(s)
- Lukasz Oldak
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland (E.G.)
| | - Zenon Lukaszewski
- Faculty of Chemical Technology, Poznan University of Technology, pl. Sklodowskiej-Curie 5, 60-965 Poznan, Poland
| | - Anna Leśniewska
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland (E.G.)
| | - Ksawery Goławski
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Piotr Laudański
- Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland
- OVIklinika Infertility Center, 01-377 Warsaw, Poland
- Women’s Health Research Institute, Calisia University, 62-800 Kalisz, Poland
| | - Ewa Gorodkiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland (E.G.)
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Tian W, Zhao J, Wang W. Targeting CDH17 with Chimeric Antigen Receptor-Redirected T Cells in Small Cell Lung Cancer. Lung 2023; 201:489-497. [PMID: 37823901 DOI: 10.1007/s00408-023-00648-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/04/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Chimeric antigen receptor T cell (CAR-T) therapy stands as a precise and targeted approach in the treatment of malignancies. In this study, we investigated the feasibility of targeting Cadherin 17 (CDH17) with CDH17 CAR-T cells as a therapeutic modality for small cell lung cancer (SCLC). METHODS CDH17 expression levels were assessed in human SCLC tumor tissues and cell lines using qPCR and Western blot. Subsequently, we established CDH17 CAR-T cells and assessed their cytotoxicity by co-culturing them with various SCLC cell lines at different effector-to-target (E:T) ratios, complemented by ELISA assays. To ascertain the specificity of CDH17 CAR-T cells, we conducted experiments on SCLC cells with and without CDH17 expression (shRNAs). Furthermore, we employed an SCLC xenograft model to evaluate the in vivo efficacy of CDH17 CAR-T cells. RESULTS Our results revealed a significant upregulation of CDH17 in both SCLC tissues and cell lines. CDH17 CAR-T cells exhibited robust cytotoxic activity against SCLC cells in vitro, while demonstrating no cytotoxicity towards CDH17-deficient SCLC cells and HEK293 cells that lack CDH17 expression. Importantly, the production of IFN-γ and TNF-α by CDH17 CAR-T cells correlated with their cytotoxic potency. Additionally, treatment with CDH17 CAR-T cells significantly decelerated the growth rate of SCLC-derived xenograft tumors in vivo. Remarkably, no significant difference in body weight was observed between the control group and the group treated with CDH17 CAR-T cells. CONCLUSIONS The preclinical data open further venues for the clinical use of CDH17 CAR-T cells as an immunotherapeutic strategy for SCLC treatment.
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Affiliation(s)
- Wen Tian
- Second Department of Oncology, Cangzhou Central Hospital, NO.16 Xinhua West Road, Cangzhou, 061000, Hebei, China.
| | - Jinhui Zhao
- Medical Oncology, Cangzhou Central Hospital Hejian Branch, NO.32 Jingkai South Street, Hejian, 062450, Hebei, China
| | - Wenzhong Wang
- Medical Oncology, Cancer Hospital of HuanXing ChaoYang District Beijing, NO.1 Lvjiaying Nanlijia, Chaoyang District, Beijing, 100020, China
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Rocha SDC, Lei P, Morales-Lange B, Mydland LT, Øverland M. From a cell model to a fish trial: Immunomodulatory effects of heat-killed Lactiplantibacillus plantarum as a functional ingredient in aquafeeds for salmonids. Front Immunol 2023; 14:1125702. [PMID: 36993984 PMCID: PMC10040762 DOI: 10.3389/fimmu.2023.1125702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/27/2023] [Indexed: 03/14/2023] Open
Abstract
Paraprobiotics (dead/inactivated probiotics) are promising candidates in functional feeds to promote growth performance, modulate intestinal microbiota and enhance immune response of fish. During industrial production, fish are exposed to several stressful conditions such as handling, sub-optimal nutrition and diseases that can lead to reduced growth, increased mortalities and large economical losses. Such problems can be mitigated by use of functional feeds, leading to more-sustainable aquaculture and improved animal welfare. Lactiplantibacillus plantarum strain L-137 is a common bacterium found in fermented Southeast Asian dish made from fish and rice. The benefits of its heat-killed form (HK L-137) related to growth performance and immunomodulation have been studied in farmed fish such as Nile Tilapia (Oreochromis niloticus), striped catfish (Pangasianodon hypophthalmus) and bighead catfish (Clarias macrocephalus). To study if such benefits can also be observed in salmonids, we worked both at in vitro level using an intestinal epithelium cell line from rainbow trout (Oncorhynchus mykiss; RTgutGC) stimulated with HK L-137 (Feed LP20™) and at in vivo level with pre-smolt Atlantic salmon (Salmo salar) fed HK L-137 at different inclusion levels (20, 100 and 500 mg of Feed LP20™ kg-1 feed). In RTgutGC, the results showed that the barrier function of the cell monolayer was strengthened along with an increased production of IL-1β and a decreased production of Anxa1, indicating a modulation of the immune response. Interestingly, a similar trend was detected at the in vivo level in distal intestine from fish fed the highest inclusion level of HK L-137. Here, a lower production of Anxa1 was also detected (after a 61-day feeding period) in addition to an increase of total plasma IgM in the same group. Furthermore, the RNA-seq analysis showed that HK L-137 was able to modulate the gene expression of pathways related to molecular function, biological process and cellular component in distal intestine, without compromising fish performance and gut microbiota. Taken together, our study has shown that HK L-137 can modulate physiological response of Atlantic salmon, making fish more robust against stressful conditions during production.
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Ghazi B, El Ghanmi A, Kandoussi S, Ghouzlani A, Badou A. CAR T-cells for colorectal cancer immunotherapy: Ready to go? Front Immunol 2022; 13:978195. [PMID: 36458008 PMCID: PMC9705989 DOI: 10.3389/fimmu.2022.978195] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/14/2022] [Indexed: 08/12/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.
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Affiliation(s)
- Bouchra Ghazi
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Adil El Ghanmi
- Mohammed VI International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
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6
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Feng Z, He X, Zhang X, Wu Y, Xing B, Knowles A, Shan Q, Miller S, Hojnacki T, Ma J, Katona BW, Gade TPF, Siegel DL, Schrader J, Metz DC, June CH, Hua X. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. NATURE CANCER 2022; 3:581-594. [PMID: 35314826 DOI: 10.1038/s43018-022-00344-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 02/09/2022] [Indexed: 12/15/2022]
Abstract
Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal epithelial cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is 'masked' in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.
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Affiliation(s)
- Zijie Feng
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xin He
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xuyao Zhang
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Yuan Wu
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Bowen Xing
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Alison Knowles
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Qiaonan Shan
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Samuel Miller
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Taylor Hojnacki
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jian Ma
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Bryson W Katona
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Terence P F Gade
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Don L Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jörg Schrader
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David C Metz
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xianxin Hua
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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8
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Li Q, Xie Y, Rice R, Maverakis E, Lebrilla CB. A proximity labeling method for protein–protein interactions on cell membrane. Chem Sci 2022; 13:6028-6038. [PMID: 35685794 PMCID: PMC9132088 DOI: 10.1039/d1sc06898a] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/29/2022] [Indexed: 01/02/2023] Open
Abstract
Modified catalytic antibodies targeting specific antigens are employed to investigate protein interactions and antigen interaction sites.
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Affiliation(s)
- Qiongyu Li
- Department of Chemistry, University of California Davis, Davis, California, USA
| | - Yixuan Xie
- Department of Chemistry, University of California Davis, Davis, California, USA
| | - Rachel Rice
- Department of Chemistry, University of California Davis, Davis, California, USA
| | - Emanual Maverakis
- Department of Dermatology, School of Medicine, University of California Davis, Davis, California, USA
| | - Carlito B. Lebrilla
- Department of Chemistry, University of California Davis, Davis, California, USA
- Department of Biochemistry, University of California Davis, Davis, California, USA
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9
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García-Martínez JM, Wang S, Weishaeupl C, Wernitznig A, Chetta P, Pinto C, Ho J, Dutcher D, Gorman PN, Kroe-Barrett R, Rinnenthal J, Giragossian C, Impagnatiello MA, Tirapu I, Hilberg F, Kraut N, Pearson M, Kuenkele KP. Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist. Mol Cancer Ther 2020; 20:96-108. [PMID: 33037135 DOI: 10.1158/1535-7163.mct-20-0253] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/12/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).
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Affiliation(s)
| | - Shirley Wang
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | | | | | - Paolo Chetta
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Catarina Pinto
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Jason Ho
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Darrin Dutcher
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Philip N Gorman
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Rachel Kroe-Barrett
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Joerg Rinnenthal
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Craig Giragossian
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | | | - Iñigo Tirapu
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Frank Hilberg
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Norbert Kraut
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Mark Pearson
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
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Immunoaffinity enrichment LC-MS/MS quantitation of CDH17 in tissues. Bioanalysis 2020; 12:1439-1447. [PMID: 33006478 DOI: 10.4155/bio-2020-0162] [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: 11/17/2022] Open
Abstract
Aim: There is little information in the literature regarding assays for measuring CDH17 in tissues. Numerous studies indicate overexpression of CDH17 in a variety of diseases including hepatocellular carcinoma, colorectal and gastric cancer. Here we present an immunoaffinity enrichment LC-MS/MS approach for analysis of CDH17 in human tissues, plasma and serum as well as preclinical models. Results: CDH17 levels were measured in colon and ileum tissues from healthy donors and inflamed tissues from patients with Ulcerative Colitus or Crohn's disease. Applicability of the immunocapture LC-MS/MS approach is demonstrated for colon tissues from non-diseased mouse and cynomolgus monkey. Conclusion: The analytical approaches discussed here are suitable for quantitation of CDH17 in various tissues to enable both preclinical and clinical assessment.
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11
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Lum YL, Luk JM, Staunton DE, Ng DKP, Fong WP. Cadherin-17 Targeted Near-Infrared Photoimmunotherapy for Treatment of Gastrointestinal Cancer. Mol Pharm 2020; 17:3941-3951. [PMID: 32931292 DOI: 10.1021/acs.molpharmaceut.0c00700] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
In cancer photodynamic therapy (PDT), a photosensitizer taken up by cancer cells can generate reactive oxygen species upon near-infrared light activation to induce cancer cell death. To increase PDT potency and decrease its adverse effect, one approach is to conjugate the photosensitizer with an antibody that specifically targets cancer cells. In the present study, IR700, a hydrophilic phthalocyanine photosensitizer, was conjugated to the humanized monoclonal antibody ARB102, which binds specifically cadherin-17 (CDH17 aka CA17), a cell surface marker highly expressed in gastrointestinal cancer to produce ARB102-IR700. Photoimmunotherapy (PIT) of gastrointestinal cancer cell lines was conducted by ARB102-IR700 treatment and near-infrared light irradiation. The results showed that ARB102-IR700 PIT could induce cell death in CDH17-positive cancer cells with high potency. In a co-culture model, CDH17-negative and CDH17-overexpressing SW480 cells were labeled with distinct fluorescent dyes and cultured together prior to PIT treatment. The results confirmed that ARB102-IR700 PIT could kill CDH17-positive cells specifically, while leaving the adjacent CDH17-negative cells unaffected. An in vivo efficacy study was conducted using a pancreatic adenocarcinoma AsPC-1 xenograft tumor model in nude mice. Fluorescence scanning indicated that ARB102-IR700 accumulated specifically in the tumor sites. To perform PIT, at 24 and 48 h postinjection, mice were irradiated with a 680 nm laser at the tumor site to activate the photosensitizer. It was shown that ARB102-IR700 PIT could inhibit tumor growth significantly. In summary, this study demonstrated that the novel ARB102-IR700 is a promising agent for PIT in gastrointestinal cancers.
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Affiliation(s)
- Yick-Liang Lum
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - John M Luk
- Arbele Limited, Shatin N.T., Hong Kong, China
| | | | - Dennis K P Ng
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Wing-Ping Fong
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
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12
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Wang X, Li Z, Fu J, Xu W, Li Z. Diagnostic value and prognostic significance of LI-cadherin and miR-378e in colorectal cancer. Oncol Lett 2020; 20:2456-2464. [PMID: 32782563 PMCID: PMC7400983 DOI: 10.3892/ol.2020.11755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 12/03/2019] [Indexed: 11/25/2022] Open
Abstract
Expression levels of LI-cadherin and miR-378e in the serum of patients with colorectal cancer, and the diagnostic value and prognostic significance in colorectal cancer were investigated. A total of 110 patients who were diagnosed with colorectal cancer in Weihai Central Hospital, from January 2012 to November 2014, were selected and enrolled in the experimental group, and 90 healthy subjects who underwent physical examination were enrolled in the control group. The expression level of miR-378e in serum was detected by reverse transcription-quantitative PCR and the expression of LI-cadherin in serum was detected by ELISA. ROC curves of LI-cadherin and miR-378e were drawn and the sensitivity and specificity of the diagnosis were estimated. The association of the expression levels of LI-cadherin and miR-378e with the survival of the patients was analyzed. LI-cadherin and miR-378e expression levels were significantly higher in the control group than those in the experimental group (P<0.001). LI-cadherin was significantly associated with the pathogenic site, the lymphatic metastasis, depth of infiltration, degree of differentiation and clinical stage (P<0.05). The sensitivity and specificity of the LI-cadherin combined with miR-378e detection were respectively 86 and 94%; the sensitivity of miR-378e detection was the highest, as well as the specificity of the combined detection. At the end of the follow-up period, the survival rates of the patients in the LI-cadherin high-expression group and miR-378e high-expression group were significantly higher than those in the low-expression groups (P<0.05). There was a significant positive correlation between the LI-cadherin and miR-378e expression levels in both the experimental and control group (r=0.5845 and 0.6356, respectively; P<0.05). In conclusion, LI-cadherin and miR-378e are expressed at low levels in colorectal cancer, suggesting that they have a good diagnostic value for colorectal cancer and can be used as biomarkers for colorectal cancer prognosis.
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Affiliation(s)
- Xujie Wang
- Department I of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Zhihua Li
- Department III of Oncology, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Jixin Fu
- Department II of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Weiwei Xu
- Department I of Gastrointestinal Surgery, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
| | - Zongxian Li
- Department III of Oncology, Weihai Central Hospital, Weihai, Shandong 264400, P.R. China
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13
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Serafín V, Valverde A, Garranzo-Asensio M, Barderas R, Campuzano S, Yáñez-Sedeño P, Pingarrón JM. Simultaneous amperometric immunosensing of the metastasis-related biomarkers IL-13Rα2 and CDH-17 by using grafted screen-printed electrodes and a composite prepared from quantum dots and carbon nanotubes for signal amplification. Mikrochim Acta 2019; 186:411. [DOI: 10.1007/s00604-019-3531-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/19/2019] [Indexed: 02/07/2023]
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14
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Vereshchaga Y, Arnold N, Baumgartner W. Physiological relevance of epithelial geometry: New insights into the standing gradient model and the role of LI cadherin. PLoS One 2018; 13:e0208791. [PMID: 30576326 PMCID: PMC6303100 DOI: 10.1371/journal.pone.0208791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 11/23/2018] [Indexed: 12/14/2022] Open
Abstract
We introduce a mathematical model of an absorbing leaky epithelium to reconsider the problem formulated by Diamond and Bossert in 1967: whether "… some distinctive physiological properties of epithelia might arise as geometrical consequences of epithelial ultrastructure". A standing gradient model of the intercellular cleft (IC) is presented that includes tight junctions (TJ) and ion channels uniformly distributed along the whole cleft. This nonlinear system has an intrinsic homogeneous concentration and the spatial scale necessary to establish it along the cleft. These parameters have not been elucidated so far. We further provide non-perturbative analytical approximations for a broad range of parameters. We found that narrowing of the IC increases ion concentration dramatically and can therefore prevent outflow through tight junctions (TJs) and the lateral membrane, as long as extremely high luminal osmolarities are not reached. Our model predicts that the system is to some extent self-regulating and thereby prevents fluxes into the lumen. Recent experimental evidence has shown that liver-intestine (LI) cadherin can control the up/down flux in intestines via regulation of the cleft width. This finding is in full agreement with predictions of our model. We suggest that LI-cadherin may increase water transport through epithelia via sequential narrowing of the cleft, starting from the highest concentration area at the beginning of the cleft and triggering a propagating squeezing motion.
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Affiliation(s)
- Yana Vereshchaga
- Institute of Biomedical Mechatronics, Johannes Kepler University Linz, Linz, Austria
| | - Nikita Arnold
- Institute of Experimental Physics/Soft Matter Physics, Johannes Kepler University Linz, Linz, Austria
| | - Werner Baumgartner
- Institute of Biomedical Mechatronics, Johannes Kepler University Linz, Linz, Austria
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15
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Chang YY, Yu LCH, Yu IS, Jhuang YL, Huang WJ, Yang CY, Jeng YM. Deletion of cadherin-17 enhances intestinal permeability and susceptibility to intestinal tumour formation. J Pathol 2018; 246:289-299. [PMID: 30047135 DOI: 10.1002/path.5138] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 04/28/2018] [Accepted: 06/05/2018] [Indexed: 01/08/2023]
Abstract
Cadherin-17 is an adhesion molecule expressed specifically in intestinal epithelial cells. It is frequently underexpressed in human colorectal cancer. The physiological function of cadherin-17 and its role in tumourigenesis have not yet been determined. We used the transcription activator-like effector nuclease technique to generate a Cdh17 knockout (KO) mouse model. Intestinal tissues were analysed with histological, immunohistochemical and ultrastructural methods. Colitis was induced by oral administration of dextran sulphate sodium (DSS), and, to study effects on intestinal tumourigenesis, mice were given azoxymethane (AOM) and DSS to induce colitis-associated cancer. Cdh17 KO mice were viable and fertile. The histology of their small and large intestines was similar to that of wild-type mice. The junctional architecture of the intestinal epithelium was preserved. The loss of cadherin-17 resulted in increased permeability and susceptibility to DSS-induced colitis. The AOM/DSS model demonstrated that Cdh17 KO enhanced tumour formation and progression in the intestine. Increased nuclear translocation of Yap1, but not of β-catenin, was identified in the tumours of Cdh17 KO mice. In conclusion, cadherin-17 plays a crucial role in intestinal homeostasis by limiting the permeability of the intestinal epithelium. Cadherin-17 is also a tumour suppressor for intestinal epithelia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Ya-Yun Chang
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan
| | - I-Shing Yu
- Laboratory Animal Centre, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Lin Jhuang
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.,Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Ju Huang
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.,Department of Oral Hygiene, Hsin-Sheng College of Medical Care and Management, Taoyuan, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.,Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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16
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Valverde A, Povedano E, Ruiz-Valdepeñas Montiel V, Yáñez-Sedeño P, Garranzo-Asensio M, Rodríguez N, Domínguez G, Barderas R, Campuzano S, Pingarrón JM. Determination of Cadherin-17 in Tumor Tissues of Different Metastatic Grade Using a Single Incubation-Step Amperometric Immunosensor. Anal Chem 2018; 90:11161-11167. [PMID: 30134108 DOI: 10.1021/acs.analchem.8b03506] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This paper reports the development of an amperometric immunosensing platform for the determination of cadherin-17 (CDH-17), an atypical adhesion protein involved in the progression, metastatic potential, and survival of high prevalence gastric, hepatocellular, and colorectal tumors. The methodology developed relies on the efficient capture and enzymatic labeling of the target protein on the magnetic microparticles (MBs) surface using commercial antibodies and amperometric transduction at screen-printed carbon electrodes (SCPEs) through the HRP/H2O2/HQ system. The developed immunosensing platform allows the selective determination of the target protein at low ng mL-1 level (LOD of 1.43 ng mL-1) in 45 min and using a single incubation step. The electrochemical immunosensor was successfully used for the accurate determination of the target protein in a small amount (0.5 μg) of raw lysates of colon cancer cells with different metastatic potential as well as in extracts from paraffin embedded cancer colon tissues of different metastatic grade.
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Affiliation(s)
- Alejandro Valverde
- Departamento de Química Analítica , Universidad Complutense de Madrid , E-28040 Madrid , Spain
| | - Eloy Povedano
- Departamento de Química Analítica , Universidad Complutense de Madrid , E-28040 Madrid , Spain
| | | | - Paloma Yáñez-Sedeño
- Departamento de Química Analítica , Universidad Complutense de Madrid , E-28040 Madrid , Spain
| | - María Garranzo-Asensio
- UFIEC, CROSADIS , National Institute of Health Carlos III , Majadahonda, E-28222 , Madrid , Spain
| | - Nuria Rodríguez
- Medical Oncology Department , Hospital Universitario La Paz , E-28046 Madrid , Spain
| | - Gemma Domínguez
- Departamento de Medicina, Facultad de Medicina , Instituto de Investigaciones Biomédicas "Alberto Sols" , CSIC-UAM, E-28029 , Madrid , Spain
| | - Rodrigo Barderas
- UFIEC, CROSADIS , National Institute of Health Carlos III , Majadahonda, E-28222 , Madrid , Spain
| | - Susana Campuzano
- Departamento de Química Analítica , Universidad Complutense de Madrid , E-28040 Madrid , Spain
| | - José M Pingarrón
- Departamento de Química Analítica , Universidad Complutense de Madrid , E-28040 Madrid , Spain
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17
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Casal JI, Bartolomé RA. RGD cadherins and α2β1 integrin in cancer metastasis: A dangerous liaison. Biochim Biophys Acta Rev Cancer 2018; 1869:321-332. [PMID: 29673969 DOI: 10.1016/j.bbcan.2018.04.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 04/13/2018] [Accepted: 04/14/2018] [Indexed: 12/24/2022]
Abstract
We propose a new cadherin family classification comprising epithelial cadherins (cadherin 17 [CDH17], cadherin 16, VE-cadherin, cadherin 6 and cadherin 20) containing RGD motifs within their sequences. Expression of some RGD cadherins is associated with aggressive forms of cancer during the late stages of metastasis, and CDH17 and VE-cadherin have emerged as critical actors in cancer metastasis. After binding to α2β1 integrin, these cadherins promote integrin β1 activation, and thereby cell adhesion, invasion and proliferation, in liver and lung metastasis. Activation of α2β1 integrin provokes an affinity increase for type IV collagen, a major component of the basement membrane and a critical partner for cell anchoring in liver and other metastatic organs. Activation of α2β1 integrin by RGD motifs breaks an old paradigm of integrin classification and supports an important role of this integrin in cancer metastasis. Recently, synthetic peptides containing the RGD motif of CDH17 elicited highly specific and selective antibodies that block the ability of CDH17 RGD to activate α2β1 integrin. These monoclonal antibodies inhibit metastatic colonization in orthotopic mouse models of liver and lung metastasis for colorectal cancer and melanoma, respectively. Hopefully, blocking the cadherin RGD ligand capacity will give us control over the integrin activity in solid tumors metastasis, paving the way for development of new agents of cancer treatment.
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Affiliation(s)
- J Ignacio Casal
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, Spain.
| | - Rubén A Bartolomé
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, Spain
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18
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Zhang C, Shen Y, Wang J, Zhou M, Chen Y. Identification of key pathways and genes in Barrett's esophagus using integrated bioinformatics methods. Mol Med Rep 2018; 17:3069-3077. [PMID: 29257318 PMCID: PMC5783528 DOI: 10.3892/mmr.2017.8274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 11/14/2017] [Indexed: 12/30/2022] Open
Abstract
Barrett's esophagus (BE) is a premalignant lesion of esophageal adenocarcinoma. The aim of the present study was to investigate the possible mechanisms and biomarkers of BE. To identify the differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) in BE, the miRNA expression profile GSE20099 and the gene expression profiles GSE26886, GSE13083 and GSE34619 were obtained from the Gene Expression Omnibus (GEO) database. DEGs and DEmiRNAs were screened for using the GEO2R tool. Using DAVID, functional and pathway enrichment analysis was performed to explore the biological function of identified DEGs. The protein‑protein interaction (PPI) network was detected using STRING and constructed by Cytoscape software. Furthermore, targets of identified DEmiRNAs were predicted by the miRecords database, then integrated with the identified DEGs to obtain key genes involved in BE. In total, 311 DEGs were identified. These genes were significantly enriched in the pancreatic secretion, metabolic pathways and cytochrome P450 drug metabolism pathways. In the PPI network, 16 hub genes, including keratin 16, cystic fibrosis transmembrane conductance regulator, involucrin, protein kinase C α and cadherin 17 were identified. Following integration of the predicted target genes of DEmiRNAs with DEGs, three key BE genes were identified: PRKCA, CDH17 and epiregulin. In conclusion, a comprehensive bioinformatics analysis of identified DEGs and DEmiRNAs was performed to elucidate potential pathways and biomarkers involved in the development of BE.
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Affiliation(s)
- Cong Zhang
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Yujie Shen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Jiazheng Wang
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Mingxia Zhou
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Yingwei Chen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, P.R. China
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19
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Downregulation of liver-intestine cadherin enhances cisplatin-induced apoptosis in human gastric cancer BGC823 cells. Cancer Gene Ther 2017; 25:1-9. [PMID: 29203930 DOI: 10.1038/s41417-017-0001-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 08/28/2017] [Accepted: 09/12/2017] [Indexed: 12/27/2022]
Abstract
Gastric cancer is the fourth most common type of cancer. Liver-intestine cadherin (CDH17) has been found to be involved in the proliferation and apoptosis of gastric cancer cells. Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumor and hematological malignancies. However, the mechanism of enhancing cisplatin-inducing effects on human gastric cancer BGC823 cells by blocking CDH17 gene, both in vitro and in vivo, remains to be clarified. In this study, we investigated the signaling pathway by which cisplatin induces apoptosis by blocking CDH17 gene in gastric cancer BGC823 cells. Our results indicate that down-expression of CDH17 gene can enhance apoptosis-inducing effects of cisplatin on human gastric cancer BGC823 cells. The expression levels of Bax and Cyt-c proteins were upregulated, but the expression levels of Bcl-2 and Bcl-xL proteins were downregulated by blocking CDH17 gene in gastric cancer BGC823 cells after treatment with cisplatin. Moreover, down-expression of CDH17 enhanced the efficacy of cisplatin-induced inhibition of tumor growth in nude mice via apoptosis induction. Down-expression of CDH17 gene can significantly improve apoptosis-inducing effects of cisplatin in vitro and in vivo, which is a new strategy to improve chemotherapeutic effects on gastric cancer.
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20
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Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F. Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. Arch Pathol Lab Med 2017; 141:1155-1180. [PMID: 28854347 DOI: 10.5858/arpa.2016-0489-ra] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CONTEXT - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.
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21
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Tian X, Liu M, Zhu Q, Tan J, Liu W, Wang Y, Chen W, Zou Y, Cai Y, Han Z, Huang X. Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells. Expert Rev Anticancer Ther 2017. [PMID: 28622054 DOI: 10.1080/14737140.2017.1344097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Xia Tian
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Meng Liu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Qingxi Zhu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Jie Tan
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Weijie Liu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yanfen Wang
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Wei Chen
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yanli Zou
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yishan Cai
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Zheng Han
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Xiaodong Huang
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
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22
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Identification and Validation of Novel Subtype-Specific Protein Biomarkers in Pancreatic Ductal Adenocarcinoma. Pancreas 2017; 46:311-322. [PMID: 27846146 DOI: 10.1097/mpa.0000000000000743] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) has been subclassified into 3 molecular subtypes: classical, quasi-mesenchymal, and exocrine-like. These subtypes exhibit differences in patient survival and drug resistance to conventional therapies. The aim of the current study is to identify novel subtype-specific protein biomarkers facilitating subtype stratification of patients with PDAC and novel therapy development. METHODS A set of 12 human patient-derived primary cell lines was used as a starting material for an advanced label-free proteomics approach leading to the identification of novel cell surface and secreted biomarkers. Cell surface protein identification was achieved by in vitro biotinylation, followed by mass spectrometric analysis of purified biotin-tagged proteins. Proteins secreted into a chemically defined serum-free cell culture medium were analyzed by shotgun proteomics. RESULTS Of 3288 identified proteins, 2 pan-PDAC (protocadherin-1 and lipocalin-2) and 2 exocrine-like-specific (cadherin-17 and galectin-4) biomarker candidates have been validated. Proximity ligation assay analysis of the 2 exocrine-like biomarkers revealed their co-localization on the surface of exocrine-like cells. CONCLUSIONS The study reports the identification and validation of novel PDAC biomarkers relevant for the development of patient stratification tools. In addition, cadherin-17 and galectin-4 may serve as targets for bispecific antibodies as novel therapeutics in PDAC.
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23
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Weth A, Dippl C, Striedner Y, Tiemann-Boege I, Vereshchaga Y, Golenhofen N, Bartelt-Kirbach B, Baumgartner W. Water transport through the intestinal epithelial barrier under different osmotic conditions is dependent on LI-cadherin trans-interaction. Tissue Barriers 2017; 5:e1285390. [PMID: 28452574 PMCID: PMC5501135 DOI: 10.1080/21688370.2017.1285390] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
In the intestine water has to be reabsorbed from the chymus across the intestinal epithelium. The osmolarity within the lumen is subjected to high variations meaning that water transport often has to take place against osmotic gradients. It has been hypothesized that LI-cadherin is important in this process by keeping the intercellular cleft narrow facilitating the buildup of an osmotic gradient allowing water reabsorption. LI-cadherin is exceptional among the cadherin superfamily with respect to its localization along the lateral plasma membrane of epithelial cells being excluded from adherens junction. Furthermore it has 7 but not 5 extracellular cadherin repeats (EC1-EC7) and a small cytosolic domain. In this study we identified the peptide VAALD as an inhibitor of LI-cadherin trans-interaction by modeling the structure of LI-cadherin and comparison with the known adhesive interfaces of E-cadherin. This inhibitory peptide was used to measure LI-cadherin dependency of water transport through a monolayer of epithelial CACO2 cells under various osmotic conditions. If LI-cadherin trans-interaction was inhibited by use of the peptide, water transport from the luminal to the basolateral side was impaired and even reversed in the case of hypertonic conditions whereas no effect could be observed at isotonic conditions. These data are in line with a recently published model predicting LI-cadherin to keep the width of the lateral intercellular cleft small. In this narrow cleft a high osmolarity can be achieved due to ion pumps yielding a standing osmotic gradient allowing water absorption from the gut even if the faeces is highly hypertonic.
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Affiliation(s)
- Agnes Weth
- a Institute of Biomedical Mechatronics, Johannes Kepler University of Linz , Linz , Austria
| | - Carsten Dippl
- a Institute of Biomedical Mechatronics, Johannes Kepler University of Linz , Linz , Austria
| | - Yasmin Striedner
- b Institute of Biophysics, Johannes Kepler University of Linz , Linz , Austria
| | - Irene Tiemann-Boege
- b Institute of Biophysics, Johannes Kepler University of Linz , Linz , Austria
| | - Yana Vereshchaga
- a Institute of Biomedical Mechatronics, Johannes Kepler University of Linz , Linz , Austria
| | - Nikola Golenhofen
- c Institute of Anatomy and Cell Biology, University of Ulm , Ulm , Germany
| | | | - Werner Baumgartner
- a Institute of Biomedical Mechatronics, Johannes Kepler University of Linz , Linz , Austria
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Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8494286. [PMID: 28197418 PMCID: PMC5288516 DOI: 10.1155/2017/8494286] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/01/2016] [Accepted: 10/16/2016] [Indexed: 01/27/2023]
Abstract
We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells' anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow.
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25
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Li R, Yang HQ, Xi HL, Feng S, Qin RH. Inhibition of CDH17 gene expression via RNA interference reduces proliferation and apoptosis of human MKN28 gastric cancer cells. Int J Oncol 2016; 50:15-22. [PMID: 27909714 PMCID: PMC5182006 DOI: 10.3892/ijo.2016.3783] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 10/24/2016] [Indexed: 01/22/2023] Open
Abstract
Gastric cancer is the fourth most common type of cancer and the second cause of cancer-related mortalities worldwide despite the use of multimodal therapy. Cadherins are transmembrane glycoproteins that are involved in tumorigenesis. CDH17 has been found to be over-expressed in gastric cancer and its overexpression was associated with lymph node metastasis and tumor-node-metastasis stage of the patients, yet the exact role and molecular mechanism of CDH17 in gastric cancer have not been determined. Using a lentiviral system as a delivery mediator of RNA interference, we found that inhibition of CDH17 can lead to reduce proliferation and increase apoptosis of gastric cancer cell line MKN28 in vitro and significantly diminish their tumorigenicity in vivo. Our results of the present study suggest that CDH17 may be a promising candidate for the therapeutic targeting of gastric cancer.
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Affiliation(s)
- Rui Li
- Department of Central Laboratory, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Hong-Qiang Yang
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Hai-Lin Xi
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Su Feng
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Rui-Hao Qin
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, Affiliated Hospital of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
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Chen ZE, Lin F. Application of immunohistochemistry in gastrointestinal and liver neoplasms: new markers and evolving practice. Arch Pathol Lab Med 2015; 139:14-23. [PMID: 25549141 DOI: 10.5858/arpa.2014-0153-ra] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Diagnosis of primary gastrointestinal and liver neoplasms is usually straightforward. Immunohistochemistry is most helpful to differentiate metastatic carcinomas with morphologic similarity and to resolve tumors of unknown origin. Recently, several new markers highly sensitive and specific for primary liver and gastrointestinal tumors have been discovered. Their potential diagnostic application has not been widely appreciated by general practicing pathologists. In addition, a new trend in immunohistochemistry application has started, focusing on assessing predictive markers (such as human epidermal growth factor receptor 2) and mutation-specific markers (v-raf murine sarcoma viral oncogene homolog B V600E) to directly guide clinical management. Practicing pathologists need to be aware of and prepared for this evolving trend. OBJECTIVES To summarize the usefulness of several recently discovered immunohistochemical markers in the study of gastrointestinal and liver tumors; to suggest the most current and effective immunohistochemical panels addressing common diagnostic challenges for these tumors; to share practical experience and useful tips for human epidermal growth factor receptor 2 testing in gastric and gastroesophageal junction adenocarcinoma and v-raf murine sarcoma viral oncogene homolog B V600E immunohistochemistry in colorectal carcinoma. DATA SOURCES Sources include literature review, and authors' research data and practice experience. The cases illustrated are selected from the pathology archives of the Geisinger Medical Center (Danville, Pennsylvania). CONCLUSIONS Application of immunohistochemistry in gastrointestinal and liver tumors continues to evolve. New tumor-specific markers constantly emerge and help pathologists to further improve diagnostic accuracy. Assessment of predictive and prognostic markers by immunohistochemistry in routine pathologic diagnosis is a new trend and will greatly facilitate the advancement of personalized cancer therapy.
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Affiliation(s)
- Zongming Eric Chen
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania
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Snow AN, Mangray S, Lu S, Clubwala R, Li J, Resnick MB, Yakirevich E. Expression of cadherin 17 in well-differentiated neuroendocrine tumours. Histopathology 2015; 66:1010-21. [DOI: 10.1111/his.12610] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/06/2014] [Indexed: 12/25/2022]
Affiliation(s)
- Anthony N Snow
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
- Department of Pathology; University of Iowa Hospitals and Clinics; Iowa City IA USA
| | - Shamlal Mangray
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
| | - Shaolei Lu
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
| | - Rashna Clubwala
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
| | - Jianhong Li
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
| | - Murray B Resnick
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
| | - Evgeny Yakirevich
- Department of Pathology; Rhode Island Hospital and Alpert Medical School of Brown University; Providence RI USA
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Pelissier-Rota MA, Chartier NT, Jacquier-Sarlin MR. Dynamic Regulation of Adherens Junctions: Implication in Cell Differentiation and Tumor Development. INTERCELLULAR COMMUNICATION IN CANCER 2015:53-149. [DOI: 10.1007/978-94-017-7380-5_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Johnson A, Wright JP, Zhao Z, Komaya T, Parikh A, Merchant N, Shi C. Cadherin 17 is frequently expressed by 'sclerosing variant' pancreatic neuroendocrine tumour. Histopathology 2014; 66:225-33. [PMID: 25307987 DOI: 10.1111/his.12535] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/17/2014] [Indexed: 01/09/2023]
Abstract
AIMS Recently, we described a series of pancreatic neuroendocrine tumours (PanNETs) featuring prominent stromal fibrosis, which we called sclerosing PanNETs. The aim of this study was to examine the pathological, immunophenotypic and clinical differences between sclerosing and non-sclerosing PanNETs. METHODS AND RESULTS One hundred and six PanNETs were identified, of which 15 (14%) were sclerosing NETs. Tissue microarrays containing 44 non-sclerosing and five sclerosing PanNETs, as well as sections from 10 additional sclerosing tumours, were immunohistochemically labelled for serotonin, CDX2, CDH17, and islet 1. Sclerosing PanNETs were smaller (P = 0.045) and more likely to show an infiltrative growth pattern (P < 0.001) than non-sclerosing PanNETs. They were frequently associated with a large pancreatic duct, causing duct stenosis. Additionally, we found significantly increased expression of the small intestinal NET markers serotonin, CDX2 and CDH17 in sclerosing PanNETs (P < 0.001) as compared with non-sclerosing PanNETs. No difference in clinical outcome was found; however, more sclerosing PanNETs were stage IIB or above (P = 0.035), with lymph node metastasis being seen in three of nine sclerosing PanNETs with a tumour size of <20 mm. CONCLUSIONS Sclerosing PanNETs have distinct pathological features and biomarker expression profiles. In addition, lymph node metastasis can be present even with small sclerosing PanNETs.
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Affiliation(s)
- Adam Johnson
- Department of Microbiology, Immunology and Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
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Baumgartner W. Possible roles of LI-Cadherin in the formation and maintenance of the intestinal epithelial barrier. Tissue Barriers 2014; 1:e23815. [PMID: 24665380 PMCID: PMC3879124 DOI: 10.4161/tisb.23815] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 01/29/2013] [Accepted: 01/29/2013] [Indexed: 02/07/2023] Open
Abstract
LI-cadherin belongs to the so called 7D-cadherins, exceptional members of the cadherin superfamily which are characterized by seven extracellular cadherin repeats and a small cytosolic domain. Under physiological conditions LI-cadherin is expressed in the intestine and colon in human and mouse and in the rat also in hepatocytes. LI-cadherin was shown to act as a functional Ca2+-dependent adhesion molecule, linking neighboring cells and a lot of biophysical and biochemical parameters were determined in the last time. It is also known that dysregulated LI-cadherin expression can be found in a variety of diseases. Although there are several hypothesis and theoretical models concerning the function of LI-cadherin, the physiological role of LI-cadherin is still enigmatic.
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Affiliation(s)
- Werner Baumgartner
- Department of Cellular Neurobionics; RWTH-Aachen University; Aachen; Germany
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Bartolomé RA, Barderas R, Torres S, Fernandez-Aceñero MJ, Mendes M, García-Foncillas J, Lopez-Lucendo M, Casal JI. Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene 2014; 33:1658-1669. [PMID: 23604127 DOI: 10.1038/onc.2013.117] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 02/19/2013] [Accepted: 02/25/2013] [Indexed: 02/07/2023]
Abstract
Liver metastasis is the major cause of death associated to colorectal cancer. Cadherin-17 (CDH17) is a non-classical, seven domain, cadherin lacking the conserved cytoplasmic domain of classical cadherins. CDH17 was overexpressed in highly metastatic human KM12SM and present in many other colorectal cancer cells. Using tissue microarrays, we observed a significant association between high expression of CDH17 with liver metastasis and poor survival of the patients. On the basis of these findings, we decided to study cellular functions and signaling mechanisms mediated by CDH17 in cancer cells. In this report, loss-of-function experiments demonstrated that CDH17 caused a significant increase in KM12SM cell adhesion and proliferation. Coimmunoprecipitation experiments demonstrated an interaction between CDH17 and α2β1 integrin with a direct effect on β1 integrin activation and talin recruitment. The formation of this complex, together with other proteins, was confirmed by mass spectrometry analysis. CDH17 modulated integrin activation and signaling to induce specific focal adhesion kinase and Ras activation, which led to the activation of extracellular signal-regulated kinase and Jun N-terminal kinase and the increase in cyclin D1 and proliferation. In vivo experiments showed that CDH17 silencing in KM12 cells suppressed tumor growth and liver metastasis after subcutaneous or intrasplenic inoculation in nude mice. Collectively, our data reveal a new function for CDH17, which is to regulate α2β1 integrin signaling in cell adhesion and proliferation in colon cancer cells for liver metastasis.
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Affiliation(s)
- R A Bartolomé
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - R Barderas
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | - S Torres
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | | | - M Mendes
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
| | | | | | - J I Casal
- Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
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Abstract
Cadherin 17 is a member of a multigene family of calcium-dependent, transmembrane proteins that mediates cell-cell adhesion, plays important roles during embryogenesis, and is crucial for tissue morphogenesis and maintenance. Cadherin 17 is exclusively expressed in the epithelial cells of embryonic and adult small intestine and colon, and pancreatic ducts. It has also been reported to be frequently expressed in adenocarcinomas arising in the gastrointestinal tract and pancreas. Owing to its restricted expression in these groups of tumors, cadherin 17 has proven to be a useful immunohistochemical marker for assisting in distinguishing these neoplasms from other malignancies with which they may be confused.
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Bernhard OK, Greening DW, Barnes TW, Ji H, Simpson RJ. Detection of cadherin-17 in human colon cancer LIM1215 cell secretome and tumour xenograft-derived interstitial fluid and plasma. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2372-9. [DOI: 10.1016/j.bbapap.2013.03.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/23/2013] [Accepted: 03/25/2013] [Indexed: 12/21/2022]
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Wang Y, Shek FH, Wong KF, Liu LX, Zhang XQ, Yuan Y, Khin E, Hu MY, Wang JH, Poon RTP, Hong W, Lee NP, Luk JM. Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenicity of hepatocellular carcinoma. PLoS One 2013; 8:e72386. [PMID: 24039755 PMCID: PMC3770615 DOI: 10.1371/journal.pone.0072386] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 07/09/2013] [Indexed: 11/18/2022] Open
Abstract
Cadherin-17 (CDH17) is an oncofetal molecule associated with poor prognostic outcomes of hepatocellular carcinoma (HCC), for which the treatment options are very limited. The present study investigates the therapeutic potential of a monoclonal antibody (Lic5) that targets the CDH17 antigen in HCC. In vitro experiments showed Lic5 could markedly reduce CDH17 expression in a dose-dependent manner, suppress β-catenin signaling, and induce cleavages of apoptotic enzymes caspase-8 and -9 in HCC cells. Treatment of animals in subcutaneous HCC xenograft model similarly demonstrated significant tumor growth inhibition (TGI) using Lic5 antibody alone (5 mg/kg, i.p., t.i.w.; ca.60–65% TGI vs. vehicle at day 28), or in combination with conventional chemotherapy regimen (cisplatin 1 mg/kg; ca. 85–90% TGI). Strikingly, lung metastasis was markedly suppressed by Lic5 treatments. Immunohistochemical and western blot analyses of xenograft explants revealed inactivation of the Wnt pathway and suppression of Wnt signaling components in HCC tissues. Collectively, anti-CDH17 antibody promises as an effective biologic agent for treating malignant HCC.
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Affiliation(s)
- Yonggang Wang
- Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiao Tong University, Shanghai, China
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Felix H. Shek
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
| | - Kwong F. Wong
- Department of Pharmacology and Department of Surgery, National University Health System, Singapore, Singapore
| | - Ling Xiao Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao Qian Zhang
- Institute of Molecular and Cell Biology, A*STAR Singapore, Singapore
| | - Yi Yuan
- Department of Pharmacology and Department of Surgery, National University Health System, Singapore, Singapore
| | - Ester Khin
- Department of Pharmacology and Department of Surgery, National University Health System, Singapore, Singapore
| | - Mei-yu Hu
- Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Hua Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ronnie T. P. Poon
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, A*STAR Singapore, Singapore
| | - Nikki P. Lee
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
- * E-mail: (NPL); (JML)
| | - John M. Luk
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
- Department of Pharmacology and Department of Surgery, National University Health System, Singapore, Singapore
- Institute of Molecular and Cell Biology, A*STAR Singapore, Singapore
- * E-mail: (NPL); (JML)
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Ryu KH, Shim KN, Jung SA, Yoo K, Joo YH, Lee JH. Significance of preoperative tissue levels of vascular-endothelial cadherin, liver-intestine cadherin and vascular endothelial growth factor in gastric cancer. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 60:229-41. [PMID: 23089909 DOI: 10.4166/kjg.2012.60.4.229] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS The aims of this study were to examine the expressions of endothelium specific VE-cadherin, intestine specific LI-cadherin, and vascular endothelial growth factor (VEGF), and to determine their relationships with the clinicopathological parameters of gastric cancer. METHODS A total 47 patients with gastric cancer who underwent surgery were enrolled. Endoscopic biopsies were obtained from the cancer and normal mucosa, respectively. Using semiquantitative RT-PCR, the mRNA expression levels of VE-cadherin, LI-cadherin and VEGF were measured by tumor/normal (T/N) ratios. The protein expressions of VE-cadherin, LI-cadherin and VEGF were examined by Western blot and immunohistochemical stain in surgically resected tissues. The clinicopathological variables were reviewed and analyzed, retrospectively. RESULTS Twenty two cases (46.8%) of VE-cadherin, 25 cases (53.2%) of LI-cadherin and 27 cases (51.1%) of VEGF mRNA expressions were overexpressed in gastric cancer compared to normal tissue. There was a tendency for T/N ratio of VE-cadherin mRNA to correlate with the lymphatic invasion (p=0.07) and the lymph node metastasis (p=0.099) in advanced gastric cancer. The T/N ratio of LI-cadherin mRNA showed significant association with distant metastasis (p=0.031) and lymphatic invasion especially in advanced gastric cancer (p=0.023). There was a tendency for the T/N ratio of VEGF mRNA to correlate with the distant metastasis (p=0.073) in advanced gastric cancer. CONCLUSIONS As increased mRNA expression of LI-cadherin was associated with distant metastasis and lymphatic invasion especially in the biopsy specimen of advanced gastric cancer before surgery, it may provide useful preoperative information on tumor aggressiveness.
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Affiliation(s)
- Kum Hei Ryu
- Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Korea
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Qiu HB, Zhang LY, Ren C, Zeng ZL, Wu WJ, Luo HY, Zhou ZW, Xu RH. Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling. PLoS One 2013; 8:e56959. [PMID: 23554857 PMCID: PMC3598811 DOI: 10.1371/journal.pone.0056959] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 01/16/2013] [Indexed: 12/27/2022] Open
Abstract
PURPOSE Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease. METHODS Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting. RESULTS CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling. CONCLUSION Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.
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Affiliation(s)
- Hai-bo Qiu
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Division of Surgical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Li-yi Zhang
- Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chao Ren
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhao-lei Zeng
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wen-jing Wu
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hui-yan Luo
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhi-wei Zhou
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Rui-hua Xu
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- * E-mail:
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Liver-intestine-cadherin is a sensitive marker of intestinal differentiation during Barrett's carcinogenesis. Dig Dis Sci 2013; 58:699-705. [PMID: 23053896 PMCID: PMC3616226 DOI: 10.1007/s10620-012-2425-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Accepted: 09/19/2012] [Indexed: 12/31/2022]
Abstract
BACKGROUND Histopathologic differentiation between the stages of Barrett's carcinogenesis is often challenging. Liver-intestine (LI)-cadherin, an intestine-specific marker, is involved in intestinal metaplasia development in gastric and colon cancers and could be of value in diagnosis and differentiation. AIMS To examine the expression of LI-cadherin in the sequence of Barrett's carcinogenesis and to evaluate its association with clinicopathological data. METHODS LI-cadherin expression was immunohistologically investigated, by use of anti-CDH17 antibody, in gastric mucosa (GM) biopsies taken from the cardia (n = 9), in Barrett's esophagus (BE) without intraepithelial neoplasia (without IEN) (n = 9) and BE with low-grade IEN (n = 11), and in esophageal adenocarcinoma (ADC) (n = 13). RESULTS The immunoreactivity score was highest in adenocarcinoma (mean IRS = 4.0), and dropped gradually from BE with IEN and BE without IEN (mean IRS = 2.0) to cardia mucosa (IRS = 0). Similarly, the intensity of staining and the percentage of positive cells increased during the sequential stages of BE carcinogenesis. Comparative analysis showed that LI-cadherin expression was significantly different between cardiac epithelium and ADC. Also, percentage of positive cells in GM was significantly different from that in BE with IEN. LI-cadherin IRS was lower for tumors with poor differentiation than for moderately differentiated tumors, but the difference was not statistically significant. CONCLUSIONS LI-cadherin is a sensitive marker of intestinal metaplasia and can be helpful for early histologic diagnosis of Barrett's esophagus; it is, however, not significantly different between BE with and without IEN, and cannot be used to distinguish between these.
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Chen RY, Cao JJ, Chen J, Yang JP, Liu XB, Zhao GQ, Zhang YF. Single nucleotide polymorphisms in the CDH17 gene of colorectal carcinoma. World J Gastroenterol 2012; 18:7251-7261. [PMID: 23326130 PMCID: PMC3544027 DOI: 10.3748/wjg.v18.i48.7251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 11/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between c.343A>G and c.2216A>C polymorphism sites in the CDH17 gene and colorectal carcinoma.
METHODS: Ninety-three non-consanguineous colorectal carcinoma patients admitted to the Department of Oncology at the First Affiliated Hospital of Zhengzhou University were included in this study. Ninety-three peripheral venous blood samples, of approximately one milliliter from each patient, were collected between December 2009 and August 2010. The genomic DNA of these peripheral venous blood samples were extracted and purified using a Fermentas Genomic DNA Purification Kit (Fermentas, CA) according to the manufacturer’s protocol. The single nucleotide polymorphisms (SNPs) of the liver-intestine cadherin (CDH17) gene c.343A>G and c.2216A>C were determined by the polymerase chain reaction-single strand conformation polymorphism method (PCR-SSCP) in 93 peripheral venous blood samples from patients suffering with colorectal carcinoma. Typical samples that showed different migration bands in SSCP were confirmed by sequencing. Directed DNA sequencing was used to check the correctness of the genotype results from the PCR-SSCP method.
RESULTS: There was a significant association between the c.2216 A>C SNPs of the CDH17 gene and the tumor-node-metastasis (TNM) grade, as well as with lymph node status, in 93 peripheral venous blood samples from colorectal carcinoma patients. The genotype frequencies of A/C, A/A, and C/C were 12.90%, 33.33% and 53.76%, respectively. There was a significant correlation between lymph node metastasis, TNM grade, and the genotype distribution (P < 0.05). The C/C genotype raised the risk of lymph node metastasis and the TNM grade. There was a significant difference in the TNM grade and lymph node metastasis between the A/A and C/C genotypes (P = 0.003 and P = 0.013, respectively). Patients with colorectal carcinoma carrying the C allele tended to have a higher risk of lymph node metastasis and have a higher TNM grade. The difference between the TNM grades, as well as the lymph node metastasis of the two alleles, was statistically significant (P < 0.01).
CONCLUSION: The SNPs of the CDH17 gene c.2216 A>C might be clinically important in the prognosis of colorectal carcinoma.
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Huang LP, Yu YH, Sheng C, Wang SH. Up-regulation of cadherin 17 and down-regulation of homeodomain protein CDX2 correlate with tumor progression and unfavorable prognosis in epithelial ovarian cancer. Int J Gynecol Cancer 2012; 22:1170-6. [PMID: 22810971 DOI: 10.1097/igc.0b013e318261d89c] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Cadherin 17 (CDH17), belonging to the 7D-cadherin superfamily, represents a novel oncogene, which is involved in tumor invasion and metastasis. Its expression has been demonstrated to be regulated by caudal-related homeobox transcription factor CDX2. The roles of 2 biomarkers have been conflictingly explained. Therefore, the aims of this study were to investigate the expression patterns of CDH17 and CDX2 in human epithelial ovarian cancer (EOC) and to evaluate the clinical significance of these 2 markers in the progression and prognosis of EOC. METHODS CDH17 and CDX2 expressions in 182 paraffin-embedded EOC specimens were detected by immunohistochemical staining. Associations of their expression with clinical pathological factors and overall survival were statistically evaluated. RESULTS Compared with normal surface ovarian epithelium tissues, CDH17 expression was upregulated and CDX2 expression was downregulated in EOC tissues. There was a negative correlation between CDH17 and CDX2 expression in EOC tissues (r = -0.76, P = 0.001). Tumors with high CDH17 expression were more likely to have advanced stage (P = 0.01) and higher grade (P = 0.03). Patients with low CDX2 expression were more frequently to be at the advanced stage of disease (P = 0.01). In addition, univariate analysis indicated that the patients with high CDH17 expression correlated with poor prognosis in patients with EOC (P = 0.001), as opposed to CDX2 (P = 0.003). Especially, the survival rate of patients with EOC with CDH17-high/CDX2-low expression was the lowest (P < 0.001). Multivariate statistical analysis showed that the conjoined expression of CDH17/CDX2 was an independent prognostic indicator of EOC (P = 0.01). CONCLUSIONS Our data suggest that both the up-regulation of CDH17 and the down-regulation of CDX2 may be associated with the advanced stage of EOC. A conjoined detection of CDH17/CDX2 expression may be associated with unfavorable prognosis in patients with this disease.
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MESH Headings
- Adenocarcinoma, Clear Cell/mortality
- Adenocarcinoma, Clear Cell/pathology
- Adenocarcinoma, Clear Cell/surgery
- Adenocarcinoma, Mucinous/mortality
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Mucinous/surgery
- CDX2 Transcription Factor
- Cadherins/metabolism
- Case-Control Studies
- Cystadenocarcinoma, Serous/mortality
- Cystadenocarcinoma, Serous/pathology
- Cystadenocarcinoma, Serous/surgery
- Disease Progression
- Endometrial Neoplasms/mortality
- Endometrial Neoplasms/pathology
- Endometrial Neoplasms/surgery
- Female
- Homeodomain Proteins/metabolism
- Humans
- Immunoenzyme Techniques
- Middle Aged
- Neoplasm Grading
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Neoplasm Staging
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/mortality
- Ovarian Neoplasms/pathology
- Ovarian Neoplasms/surgery
- Ovary/metabolism
- Ovary/pathology
- Prognosis
- Survival Rate
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Affiliation(s)
- Li-Ping Huang
- Department of Obstetrics and Gynecology, Nan Fang Hospital, Guangzhou, China
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Xu Y, Zhang J, Liu QS, Dong WG. Knockdown of liver-intestine cadherin decreases BGC823 cell invasiveness and metastasis in vivo. World J Gastroenterol 2012; 18:3129-37. [PMID: 22791949 PMCID: PMC3386327 DOI: 10.3748/wjg.v18.i24.3129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 05/06/2011] [Accepted: 05/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess BGC823 gastric cancer (GC) cell metastasis after knockdown of liver-intestine cadherin (CDH17) and the therapeutic value of CDH17-RNAi-lentivirus in vivo.
METHODS: We evaluated primary tumor growth and assessed local infiltration and systemic tumor dissemination using an orthotopic implantation technique. The therapeutic value of CDH17 knockdown was examined by intratumoral administration of CDH17-RNA interference (RNAi)-lentivirus in an established GC tumor xenograft mouse model. Furthermore, a comparative proteomic approach was utilized to identify differentially expressed proteins in BGC823 and lenti-CDH17-miR-neg cells following CDH17 knockdown.
RESULTS: Metastases in the liver and lung appeared earlier and more frequently in animals with tumors derived from BGC823 or lenti-CDH17-miR-neg cells than in tumors derived from lenti-CDH17-miR-B cells. Average tumor weight and volume in the CDH17-RNAi-lentivirus-treated group were significantly lower than those in the control group (tumor volume: 0.89 ± 0.04 cm3vs 1.16 ± 0.06 cm3, P < 0.05; tumor weight: 1.15 ± 0.58 g vs 2.09 ± 0.08 g, P < 0.05). Fifteen differentially expressed proteins were identified after CDH17 silencing in BGC823 cells, including a variety of cytoskeletal and chaperone proteins as well as proteins involved in metabolism, immunity/defense, cell proliferation and differentiation, cell cycle, and signal transduction.
CONCLUSION: Our data establish a foundation for future studies of the comprehensive protein expression patterns and effects of CDH17 in GC.
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Calì G, Gentile F, Mogavero S, Pallante P, Nitsch R, Ciancia G, Ferraro A, Fusco A, Nitsch L. CDH16/Ksp-cadherin is expressed in the developing thyroid gland and is strongly down-regulated in thyroid carcinomas. Endocrinology 2012; 153:522-34. [PMID: 22028439 DOI: 10.1210/en.2011-1572] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cadherin (CDH)16/kidney-specific-cadherin was first described as a kidney-specific adhesion molecule and thereafter found expressed also in the thyroid gland. We show here that CDH16 fully colocalizes with CDH1/E-cadherin on the basolateral plasma membrane of mouse and human thyrocytes. In thyrocyte cultures, the expression of CDH16 is dependent upon TSH, as other thyroid differentiation markers. In the developing mouse thyroid, CDH16 is expressed at embryonic day 10.5, 1-2 d after the main thyroid-specific transcription factors involved in thyroid cell differentiation. In human thyroid carcinomas, as determined by quantitative RT-PCR, CDH16 expression decreases in papillary, follicular, and anaplastic thyroid carcinomas, and the decrease is more pronounced than that of CDH1. Moreover, by immunofluorescence and confocal microscopy, it appears that although CDH16-negative tumor cells may still be positive for CDH1, CDH1-negative cells are also negative for CDH16, indicating a more extensive loss of the latter and suggesting that CDH16 loss might precede that of CDH1. Loss of CDH16 appears to be a marker of epithelial-mesenchymal transition as indicated by its decrease in cultured thyroid cells after TGF-β treatment. Finally, the decrease in CDH16 is paralleled in part by the decrease in α B-crystallin, which was proposed to mediate the interaction of CDH16 cytosolic tail with the cell cytoskeleton. In conclusion, CDH16 is a thyroid-selective and hormone-dependent adhesion protein that might play a role during thyroid development and that may be a useful marker to monitor thyroid carcinomas.
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Affiliation(s)
- Gaetano Calì
- Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy
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Morimatsu K, Aishima S, Kayashima T, Hayashi A, Nakata K, Oda Y, Taguchi T, Tsuneyoshi M, Tanaka M, Oda Y. Liver-Intestine Cadherin Expression Is Associated with Intestinal Differentiation and Carcinogenesis in Intraductal Papillary Mucinous Neoplasm. Pathobiology 2012; 79:107-14. [DOI: 10.1159/000334269] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2011] [Accepted: 10/06/2011] [Indexed: 12/26/2022] Open
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Suh YS, Lee HJ, Jung EJ, Kim MA, Nam KT, Goldenring JR, Yang HK, Kim WH. The combined expression of metaplasia biomarkers predicts the prognosis of gastric cancer. Ann Surg Oncol 2011; 19:1240-9. [PMID: 22048633 DOI: 10.1245/s10434-011-2125-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer. METHODS The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers. RESULTS MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis. CONCLUSIONS The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Zhang J, Liu QS, Dong WG. Blockade of proliferation and migration of gastric cancer via targeting CDH17 with an artificial microRNA. Med Oncol 2011; 28:494-501. [PMID: 20393816 DOI: 10.1007/s12032-010-9489-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2010] [Accepted: 03/10/2010] [Indexed: 02/07/2023]
Abstract
Liver-intestine cadherin (CDH17) is a novel member of the cadherin superfamily implicated in gastric cancer progression. To determine the role of CDH17 in the process of gastric cancer invasive growth, in the present study, RNA interference mediated by recombinant lentivirus vectors expressing artificial CDH17 miRNA was applied to induce a long-lasting down-regulation of CDH17 gene expression in BGC823 cells. The expression levels of CDH17, tumor cell motility, migration potential, and pro-liferation were measured by flow cytometry, real-time RT-PCR, Western blot analysis, immunofluorescence staining, wound healing assay, and MTT assay, respectively. Results show that four recombinant plasmid expression vectors encoding pre-miRNA against CDH17, pcDNA-CDH17-miR-SR1, -SR2, -SR3, and -SR4 were constructed correctly and down-regulated the CDH17 mRNA levels by 5.5, 57, 91, and 98%, respectively, in BGC823 cells which had an overexpression of CDH17. We packaged the recombinant lentiviral vector for CDH17 RNA interference with pcDNA-CDH17-miR-SR4 which had the highest interfering efficiency and succeeded in construction of the stable transfectants. Of note, more than 90% knockdown of CDH17 expression in BGC823 cells was obtained by miRNA technique. The CDH17-miRNA-transfected cells showed significant decrease in cell proliferation, cell motility, and migration in comparison with the control cells. Thus, we proposed that CDH17 may be an oncogene up-regulating invasive features of gastric cancer cells and could be a hopeful target for the control of gastric cancer progression.
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Affiliation(s)
- Jin Zhang
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, Hubei Province, China
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Ahl M, Weth A, Walcher S, Baumgartner W. The function of 7D-cadherins: a mathematical model predicts physiological importance for water transport through simple epithelia. Theor Biol Med Model 2011; 8:18. [PMID: 21663598 PMCID: PMC3138449 DOI: 10.1186/1742-4682-8-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Accepted: 06/10/2011] [Indexed: 01/03/2023] Open
Abstract
Background 7D-cadherins like LI-cadherin are cell adhesion molecules and represent exceptional members of the cadherin superfamily. Although LI-cadherin was shown to act as a functional Ca2+-dependent adhesion molecule, linking neighboring cells together, and to be dysregulated in a variety of diseases, the physiological role is still enigmatic. Interestingly 7D-cadherins occur only in the lateral plasma membranes of cells from epithelia of water transporting tissues like the gut, the liver or the kidney. Furthermore LI-cadherin was shown to exhibit a highly cooperative Ca2+-dependency of the binding activity. Thus it is tempting to assume that LI-cadherin regulates the water transport through the epithelium in a passive fashion by changing its binding activity in dependence on the extracellular Ca2+. Results We developed a simple mathematical model describing the epithelial lining of a lumen with a content of variable osmolarity covering an interstitium of constant osmolarity. The width of the lateral intercellular cleft was found to influence the water transport significantly. In the case of hypertonic luminal content a narrow cleft is necessary to further increase concentration of the luminal content. If the cleft is too wide, the water flux will change direction and water is transported into the lumen. Electron microscopic images show that in fact areas of the gut can be found where the lateral intercellular cleft is narrow throughout the lateral cell border whereas in other areas the lateral intercellular cleft is widened. Conclusions Our simple model clearly predicts that changes of the width of the lateral intercellular cleft can regulate the direction and efficiency of water transport through a simple epithelium. In a narrow cleft the cells can increase the concentration of osmotic active substances easily by active transport whereas if the cleft is wide, friction is reduced but the cells can hardly build up high osmotic gradients. It is now tempting to speculate that 7D-cadherins, owing to their location and their Ca2+-dependence, will adapt their binding activity and thereby the width of the lateral intercellular cleft automatically as the Ca2+-concentration is coupled to the overall electrolyte concentration in the lateral intercellular cleft. This could provide a way to regulate the water resorption in a passive manner adapting to different osmotic conditions.
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Affiliation(s)
- Mareike Ahl
- Department of Cellular Neurobionics, Institute of Zoology, RWTH-Aachen University, Aachen, Germany
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Park JH, Seol JA, Choi HJ, Roh YH, Choi PJ, Lee KE, Roh MS. Comparison of cadherin-17 expression between primary colorectal adenocarcinomas and their corresponding metastases: the possibility of a diagnostic marker for detecting the primary site of metastatic tumour. Histopathology 2011; 58:315-8. [PMID: 21323956 DOI: 10.1111/j.1365-2559.2011.03746.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Malaguarnera G, Giordano M, Paladina I, Rando A, Uccello M, Basile F, Biondi A, Carnazzo S, Alessandria I, Mazzarino C. Markers of bile duct tumors. World J Gastrointest Oncol 2011; 3:49-59. [PMID: 21528090 PMCID: PMC3083496 DOI: 10.4251/wjgo.v3.i4.49] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 02/23/2011] [Accepted: 03/02/2011] [Indexed: 02/05/2023] Open
Abstract
Biliary tract carcinomas are relatively rare, representing less than 1% of cancers. However, their incidence has increased in Japan and in industrialized countries like the USA. Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease; therapeutic treatment options are often limited and of minimal utility. Recent studies have shown the importance of serum and molecular markers in the diagnosis and follow up of biliary tract tumors. This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors. Some considerable tumor markers are cancer antigen 125, carbohydrate antigen 19-9, carcinoembryonic antigen, chromogranin A, mucin 1, mucin 5, alpha-fetoprotein, claudins and cytokeratins.
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Affiliation(s)
- Giulia Malaguarnera
- Giulia Malaguarnera, Clorinda Mazzarino, Department of Biomedical Science, University of Catania, via Androne 83, 95124 Catania, Italy
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Yu QF, Dong WG, Ren JL. Knockdown of Li-cadherin increases metastatic behaviors of LoVo cells. J Cancer Res Clin Oncol 2010; 136:1641-9. [PMID: 20204409 DOI: 10.1007/s00432-010-0822-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Accepted: 02/01/2010] [Indexed: 01/01/2023]
Abstract
PURPOSE The aim of this study was to investigate the role of Li-cadherin in invasion and metastasis in LoVo cells. METHODS We applied RNA interference mediated downregulation of Li-cadherin expression in LoVo cells. Li-cadherin expression in LoVo cells was examined by semiquantitative polymerase chain reaction, immunofluorescence, western blot, and immunoprecipitation, respectively. Effect of suppression of Li-cadherin expression on cell migration, invasion, and adhesion was detected by wound healing assay, migration assay, invasion assay, and adhesion assay. Expression and activity of MMP-2 and MMP-9 were analyzed by gelatin zymography. RESULTS Cell migration, invasion, and adhesion were increased concomitantly with the reduction in Li-cadherin protein expression. Furthermore, downregulation of Li-cadherin expression induced secretion of proMMP-9, active MMP-9 and active MMP-2. CONCLUSIONS This study suggests that silencing Li-cadherin has positive actions in the processes of LoVo cells invasion and metastasis, and the interactions among MMP-2, MMP-9, and Li-cadherin participate in the multiple steps of invasion and metastasis in LoVo colorectal cancer cells.
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Affiliation(s)
- Qiong-Fang Yu
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Weimann A, Rieger A, Zimmermann M, Gross M, Hoffmann P, Slevogt H, Morawietz L. Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett's esophagus. Virchows Arch 2010; 457:537-45. [PMID: 20844891 DOI: 10.1007/s00428-010-0972-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 08/20/2010] [Accepted: 08/24/2010] [Indexed: 12/28/2022]
Abstract
In esophageal neoplasms, the histopathologic differentiation between Barrett's esophagus with or without intraepithelial neoplasia and adenocarcinoma is often challenging. Immunohistochemistry might help to differentiate between these lesions. The expression of CDX2, LI-cadherin, mucin 2 (MUC2), blood group 8 (BG8, Lewis(y)), claudin-2, and villin was investigated in normal gastroesophageal (n = 23) and in Barrett's (n = 17) mucosa, in low-grade (n = 12) and high-grade (n = 9) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. For CDX2 and LI-cadherin, the immunoreactivity score was highest in IEN while for MUC2, BG8, and villin, it dropped gradually from Barrett's via IEN to adenocarcinoma, and expression of Claudin-2 was only weak and focal in all lesions. The expression of MUC2 and LI-cadherin differed significantly between all examined lesions except between low-grade and high-grade IEN. MUC2 and LI-cadherin are useful immunohistochemical markers for the differentiation between normal glandular mucosa, Barrett's mucosa, IEN, and invasive carcinoma of the esophagus; however, none of the examined markers was helpful for the differentiation between low-grade and high-grade IEN.
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Affiliation(s)
- Andreas Weimann
- Institute for Laboratory Medicine and Pathobiochemistry, Charité-University Medical Center, Berlin, Germany
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Liu QS, Zhang J, Liu M, Dong WG. Lentiviral-mediated miRNA against liver-intestine cadherin suppresses tumor growth and invasiveness of human gastric cancer. Cancer Sci 2010; 101:1807-12. [PMID: 20500517 PMCID: PMC11159871 DOI: 10.1111/j.1349-7006.2010.01600.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liver-intestine cadherin (CDH17) represents a novel type of cadherin within the cadherin superfamily, and is distinguished from other cadherins by its distinct structural and functional features. Our previous studies had identified that increased CDH17 was significantly associated with tumor differentiation and lymph node metastasis in gastric cancer. In this study, we tested the hypothesis that CDH17 was associated with proliferation and invasiveness in gastric cancer using recombinant lentivirus-mediated miRNA targeting to CDH17 both in vitro and in vivo. We also detected the activity of matrix metalloproteinase (MMP)-2 and MMP-9 with gelatin zymography to explore the mechanisms underlying the inhibition of the CDH17 gene. Our results showed that a well-differentiated gastric cancer cell line had higher CDH17 expression. Down-regulation of CDH17 inhibited proliferation, adherence, and invasion of the poorly differentiated BGC823 gastric cancer cells in vitro, and induced cell cycle arrest. The activities of MMP-2 and MMP-9 were lower in the CDH17-miRNA-transfected cells compared to the control cells. Using an in vivo tumor growth assay, we confirmed that CDH17 silencing could obviously slow the growth of gastric cancer derived from BGC823 cells. Taken together, we have demonstrated that CDH17 maybe a positive regulator for proliferative, adhesive, and invasive behaviors of gastric cancer.
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Affiliation(s)
- Qi-Sheng Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
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