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Boldrup L, Coates P, Gu X, Wang L, Fåhraeus R, Wilms T, Sgaramella N, Baumgarth J, Norberg-Spaak L, Nylander K. Levels of MUC1 in tumours and serum of patients with different sub-types of squamous cell carcinoma of the head and neck. Oncol Lett 2020; 20:1709-1718. [PMID: 32724413 PMCID: PMC7377060 DOI: 10.3892/ol.2020.11746] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 05/14/2020] [Indexed: 01/27/2023] Open
Abstract
Mucin 1 (MUC1) is a membrane-bound and secreted glycoprotein that has a protective role in surface epithelia. We recently demonstrated that MUC1 mRNA expression was upregulated in tumour-free tongue tissues adjacent to squamous cell carcinoma of the oral tongue (SCCOT) compared with that in the tumour tissues. The present study investigated MUC1 protein in SCCOT tissue and serum from patients with squamous cell carcinoma of the head and neck (SCCHN) at different sub-sites. The results from immunohistochemistry demonstrated that all SCCOT tissues expressed MUC1; however, the protein levels were not correlated with MUC1 mRNA levels in the same tumours. Furthermore, serum MUC1 level was lower in patients with SCCOT, tonsil SCC and gingival SCC compared with that in healthy subjects; however, the difference was only significant for patients with SCCOT (P=0.0421). No correlation was seen between MUC1 level in tumour tissues and MUCI level in serum from the same patients. The absence of correlation between MUC1 protein and mRNA levels in SCCOT tissues emphasized the importance of validating genomic data in clinical samples. Although significant MUC1 downregulation was observed in the serum of patients with SCCOT, there was a large variation within the groups, suggesting that MUC1 may not be used as a biomarker for these types of tumors.
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Affiliation(s)
- Linda Boldrup
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden
| | - Philip Coates
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Southern Moravia 656 53, Czech Republic
| | - Xiaolian Gu
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden
| | - Lixiao Wang
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden
| | - Robin Fåhraeus
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden.,Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Southern Moravia 656 53, Czech Republic.,Institute of Molecular Genetics, University of Paris St. Louis Hospital, Paris, Île-de-France 750 10, France
| | - Torben Wilms
- Department of Clinical Sciences, Umeå University Hospital, Umeå, Västerbotten 901 87, Sweden
| | - Nicola Sgaramella
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden
| | - Jonathan Baumgarth
- Department of Clinical Sciences, Umeå University Hospital, Umeå, Västerbotten 901 87, Sweden
| | - Lena Norberg-Spaak
- Department of Clinical Sciences, Umeå University Hospital, Umeå, Västerbotten 901 87, Sweden
| | - Karin Nylander
- Department of Medical Biosciences, Umeå University, Umeå, Västerbotten 901 87, Sweden
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2
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Quinchia J, Echeverri D, Cruz-Pacheco AF, Maldonado ME, Orozco J. Electrochemical Biosensors for Determination of Colorectal Tumor Biomarkers. MICROMACHINES 2020; 11:E411. [PMID: 32295170 PMCID: PMC7231317 DOI: 10.3390/mi11040411] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 12/15/2022]
Abstract
The accurate determination of specific tumor markers associated with cancer with non-invasive or minimally invasive procedures is the most promising approach to improve the long-term survival of cancer patients and fight against the high incidence and mortality of this disease. Quantification of biomarkers at different stages of the disease can lead to an appropriate and instantaneous therapeutic action. In this context, the determination of biomarkers by electrochemical biosensors is at the forefront of cancer diagnosis research because of their unique features such as their versatility, fast response, accurate quantification, and amenability for multiplexing and miniaturization. In this review, after briefly discussing the relevant aspects and current challenges in the determination of colorectal tumor markers, it will critically summarize the development of electrochemical biosensors to date to this aim, highlighting the enormous potential of these devices to be incorporated into the clinical practice. Finally, it will focus on the remaining challenges and opportunities to bring electrochemical biosensors to the point-of-care testing.
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Affiliation(s)
- Jennifer Quinchia
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 No. 52-20, Medellín 050010, Colombia; (J.Q.); (D.E.); (A.F.C.-P.)
| | - Danilo Echeverri
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 No. 52-20, Medellín 050010, Colombia; (J.Q.); (D.E.); (A.F.C.-P.)
| | - Andrés Felipe Cruz-Pacheco
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 No. 52-20, Medellín 050010, Colombia; (J.Q.); (D.E.); (A.F.C.-P.)
| | - María Elena Maldonado
- Grupo Impacto de los Componentes Alimentarios en la Salud, School of Dietetics and Human Nutrition, University of Antioquia, A.A. 1226, Medellín 050010, Colombia;
| | - Jahir Orozco
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 No. 52-20, Medellín 050010, Colombia; (J.Q.); (D.E.); (A.F.C.-P.)
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Wang W, Wang Y, Pan H, Cheddah S, Yan C. Aptamer-based fluorometric determination for mucin 1 using gold nanoparticles and carbon dots. Mikrochim Acta 2019; 186:544. [DOI: 10.1007/s00604-019-3516-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/18/2019] [Indexed: 12/12/2022]
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Yang S, Zhang F, Liang Q, Wang Z. A three-dimensional graphene-based ratiometric signal amplification aptasensor for MUC1 detection. Biosens Bioelectron 2018; 120:85-92. [DOI: 10.1016/j.bios.2018.08.036] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 08/03/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023]
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Hori SI, Herrera A, Rossi JJ, Zhou J. Current Advances in Aptamers for Cancer Diagnosis and Therapy. Cancers (Basel) 2018; 10:cancers10010009. [PMID: 29301363 PMCID: PMC5789359 DOI: 10.3390/cancers10010009] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 12/22/2017] [Accepted: 12/26/2017] [Indexed: 12/24/2022] Open
Abstract
Nucleic acid aptamers are single-stranded oligonucleotides that interact with target molecules with high affinity and specificity in unique three-dimensional structures. Aptamers are generally isolated by a simple selection process called systematic evolution of ligands by exponential enrichment (SELEX) and then can be chemically synthesized and modified. Because of their high affinity and specificity, aptamers are promising agents for biomarker discovery, as well as cancer diagnosis and therapy. In this review, we present recent progress and challenges in aptamer and SELEX technology and highlight some representative applications of aptamers in cancer therapy.
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Affiliation(s)
- Shin-Ichiro Hori
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
| | - Alberto Herrera
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
| | - John J Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
| | - Jiehua Zhou
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
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Menon B, Tiwari M, Gopi A, Raj P, Panwar K. Serum krebs von den lungen-6 (KL-6): a promising biomarker in sarcoidosis. ACTA ACUST UNITED AC 2018. [DOI: 10.15406/mojcrr.2018.01.00009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Cao H, Fang X, Li H, Li H, Kong J. Ultrasensitive detection of mucin 1 biomarker by immuno-loop-mediated isothermal amplification. Talanta 2016; 164:588-592. [PMID: 28107977 DOI: 10.1016/j.talanta.2016.07.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/24/2016] [Accepted: 07/04/2016] [Indexed: 02/07/2023]
Abstract
Mucin 1 (MUC-1), a glycoprotein over-expressed on most malignant epithelial cell surfaces, such as colorectal, lung, prostate, pancreatic, ovarian, and bladder carcinomas, has been confirmed as a useful biomarker for the diagnosis of early cancers. Therefore, it is very important for early cancer diagnoses to develop the sensitive and specific detection approach of MUC-1. In this paper, we report a novel technique of aptamer-based Immuno-Loop-Mediated Isothermal Amplification (Im-LAMP) for the quantitative detection of MUC-1 by MUC-1 aptamer with high affinity for MUC-1. The cycle time is linearly dependent on the logarithm (log) of the concentration of mucin 1 ranging from 1.0 pM to 1.0 aM. We call this technique Im-LAMP, which is a novel method for the detection of low-abundance proteins with high sensitivity (a low detection limit of 120 MUC-1 molecules by calculation)and specificity. Finally, this approach is also successfully applied in the analysis of human blood serum samples. It also lays the foundation for the early diagnosis of different types of low-abundance cancer biomarkers.
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Affiliation(s)
- Hongmei Cao
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Xueen Fang
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China.
| | - Haipeng Li
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Hua Li
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China
| | - Jilie Kong
- Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, PR China.
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Cao H, Ye D, Zhao Q, Luo J, Zhang S, Kong J. A novel aptasensor based on MUC-1 conjugated CNSs for ultrasensitive detection of tumor cells. Analyst 2015; 139:4917-23. [PMID: 25078888 DOI: 10.1039/c4an00844h] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A novel strategy for the quantitative determination of human colon cancer DLD-1 cells utilizing an electrochemical aptasensor was developed by effective surface recognition between Mucin 1 glycoprotein over-expressed on the cell membrane and MUC-1 aptamer (MUC-1) bound on carbon nanospheres (CNSs). An MTT assay revealed that the as-prepared CNSs by green route exhibited satisfactory biocompatibility for cell viability, providing a suitable platform for the cell adhesion study. Furthermore, using CNSs as a sensing layer accelerated electron transfer and provided a highly stable matrix for the convenient conjugation of target MUC-1 aptamer, considerably amplifying the electrochemical signals. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were applied to assess the optimal conditions and detection performance of the as-fabricated aptasensor. The attachment of colon cancer DLD-1 cells onto the MUC-1 aptamer immobilized CNSs led to increased EIS responses, which changed linearly in cell concentration ranging from 1.25 × 10(2) to 1.25 × 10(6) cells per mL with a lower detection limit of 40 cells per mL. With this method, colon cancer DLD-1 cells can be easily distinguished from normal cells, Human astrocytes 1800. The novel aptasensor revealed high specificity to DLD-1 cells. Furthermore, the aptasensor described here showed good reproducibility and high stability because of the CNSs of high stability and biocompatibility. The proposed protocols are a promising technique for the early monitoring of human colon cancer, and might have potential clinical applications such as cancer diagnosis, drug screening.
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Affiliation(s)
- Hongmei Cao
- Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, PR China.
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Molecular beacon-based quantitiation of epithelial tumor marker mucin 1. Bioorg Med Chem Lett 2012; 22:6081-4. [PMID: 22959521 DOI: 10.1016/j.bmcl.2012.08.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 08/07/2012] [Accepted: 08/10/2012] [Indexed: 11/24/2022]
Abstract
Mucin 1 (Muc1) is a glycoprotein expressed on most epithelial cell surfaces, which has been confirmed as a useful biomarker for the diagnosis of early cancers. In this study, we demonstrate that a quantum dot (QD)-aptamer beacon acts by folding-induced dissociation of a DNA intercalating dye, BOBO-3, in the presence of the target molecules, Muc1. Release of intercalated BOBO-3s from the QD-conjugated aptamers results in a decrease in QD fluorescence resonance energy transfer (FRET)-mediated BOBO-3 emission, allowing for label-free Muc1 detection and quantitation. We attain highly specific and wide-range detection (from 50nM to 20μM) of Muc1, suggesting that our QD-aptamer beacon can be a potential alternative to immuno-based assays for Muc1 detection. The detection methodology is expected to be improved for the early diagnosis of different types of epithelial cancers of large populations.
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Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig 2012; 50:3-13. [PMID: 22554854 DOI: 10.1016/j.resinv.2012.02.001] [Citation(s) in RCA: 285] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 02/03/2012] [Accepted: 02/08/2012] [Indexed: 12/19/2022]
Abstract
Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. Because injury and/or regeneration of type II pneumocytes are prominent histological features of ILDs, substances derived from type II pneumocytes have been the focus of research investigating potential biomarkers for ILD. One important biomarker for ILD is the high-molecular-weight glycoprotein, Krebs von den Lungen-6 (KL-6). KL-6 is now classified as a human MUC1 mucin protein, and regenerating type II pneumocytes are the primary cellular source of KL-6/MUC1 in the affected lungs of patients with ILD. KL-6/MUC1 is detectable in the serum of patients with ILD, and extensive investigations performed primarily in Japan have revealed that serum KL-6/MUC1 is elevated in 70-100% of patients with various ILDs, including idiopathic interstitial pneumonias, collagen vascular disease-associated interstitial pneumonia, hypersensitivity pneumonia, radiation pneumonitis, drug-induced ILDs, acute respiratory distress syndrome, pulmonary sarcoidosis, and pulmonary alveolar proteinosis. The results from these various studies have supported the utility of KL-6/MUC1 as a serum biomarker for detecting these various ILDs. Moreover, KL-6/MUC1 serum levels have been demonstrated to be useful for evaluating disease activity and predicting the clinical outcomes of various ILD types. Based on these observations, we believe that KL-6/MUC1 is currently one of the best and most reliable serum biomarkers available for ILD management.
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Affiliation(s)
- Nobuhisa Ishikawa
- Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Cheng AKH, Su H, Wang YA, Yu HZ. Aptamer-based detection of epithelial tumor marker mucin 1 with quantum dot-based fluorescence readout. Anal Chem 2010; 81:6130-9. [PMID: 19572710 DOI: 10.1021/ac901223q] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Mucin 1 (MUC1) is a glycoprotein expressed on most epithelial cell surfaces, which has been confirmed as a useful biomarker for the diagnosis of early cancers. In this paper, we report an aptamer-based, quantitative detection protocol for MUC1 using a 3-component DNA hybridization system with quantum dot (QD)-labeling: in the absence of MUC1 peptides, strong fluorescence is observed upon mixing the three specially designed DNA strands (quencher, QD-labeled reporter, and the MUC1 aptamer stem); in the presence of MUC1 peptides, a successive decrease in fluorescence intensity is detected since the MUC1 peptide binds to the aptamer strand in such a way to allow the quencher and fluorescence reporter to be brought into close proximity (which leads to the occurrence of fluorescence resonance energy transfer, FRET, between the quencher and QD). The detection limit for MUC1 with this novel approach is in the nanomolar (nM) level, and a linear response can be established for the approximate range found in blood serum. This study also provided further insight into the aptamer/analyte binding site/mode for MUC1, which augments the possibility of improving this detection methodology for the early diagnosis of different types of epithelial cancers of large populations.
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Affiliation(s)
- Alan K H Cheng
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
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Jonckheere N, Van Seuningen I. The membrane-bound mucins: From cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie 2009; 92:1-11. [PMID: 19818375 DOI: 10.1016/j.biochi.2009.09.018] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2009] [Accepted: 09/30/2009] [Indexed: 12/26/2022]
Abstract
The membrane-bound mucins belong to an ever-increasing family of O-glycoproteins. Based on their structure and localization at the cell surface they are thought to play important biological roles in cell-cell and cell-matrix interactions, in cell signalling and in modulating biological properties of cancer cells. Among them, MUC1 and MUC4 mucins are best characterized. Their altered expression in cancer (overexpression in the respiratory, gastro-intestinal, urogenital and hepato-biliary tracts) indicates an important role for these membrane-bound mucins in tumour progression, metastasis, cancer cell resistance to chemotherapeutics drugs and as specific markers of epithelial cancer cells. Some mechanisms responsible for MUC1 and MUC4 role in tumour cell properties have been deciphered recently. However, much remains to be done in order to understand the molecular mechanisms and signalling pathways that control the expression of membrane-bound mucins during the different steps of tumour progression toward adenocarcinoma and evaluate their potential as prognostic/diagnostic markers and as therapeutic tools. In this review we focus on the molecular mechanisms and signalling pathways known to control the expression of membrane-bound mucins in cancer. We will discuss the mechanisms of regulation at the promoter level (including genetic and epigenetic modifications) that may be responsible for the mucin altered pattern of expression in epithelial cancers.
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Hashimoto K, Shimizu Y, Suehiro Y, Okayama N, Hashimoto S, Okada T, Hiura M, Ueno K, Hazama S, Higaki S, Hamanaka Y, Oka M, Sakaida I, Hinoda Y. Hypermethylation status of APC inversely correlates with the presence of submucosal invasion in laterally spreading colorectal tumors. Mol Carcinog 2008; 47:1-8. [PMID: 17620311 DOI: 10.1002/mc.20363] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Little is known about epigenetic alterations in laterally spreading colorectal tumors (LSTs). The goal of the present study was to elucidate the epigenetic background of LSTs and compare the methylation status of DNA CpG islands (CGIs) with clinicopathologic features. Methylation of MINT1, MINT2, MINT31, p16, O(6)-methylguanine-DNA methyltransferase (MGMT), adenomatous polyposis coli (APC), and human MutL homologue 1 (hMLH1) in 42 LSTs was assessed by methylation-specific polymerase chain reaction (MSP) and compared with clinicopathologic parameters. The frequency of hypermethylation was 12.5% (4/32) for MINT1, 40.0% (16/40) for MINT2, 25.0% (10/40) for MINT31, 25.7% (9/35) for p16, 7.7% (3/39) for hMLH1, 26.5% (9/34) for MGMT, and 35.9% (14/39) for APC. APC methylation was inversely associated with submucosal invasion (P = 0.034), which was not found in any of 14 LST cases with APC methylation, whereas submucosal invasion was present in 8 of 25 (32.0%) cases without APC methylation. These data suggest that hypermethylation of APC could be a predictive marker for the absence of submucosal invasion of LSTs.
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Affiliation(s)
- Kazuo Hashimoto
- Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi, Japan
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Gad A, Tanaka E, Matsumoto A, Wahab MAE, Serwah AEH, Attia F, Ali K, Hassouba H, el-Deeb AER, Ichijyo T, Umemura T, Muto H, Yoshizawa K, Kiyosawa K. Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma. World J Gastroenterol 2005; 11:6607-12. [PMID: 16425352 PMCID: PMC4355752 DOI: 10.3748/wjg.v11.i42.6607] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics.
METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracer Ab according to the manufacturer’s instructions (Eisai, Tokyo, Japan). Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-II) was performed in both groups using commercially available kits.
RESULTS: A significantly higher mean serum KL-6 (556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001) or without (361±161 U/L; P<0.001) liver cirrhosis (LC). Serum KL-6 level did not correlate with either AFP or PIVKA-II serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64) and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer’s instructions; a cut-off point of 500 U/L was used that showed the highest specificity (80%) in comparison with AFP and PIVKA-II (78% vs 72% respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78% for AFP alone; 93% for AFP plus PIVKA-II to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6 positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups.
CONCLUSION: KL-6 is suggested as a tumor for HCC. Its positivity may reflect HCC-associated cholestasis and/or local tumor invasion.
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Affiliation(s)
- Amal Gad
- Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Tang W, Inagaki Y, Kokudo N, Guo Q, Seyama Y, Nakata M, Imamura H, Sano K, Sugawara Y, Makuuchi M. KL-6 mucin expression in carcinoma of the ampulla of Vater: Association with cancer progression. World J Gastroenterol 2005; 11:5450-4. [PMID: 16222735 PMCID: PMC4320352 DOI: 10.3748/wjg.v11.i35.5450] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess histochemical expression of KL-6 and its clinicopathological significance in carcinoma of the ampulla of Vater.
METHODS: Ampullary carcinoma tissues were collected from 38 patients who underwent pancreatoduodenectomy or local resection. Tissues were subjected to immunohi-stochemical analysis using KL-6 antibody.
RESULTS: Positive staining of ampullary carcinoma cells was observed in 26 (68.4%) cases. Staining was not found in the surrounding non-cancer regions of the ampullary tissues. Remarkable KL-6 expression was observed in invasive carcinoma cells in pancreatic and duodenal tissues and in metastatic carcinoma cells in lymph nodes. Positive KL-6 expression was related to lymph node metastasis (P = 0.020), pancreatic invasion (P = 0.016), duodenal invasion (P = 0.034), and advanced stage of TNM clinical classification (P = 0.010). Survival analysis showed that positive expression of KL-6 was related to a poorer prognosis (P = 0.029).
CONCLUSION: The aberrant expression of KL-6 mucin is significantly related to unfavorable behaviors of carcinoma of the ampulla of Vater.
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Affiliation(s)
- Wei Tang
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
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Pisarev VM, Kinarsky L, Caffrey T, Hanisch FG, Sanderson S, Hollingsworth MA, Sherman S. T cells recognize PD(N/T)R motif common in a variable number of tandem repeat and degenerate repeat sequences of MUC1. Int Immunopharmacol 2005; 5:315-30. [PMID: 15652762 DOI: 10.1016/j.intimp.2004.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2004] [Revised: 10/04/2004] [Accepted: 10/04/2004] [Indexed: 11/30/2022]
Abstract
The tumor-associated antigen MUC1 is a transmembrane glycoprotein, which is overexpressed in human carcinomas. Peptide epitopes, containing the PDTR fragment from the variable number of tandem repeat (VNTR) domains of MUC1 have been found to be immunodominant in T-cell and B-cell responses. However, little is known about the immunogenicity and specificity of T-cell epitopes from other regions of MUC1 that may also participate in immune responses against tumors. In this study, the combination of immunoinformatics, molecular modeling and a vaccine adjuvant strategy were used to predict and describe a novel T-cell epitope, SAPDNRPAL, located within the degenerate tandem repeat of MUC1. This peptide possesses structural similarity to both VNTR-derived SAPDTRPAP and Sendai virus peptide FAPGNYPAL, which are known to induce cytotoxic T lymphocytes (CTL). We found that SAPDNRPAL had a higher affinity for mouse H-D(b), H-2K(b) and human HLA-A2 molecules than SAPDTRPAP. A chimeric peptide (CP) containing SAPDNRPAL and an adjuvant C5a-derived decapeptide induced epitope-specific type 1 T cells in human MUC1 transgenic mice (ELISPOT). Mice that received dendritic cells (DC) pulsed with the CP or a 25-mer peptide containing the SAPDNRPAL sequence showed increased frequencies of SAPDNRPAL- and SAPDTRPAP-specific interferon-gamma producing T cells. PDTR-specific antibody 214D4 reacted with both SAPDNRPAL and SAPDTRPAP (ELISA). Altogether, our data suggest that the degenerate MUC1 repeat sequence contains the immunogenic T-cell epitope SAPDNRPAL, which is cross-reactive with the VNTR-derived peptide SAPDTRPAP. We suggest that the use of immunogenic PDNR-containing epitope(s) in vaccine strategies could be beneficial for developing increased, PD(N/T)R motif-specific T-cell responses against tumors expressing MUC1.
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Affiliation(s)
- Vladimir M Pisarev
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA
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Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ. MUC1 immunobiology: from discovery to clinical applications. Adv Immunol 2004; 82:249-93. [PMID: 14975259 DOI: 10.1016/s0065-2776(04)82006-6] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Anda M Vlad
- Department of Immunology, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15261, USA
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Nagata S, Tanaka S, Haruma K, Kitadai Y, Yoshihara M, Shimamoto F, Chayama K. Advanced colorectal carcinoma smaller than 10 mm in maximum diameter with special reference to clinicopathologic and molecular features: a report of 3 cases. Gastrointest Endosc 2002; 56:299-303. [PMID: 12145617 DOI: 10.1016/s0016-5107(02)70198-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Shinji Nagata
- Department of Endoscopy, Hiroshima University School of Medicine, and Health Service Center, Hiroshima University, Higashi-Hiroshima, Japan
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Sivridis E, Giatromanolaki A, Koukourakis MI, Georgiou L, Anastasiadis P. Patterns of episialin/MUC1 expression in endometrial carcinomas and prognostic relevance. Histopathology 2002; 40:92-100. [PMID: 11903603 DOI: 10.1046/j.1365-2559.2002.01316.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS To investigate episialin/MUC1 expression in the normal, hyperplastic and neoplastic endometrium, and relate patterns of tumour MUC1 reactivity with histopathological characteristics, oestrogen and progesterone receptor (ER and PR) status, bcl-2 and p53 oncoproteins and with clinical behaviour. METHODS AND RESULTS We studied 42 normally cycling endometria, 45 endometrial hyperplasias of various forms, and 111 endometrial carcinomas of endometrioid and non-endometrioid cell types with specific monoclonal antibodies employing standard immunohistochemical techniques. The follow-up period ranged from 34 to 182 months with a median of 86 months. Epithelial mucin episialin/MUC1 was consistently expressed in the normal endometrium, following a cyclical pattern: "apical membrane staining" in early and mid-proliferative endometrium; "purely cytoplasmic staining" in late proliferative endometrium; and "cytoplasmic staining with intraluminal secretions" in secretory endometrium. Immunostaining patterns in simple and complex hyperplasia were similar to late proliferative endometrium, while atypical hyperplasias and endometrial carcinomas either simulated patterns of proliferative endometrium or lacked MUC1 reactivity. Membranous MUC1 positivity was statistically more frequent in endometrioid carcinomas compared with carcinomas of non-endometrioid type (P = 0.006). Cytoplasmic MUC1 positivity was significantly associated with poor prognosis, while MUC1-negative carcinomas were associated with PR expression and an improved survival (P=0.04). There was no association of MUC1 patterns with bcl-2 and p53 immunoreactivity or with other histopathological variables. CONCLUSIONS Episialin/MUC1 is an integral component of the normal premenopausal endometrium and is probably hormonally regulated. It is frequently expressed in endometrial hyperplasias and carcinomas. The loss of MUC1 expression from endometrial carcinomas is associated with a favourable prognosis.
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Affiliation(s)
- E Sivridis
- Department of Pathology, Democritus University of Thrace, Alexandroupolis 681 00, PO Box 128, Greece.
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Li A, Goto M, Horinouchi M, Tanaka S, Imai K, Kim YS, Sato E, Yonezawa S. Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia. Pathol Int 2001; 51:853-60. [PMID: 11844051 DOI: 10.1046/j.1440-1827.2001.01291.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Our previous studies on MUC1 and MUC2 mucin expression in various human neoplasms have found that MUC1 expression is related with a poor outcome whereas MUC2 expression is related with a favorable outcome. In the present study, we examined the alteration of MUC1 and MUC2 antigens on malignant transformation of colorectal mucosa, and also its relationship with cell proliferative activity (Ki-67 labeling index) of neoplastic epithelial cells in 200 adenomas and 58 carcinomas. In the 200 adenomas, we analyzed a total of 400 adenomatous lesions (mild dysplasia, 200 lesions; moderate dysplasia, 153 lesions; severe dysplasia, 47 lesions). MUC1 was expressed in carcinomas (24%) and adenomas with severe dysplasia (4%), but was not expressed in adenomas with mild or moderate dysplasia. MUC2 was expressed in a significantly greater number of adenomas with mild dysplasia (72%) than in adenomas with moderate dysplasia (45%) or severe dysplasia (47%), as well as in the carcinomas (38%; P < 0.0001). The Ki-67 labeling index was significantly lower in the MUC2-positive cases than in the MUC2-negative cases in the adenomas with mild dysplasia (13.6 vs 24.2%; P < 0.0001) or moderate dysplasia (25.7 vs 44.4%; P < 0.0001), and in the carcinomas (32.5 vs 48.4%; P < 0.05). In conclusion, the data from our study indicate that increased MUC1 expression and reduced MUC2 expression may be related to malignant transformation of colorectal neoplasia. We also demonstrated that decreased MUC2 expression, which is correlated with increased Ki-67 labeling, may play an important role in the progression of colorectal adenomatous change.
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Affiliation(s)
- A Li
- Second Department of Pathology, Kagoshima University Faculty of Medicine, Sakuragaoka, Kagoshima, Japan
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Carr NJ. M30 expression demonstrates apoptotic cells, correlates with in situ end-labeling, and is associated with Ki-67 expression in large intestinal neoplasms. Arch Pathol Lab Med 2000; 124:1768-72. [PMID: 11100055 DOI: 10.5858/2000-124-1768-medacc] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The monoclonal antibody M30 recognizes a neoepitope of cytokeratin 18 produced during apoptosis. It is reactive in formalin-fixed, paraffin-embedded tissue and has great potential in the study of apoptosis in clinical and experimental material. OBJECTIVES To compare the results of M30 immunoexpression with a more established technique of demonstrating apoptosis in tissue sections, in situ end-labeling. A secondary objective was to compare the results with immunoexpression of the proliferation-associated antigen Ki-67. DESIGN Retrospective analysis of adenomas and adenocarcinomas of the large intestine. INTERVENTIONS Immunohistochemistry for M30 and Ki-67, and in situ end-labeling. Formalin-fixed, paraffin-embedded tissue was used. MAIN OUTCOME MEASURES The number of cells positive for M30, Ki-67, and in situ end-labeling, expressed as a proportion of the total number of cells counted. RESULTS A strong positive correlation was found between in situ end-labeling and expression of M30, although the counts were widely scattered around the regression line. Counts of Ki-67 were strongly correlated with both M30 expression and in situ end-labeling. Immunoexpression of M30 was generally easier to interpret than in situ end-labeling, and the procedures for M30 immunohistochemistry were technically less exacting. CONCLUSION These findings support the application of M30 immunoreactivity in the study of apoptosis.
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Affiliation(s)
- N J Carr
- Department of Pathology, Royal Hospital Haslar, Gosport, Hampshire, United Kingdom
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Baldus SE, Hanisch FG. Biochemistry and pathological importance of mucin-associated antigens in gastrointestinal neoplasia. Adv Cancer Res 2000; 79:201-48. [PMID: 10818682 DOI: 10.1016/s0065-230x(00)79007-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- S E Baldus
- Institute of Pathology, Medical Faculty, University of Cologne, Germany
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MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood 2000. [DOI: 10.1182/blood.v95.8.2666.008k02_2666_2671] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cγ) probe. The translocation linked theIGHG4 switch (Sγ4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably,MUC1 transcription is aberrantly regulated by the IGHA(C) 3′ enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3′ MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis.
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MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood 2000. [DOI: 10.1182/blood.v95.8.2666] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractThe band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cγ) probe. The translocation linked theIGHG4 switch (Sγ4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably,MUC1 transcription is aberrantly regulated by the IGHA(C) 3′ enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3′ MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis.
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