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Kawakami GDS, Pereira MA, Kubrusly MS, Carrasco AGM, Ramos MFKP, Ribeiro Júnior U. TUMOR MARKERS EXPRESSION LEVELS IN GASTRIC CANCER PATIENT'S PERIPHERAL BLOOD BY RT-PCR ASSESSMENT. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2024; 36:e1789. [PMID: 38324850 PMCID: PMC10841496 DOI: 10.1590/0102-672020230071e1789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 02/09/2024]
Abstract
BACKGROUND Hematological recurrence is the second most frequent cause of failure in the treatment of gastric cancer. The detection of circulating tumor markers in peripheral blood by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method may be a useful tool to predict recurrence and determine the patient's prognosis. However, no consensus has been reached regarding the association between the tumor markers level in peripheral blood and its impact on patient survival. AIMS To evaluate the expression of the circulating tumor markers CK20 and MUC1 in peripheral blood samples from patients with gastric cancer by qRT-PCR, and to verify the association of their expression levels with clinicopathological characteristics and survival. METHODS A total of 31 patients with gastric adenocarcinoma were prospectively included in this study. CK20 and MUC1 expression levels were analyzed from peripheral blood by the qRT-PCR technique. RESULTS There was no statistically significant (p>0.05) association between CK20 expression levels and clinical, pathological, and surgical features. Higher MUC1 expression levels were associated with female patients (p=0.01). There was a correlation between both gene levels (R=0.81, p<0.001), and CK20 level and tumor size (R=0.39, p=0.034). CONCLUSIONS CK20 and MUC1 expression levels could be assessed by qRT-PCR from total peripheral blood samples of patients with gastric cancer. CK20 levels were correlated to MUC1 levels as well as to tumor size. There was no difference in disease-free survival and overall survival regarding both genetic markers expression in this series.
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Affiliation(s)
- Gabriel da Silva Kawakami
- Universidade de São Paulo, Instituto do Câncer, Hospital das Clínicas, Faculty of Medicine, Department of Gastroenterology, São Paulo (SP), Brazil
| | - Marina Alessandra Pereira
- Universidade de São Paulo, Instituto do Câncer, Hospital das Clínicas, Faculty of Medicine, Department of Gastroenterology, São Paulo (SP), Brazil
| | - Márcia Saldanha Kubrusly
- Universidade de São Paulo, Instituto do Câncer, Hospital das Clínicas, Faculty of Medicine, Department of Gastroenterology, São Paulo (SP), Brazil
| | - Alexis Germán Murillo Carrasco
- Universidade de São Paulo, Instituto do Câncer, Hospital das Clínicas, Faculty of Medicine, Department of Gastroenterology, São Paulo (SP), Brazil
| | | | - Ulysses Ribeiro Júnior
- Universidade de São Paulo, Instituto do Câncer, Hospital das Clínicas, Faculty of Medicine, Department of Gastroenterology, São Paulo (SP), Brazil
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Patel NM, Geropoulos G, Patel PH, Bhogal RH, Harrington KJ, Singanayagam A, Kumar S. The Role of Mucin Expression in the Diagnosis of Oesophago-Gastric Cancer: A Systematic Literature Review. Cancers (Basel) 2023; 15:5252. [PMID: 37958425 PMCID: PMC10650431 DOI: 10.3390/cancers15215252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Survival in oesophago-gastric cancer (OGC) is poor due to early diagnostic challenges. Non-invasive risk stratification may identify susceptible patients with pre-malignant or benign disease. Following diagnostic confirmation with endoscopic biopsy, early OGC may be treated sooner. Mucins are transmembrane glycoproteins implicated in OGC with potential use as biomarkers of malignant transformation. This systematic review defines the role of mucins in OGC diagnosis. A literature search of MEDLINE, Web of Science, Embase and Cochrane databases was performed following PRISMA protocols for studies published January 1960-December 2022. Demographic data and data on mucin sampling and analysis methods were extracted. The review included 124 studies (n = 11,386 patients). Gastric adenocarcinoma (GAc) was the commonest OG malignancy (n = 101) followed by oesophageal adenocarcinoma (OAc, n = 24) and squamous cell carcinoma (OSqCc, n = 10). Mucins MUC1, MUC2, MUC5AC and MUC6 were the most frequently implicated. High MUC1 expression correlated with poorer prognosis and metastases in OSqCc. MUC2 expression decreases during progression from healthy mucosa to OAc, causing reduced protection from gastric acid. MUC5AC was upregulated, and MUC6 downregulated in GAc. Mucin expression varies in OGC; changes may be epigenetic or mutational. Profiling upper GI mucin expression in OGC, with pre-malignant, benign and healthy controls may identify potential early diagnostic biomarkers.
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Affiliation(s)
- Nikhil Manish Patel
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Georgios Geropoulos
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Pranav Harshad Patel
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Ricky Harminder Bhogal
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Kevin Joseph Harrington
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW7 3RP, UK
| | - Aran Singanayagam
- Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK
| | - Sacheen Kumar
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
- Department of Upper Gastrointestinal Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic London Hospital, London SW1X 7HY, UK
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Satala CB, Jung I, Gurzu S. Mucin-Phenotype and Expression of the Protein V-Set and Immunoglobulin Domain Containing 1 (VSIG1): New Insights into Gastric Carcinogenesis. Int J Mol Sci 2023; 24:8697. [PMID: 37240039 PMCID: PMC10218608 DOI: 10.3390/ijms24108697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/07/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
In gastric cancer (GC), intestinal metaplasia (IM) is a common precursor lesion, but its relationship to the MUC2/MUC5AC/CDX2 axis is not completely understood. Although V-set and immunoglobulin domain containing 1 (VSIG1) is supposed to be a specific marker for gastric mucosa and GC, respectively, no data about its relationship with IM or mucin phenotype have been published. The aim of our study was to explore the possible linkage between IM and these four molecules. The clinicopathological features of 60 randomly selected GCs were examined in association with VSIG1, MUC2, MUC5AC and CDX2. Two online database platforms were also used to establish the transcription factors (TFs) network involved in MUC2/MUC5AC/CDX2 cascade. IM was more frequently encountered in females (11/16 cases) and in patients below 60 years old (10/16 cases). Poorly differentiated (G3) carcinomas tended to show a loss of CDX2 (27/33 cases) but not of MUC2 and MUC5AC. MUC5AC and CDX2 were lost in parallel with the depth of invasion of the pT4 stage (28/35 and 29/35 cases), while an advanced Dukes-MAC-like stage was only correlated with CDX2 and VSIG1 loss (20/37 and 30/37 cases). VSIG1 was directly correlated with MUC5AC (p = 0.04) as an indicator of gastric phenotype. MUC2-negative cases showed a propensity towards lymphatic invasion (37/40 cases) and distant metastases, while CDX2-negative cases tended to associate with hematogenous dissemination (30/40 cases). Regarding the molecular network, only 3 of the 19 TFs involved in this carcinogenic cascade (SP1, RELA, NFKB1) interacted with all targeted genes. In GC, VSIG1 can be considered an indicator of gastric phenotype carcinomas, where carcinogenesis is mainly driven by MUC5AC. Although infrequently encountered in GC, CDX2 positivity might indicate a locally advanced stage and risk for vascular invasion, especially in tumors developed against the background of IM. The loss of VSIG1 indicates a risk for lymph node metastases.
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Affiliation(s)
- Catalin-Bogdan Satala
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania; (C.-B.S.); (I.J.)
- Department of Pathology, Clinical County Emergency Hospital, 540136 Targu Mures, Romania
| | - Ioan Jung
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania; (C.-B.S.); (I.J.)
| | - Simona Gurzu
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania; (C.-B.S.); (I.J.)
- Department of Pathology, Clinical County Emergency Hospital, 540136 Targu Mures, Romania
- Research Center for Oncopathology and Translational Medicine (CCOMT), George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540136 Targu Mures, Romania
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Johnson SE, Galan MC. Synthesis of 2-deoxy mucin-type O-glycan analogues as biological probes. Carbohydr Res 2022; 514:108542. [DOI: 10.1016/j.carres.2022.108542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
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Mucin 1 as a Molecular Target of a Novel Diisoquinoline Derivative Combined with Anti-MUC1 Antibody in AGS Gastric Cancer Cells. Molecules 2021; 26:molecules26216504. [PMID: 34770912 PMCID: PMC8588261 DOI: 10.3390/molecules26216504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The aim of the study was to examine the molecular mechanism of the anticancer action of a monoclonal antibody against MUC1 and a diisoquinoline derivative (OM-86II) in human gastric cancer cells. METHODS The cell viability was measured by the MTT assay. The disruption of mitochondrial membrane potential and activity of caspase-8 and caspase-9 was performed by flow cytometry. Fluorescent microscopy was used to confirm the proapoptotic effect of compounds. LC3A, LC3B and Beclin-1 concentrations were analyzed to check the influence of the compounds on induction of autophagy. ELISA assessments were performed to measure the concentration of mTOR, sICAM1, MMP-2, MMP-9 and pro-apoptotic Bax. RESULTS The anti-MUC1 antibody with the diisoquinoline derivative (OM-86II) significantly reduced gastric cancer cells' viability. This was accompanied by an increase in caspase-8 and caspase-9 activity as well as high concentrations of pro-apoptotic Bax. We also proved that the anti-MUC1 antibody with OM-86II decreased the concentrations of MMP-9, sICAM1 and mTOR in gastric cancer cells. After 48 h of incubation with such a combination, we observed higher levels of the crucial component of autophagosomes (LC3) and Beclin-1. CONCLUSIONS Our study proved that the anti-MUC1 antibody sensitizes human gastric cancer cells to the novel diisoquinoline derivative (OM-86II) via induction of apoptosis and autophagy, and inhibition of selected proteins such as mTOR, sICAM1 and MMP-9.
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Gundamaraju R, Chong WC. Consequence of distinctive expression of MUC2 in colorectal cancers: How much is actually bad? Biochim Biophys Acta Rev Cancer 2021; 1876:188579. [PMID: 34139275 DOI: 10.1016/j.bbcan.2021.188579] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) exhibits complex pathogenesis via compromised intestinal mucosal barrier. It is accepted that goblet cells secrete mucin which line the intestinal mucosal barrier and offer wide range protection and maintain the gut integrity. The principal mucin in the small and large intestine which is Mucin2 (MUC2) is predominantly expressed in the goblet cells which play a pivotal role in intestinal homeostasis. Its disruption is associated with diverse diseases and carcinomas. MUC2 has lately been identified as a principal marker in various mechanisms and secretory cell lineage. While MUC2 expression is regulated by various modulators, alterations in its expression are associated with immunomodulation, differences in tumor immunity and also regulation of microbiota. In the light of current literature, the present review explicates the regulation, functional mechanisms and essential role of MUC2 in colorectal cancer and aids in providing deep understanding of pathogenesis of the disease and also specifies the importance of the MUC2 in gaining more insights about the subtypes of colorectal cancer and how it can succour in approximating the prognosis and survival of the patients.
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Affiliation(s)
- Rohit Gundamaraju
- ER Stress and Gut Mucosal Immunology Laboratory, School of Health Sciences, University of Tasmania, Launceston, Tasmania 7248, Australia.
| | - Wai Chin Chong
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, School of Medicine, Nursing, and Health Science, Monash University, Clayton, Victoria 3168, Australia
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Effects of antibacterial peptide combinations on growth performance, intestinal health, and immune function of broiler chickens. Poult Sci 2020; 99:6481-6492. [PMID: 33248563 PMCID: PMC7810918 DOI: 10.1016/j.psj.2020.08.068] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/16/2020] [Accepted: 08/19/2020] [Indexed: 12/20/2022] Open
Abstract
To study the effects of antibacterial peptides (ABPs) on feeding broilers, this experiment compared the 2 combinations of ABP with antibiotics by separately adding the supplement to the diet of 818 broilers as follows—antibiotics, Pratt and Full-tide, and Pratt and plant essential oil—and then the effect of them on production performance, immune function, antioxidant capacity, serum biochemical indicators, and microorganisms of the experimental flocks was investigated and compared. It was found that the aforementioned indicators among the 2 groups of ABP and the antibiotic group were close to or even better than those of antibiotics, and the combination added with plant essential oils had generally better effects. These results indicated that ABPs could improve economic benefits by promoting growth, preventing disease, and reducing the rate of death. This study deepened the research on the action mechanism of ABPs and not only explored the feasibility of ABPs as a novel feed additive for broilers but also provided experimental data and theoretical basis for the application of ABPs.
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Uemura S, Higuchi R, Yazawa T, Izumo W, Matsunaga Y, Shiihara M, Ota T, Furukawa T, Yamamoto M. Prognostic Factors for Surgically Resected Intraductal Papillary Neoplasm of the Bile Duct: A Retrospective Cohort Study. Ann Surg Oncol 2020; 28:826-834. [PMID: 32651697 DOI: 10.1245/s10434-020-08835-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND To date, postoperative prognostic factors for intraductal papillary neoplasm of the bile duct (IPNB) have not been well-established. This study aimed to examine the histopathologic features and postoperative prognosis of the two IPNB subclassifications, as well as factors affecting prognosis, based on the authors' experience at a single institution. METHODS The study enrolled 83 patients who underwent surgical resection for pathologically diagnosed IPNB at the authors' institution. The clinicopathologic features and postoperative outcomes for these patients were examined. The study also investigated postoperative prognostic factors for IPNB using uni- and multivariate analyses. RESULTS More than half of the tumors (64%) diagnosed as IPNB were early-stage cancer (UICC Tis or T1). However, none were diagnosed as benign. The multivariate analysis showed that lymph node metastasis (hazard ratio [HR], 5.78; p = 0.002) and bile duct margin status with carcinoma in situ (D-CIS; HR, 5.10; p = 0.002) were independent prognostic factors, whereas MUC6 expression showed only a marginal influence on prediction of prognosis (HR, 0.32; p = 0.07). The tumor recurrence rate and the proportion of locoregional recurrence were significantly greater among the patients with D-CIS than among those with negative bile duct margins, including those patients with low-grade dysplasia. The patients with D-CIS showed a significantly poorer prognosis than those with negative bile duct margins (5-year survival, 38% versus 87%; p = 0.0002). CONCLUSIONS Evaluation of resected IPNBs showed cancer in all cases. Avoiding positive biliary stumps during surgery, including resection of carcinoma in situ, would improve the prognosis for patients with IPNB.
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Affiliation(s)
- Shuichiro Uemura
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Ryota Higuchi
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Takehisa Yazawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Wataru Izumo
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yutaro Matsunaga
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masahiro Shiihara
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Takehiro Ota
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Toru Furukawa
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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Abbaszadegan MR, Mojarrad M, Moghbeli M. Role of extra cellular proteins in gastric cancer progression and metastasis: an update. Genes Environ 2020; 42:18. [PMID: 32467737 PMCID: PMC7227337 DOI: 10.1186/s41021-020-00157-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Background Gastric cancer (GC) is one of the most common cancers in the world with a high ratio of mortality. Regarding the late diagnosis, there is a high ratio of distant metastasis among GC cases. Despite the recent progresses in therapeutic modalities, there is not still an efficient therapeutic method to increase survival rate of metastatic GC cases. Main body Apart from the various intracellular signaling pathways which are involved in tumor cell migration and metastasis, the local microenvironment is also a critical regulator of tumor cell migration. Indeed, the intracellular signaling pathways also exert their final metastatic roles through regulation of extra cellular matrix (ECM). Therefore, it is required to assess the role of extra cellular components in biology of GC. Conclusion In the present review, we summarize 48 of the significant ECM components including 17 ECM modifying enzymes, seven extracellular angiogenic factors, 13 cell adhesion and cytoskeletal organizers, seven matricellular proteins and growth factors, and four proteoglycans and extra cellular glycoproteins. This review paves the way of determination of a specific extra cellular diagnostic and prognostic panel marker for the GC patients.
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Affiliation(s)
| | - Majid Mojarrad
- 2Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- 2Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Harada F, Matsuyama R, Mori R, Kumamoto T, Morioka D, Taguri M, Yamanaka S, Endo I. Outcomes of surgery for 2010 WHO classification-based intraductal papillary neoplasm of the bile duct: Case–control study of a single Japanese institution's experience with special attention to mucin expression patterns. Eur J Surg Oncol 2019; 45:761-768. [DOI: 10.1016/j.ejso.2018.10.532] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 10/20/2018] [Accepted: 10/22/2018] [Indexed: 01/18/2023] Open
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Krishn SR, Ganguly K, Kaur S, Batra SK. Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. Carcinogenesis 2019; 39:633-651. [PMID: 29415129 DOI: 10.1093/carcin/bgy019] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022] Open
Abstract
Heavily glycosylated secreted mucin MUC5AC, by the virtue of its cysteine-rich repeats, can form inter- and intramolecular disulfide linkages resulting in complex polymers, which in turn craft the framework of the polymeric mucus gel on epithelial cell surfaces. MUC5AC is a molecule with versatile functional implications including barrier functions to epithelial cells, host-pathogen interaction, immune cell attraction to sites of premalignant or malignant lesions and tumor progression in a context-dependent manner. Differential expression, glycosylation and localization of MUC5AC have been associated with a plethora of benign and malignant pathologies. In this era of robust technologies, overexpression strategies and genetically engineered mouse models, MUC5AC is emerging as a potential diagnostic, prognostic and therapeutic target for various malignancies. Considering the clinical relevance of MUC5AC, this review holistically encompasses its genomic organization, domain structure, glycosylation patterns, regulation, functional and molecular connotation from benign to malignant pathologies. Furthermore, we have here explored the incipient and significant experimental tools that are being developed to study this structurally complex and evolutionary conserved gel-forming mucin.
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Affiliation(s)
- Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
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Yamashita MSDA, Melo EO. Mucin 2 (MUC2) promoter characterization: an overview. Cell Tissue Res 2018; 374:455-463. [PMID: 30218241 DOI: 10.1007/s00441-018-2916-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 08/13/2018] [Indexed: 12/24/2022]
Abstract
Transgenic livestock have been studied with a well-known interest in improving quantitative and qualitative traits. In order to direct heterologous gene expression, it is indispensable to identify and characterize a promoter suitable for directing the expression of the gene of interest (GOI) in a tissue-specific way. The gastrointestinal tract is a desirable target for gene expression in several mammalian models. Throughout the surface of the intestinal epithelium, there is an intricate polymer network, formed by gel-forming mucins (especially MUC2 and MUC5AC, of which MUC2 is the major one), which plays a protective role due to the formation of a physical, chemical and immunological barrier between the organism and the environment. The characterization of the gel-forming mucins is difficult because of their large size and repetitive DNA sequences and domains. The main mucin in the small and large intestine, mucin 2 (MUC2), is expressed specifically in goblet cells. MUC2 plays an important role in intestinal homeostasis and its disruption is associated with several diseases and carcinomas. This mucin is also an important marker for elucidating mechanisms that regulate differentiation of the secretory cell lineage. This review presents the state of the art of MUC2 promoter structure and functional characterization.
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Affiliation(s)
| | - Eduardo O Melo
- EMBRAPA Genetic Resources and Biotechnology, PqEB Av W5 Norte, Brasilia, DF, 70770-917, Brazil
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Hondo FY, Kishi H, Safatle-Ribeiro AV, Pessorrusso FCS, Ribeiro U, Maluf-Filho F. CHARACTERIZATION OF THE MUCIN PHENOTYPE CAN PREDICT GASTRIC CANCER RECURRENCE AFTER ENDOSCOPIC MUCOSAL RESECTION. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:308-314. [PMID: 28954038 DOI: 10.1590/s0004-2803.201700000-38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 05/22/2017] [Indexed: 01/27/2023]
Abstract
BACKGROUND Endoscopic mucosal resection is still considered an accepted treatment for early gastric cancer for selected cases. Histopathologic criteria for curative endoscopic resection are intramucosal well-differentiated adenocarcinoma, lateral and deep margins free of tumor, no histological ulceration, and no venous or lymphatic embolism. A 5% local recurrence rate has been described even when all the above-mentioned criteria are met. On the other hand, antigen expression by tumoral cells has been related to the biological behavior of several tumors. OBJECTIVE To evaluate whether early gastric cancer mucin immunoexpression, p53 and Ki-67, can predict recurrence after endoscopic mucosal resection, even when standard histopathologic criteria for curative measures have been attempted. METHODS Twenty-two patients with early gastric cancer were considered to have been completely resected by endoscopic mucosal resection. Local recurrence occurred in 5/22 (22.7%). Immunohistochemical study was possible in 18 (81.8%) resected specimens. Patients were divided in two groups: those with and those without local recurrence. They were compared across demographic, endoscopic, histologic data, and immunohistochemical factors for MUC2, MUC5a, CD10, p53, and Ki-67. RESULTS Mucin immunoexpression allowed a reclassification of gastric adenocarcinoma in intestinal (10), gastric (2), mixed (4), and null phenotypes (2). Mixed phenotype (positive for both MUC2 and MUC5a) was found in 80% of cases in the local recurrence group, while the intestinal type (positive MUC2 and negative MUC5a) was found in 76.9% of cases without local recurrence (P=0.004). Other observed features did not correlate with neoplastic recurrence. CONCLUSION The mixed phenotype of early gastric adenocarcinoma is associated with a higher probability of local recurrence after endoscopic mucosal resection.
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Affiliation(s)
- Fabio Yuji Hondo
- Gastrocirurgia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | - Humberto Kishi
- Patologia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
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Kang H, An HJ, Song JY, Kim TH, Heo JH, Ahn DH, Kim G. Notch3 and Jagged2 contribute to gastric cancer development and to glandular differentiation associated with MUC2 and MUC5AC expression. Histopathology 2016; 61:576-86. [PMID: 22691042 DOI: 10.1111/j.1365-2559.2012.04274.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIMS Notch signalling plays diverse roles in malignant tumours as well as in normal tissue development. In this study we investigated the expression of Notch signalling pathway genes and their clinicopathological significance in gastric carcinomas. METHODS AND RESULTS Notch1, Notch3, Jagged1, Jagged2 and Hes1 expression were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) (n = 81) and immunohistochemistry (n = 103) in gastric carcinomas. MUC2 and MUC5AC expression were also assessed, using immunohistochemistry only. With qRT-PCR, Notch1, Notch3, Jagged1 and Jagged2 expression were increased significantly in tumour compared to normal tissue (P < 0.001, P = 0.002, P = 0.008 and P < 0.001, respectively). Overexpression of Notch3 and Jagged2 was associated with intestinal-type carcinomas (P = 0.024) and better histological differentiation (P = 0.047), respectively. Immunohistochemistry showed a reverse correlation between MUC2 and Notch3 or Jagged1 (P = 0.033 and P = 0.005, respectively) and between MUC5AC and Jagged1 or Hes1 (P = 0.004 and P = 0.002, respectively). Notch3 and Jagged2 gene overexpression related to a favourable outcome on univariate (P = 0.046 and P = 0.042, respectively) and multivariate (P = 0.045, Notch3) analysis. CONCLUSION The expression of Notch3 and Jagged2 is associated not only with gastric cancer development but also with the intestinal/glandular differentiation of gastric carcinoma cells, suggesting a role as a possible favourable prognostic indicator.
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Affiliation(s)
- Haeyoun Kang
- Department of PathologyClinical Research InstituteDepartment of Surgery, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Korea
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15
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Ok KS, Kim GH, Park DY, Lee HJ, Jeon HK, Baek DH, Lee BE, Song GA. Magnifying Endoscopy with Narrow Band Imaging of Early Gastric Cancer: Correlation with Histopathology and Mucin Phenotype. Gut Liver 2016; 10:532-541. [PMID: 27021504 PMCID: PMC4933412 DOI: 10.5009/gnl15364] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 09/11/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Magnifying endoscopy with narrow band imaging (ME-NBI) is a useful modality for the detailed visualization of microsurface (MS) and microvascular (MV) structures in the gastrointestinal tract. This study aimed to determine whether the MS and MV patterns in ME-NBI differ according to the histologic type, invasion depth, and mucin phenotype of early gastric cancers (EGCs). METHODS The MS and MV patterns of 160 lesions in 160 patients with EGC who underwent ME-NBI before endoscopic or surgical resection were prospectively collected and analyzed. EGCs were categorized as either differentiated or undifferentiated and as either mucosal or submucosal, and their mucin phenotypes were determined via immunohistochemistry of the tumor specimens. RESULTS Differentiated tumors mainly displayed an oval and/or tubular MS pattern and a fine network or loop MV pattern, whereas undifferentiated tumors mainly displayed an absent MS pattern and a corkscrew MV pattern. The destructive MS pattern was associated with submucosal invasion, and this association was more prominent in the differentiated tumors than in the undifferentiated tumors. MUC5AC expression was increased in lesions with either a papillary or absent MS pattern and a corkscrew MV pattern, whereas MUC6 expression was increased in lesions with a papillary MS pattern and a loop MV pattern. CD10 expression was more frequent in lesions with a fine network MV pattern. CONCLUSIONS ME-NBI can be useful for predicting the histopathology and mucin phenotype of EGCs.
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Affiliation(s)
- Kyung-Sun Ok
- Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan,
Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Do Youn Park
- Department of Pathology, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Hyun Jeong Lee
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Hye Kyung Jeon
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Dong Hoon Baek
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Bong Eun Lee
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Geun Am Song
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
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16
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Duarte HO, Freitas D, Gomes C, Gomes J, Magalhães A, Reis CA. Mucin-Type O-Glycosylation in Gastric Carcinogenesis. Biomolecules 2016; 6:E33. [PMID: 27409642 PMCID: PMC5039419 DOI: 10.3390/biom6030033] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 07/01/2016] [Accepted: 07/04/2016] [Indexed: 12/15/2022] Open
Abstract
Mucin-type O-glycosylation plays a crucial role in several physiological and pathological processes of the gastric tissue. Modifications in enzymes responsible for key glycosylation steps and the consequent abnormal biosynthesis and expression of their glycan products constitute well-established molecular hallmarks of disease state. This review addresses the major role played by mucins and associated O-glycan structures in Helicobacter pylori adhesion to the gastric mucosa and the subsequent establishment of a chronic infection, with concomitant drastic alterations of the gastric epithelium glycophenotype. Furthermore, alterations of mucin expression pattern and glycan signatures occurring in preneoplastic lesions and in gastric carcinoma are also described, as well as their impact throughout the gastric carcinogenesis cascade and in cancer progression. Altogether, mucin-type O-glycosylation alterations may represent promising biomarkers with potential screening and prognostic applications, as well as predictors of cancer patients' response to therapy.
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Affiliation(s)
- Henrique O Duarte
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira no. 228, Porto 4050-313, Portugal.
| | - Daniela Freitas
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira no. 228, Porto 4050-313, Portugal.
| | - Catarina Gomes
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
| | - Joana Gomes
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
| | - Ana Magalhães
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
| | - Celso A Reis
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Institute of Molecular Pathology and Immunology of University of Porto, Ipatimup, Rua Júlio Amaral de Carvalho, 45, Porto 4200-135, Portugal.
- Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira no. 228, Porto 4050-313, Portugal.
- Medical Faculty, University of Porto, Alameda Prof Hernâni Monteiro, Porto 4200-319, Portugal.
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Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary. Int J Gynecol Pathol 2016; 35:191-208. [DOI: 10.1097/pgp.0000000000000238] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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18
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Wang XT, Kong FB, Mai W, Li L, Pang LM. MUC1 Immunohistochemical Expression as a Prognostic Factor in Gastric Cancer: Meta-Analysis. DISEASE MARKERS 2016; 2016:9421571. [PMID: 27190429 PMCID: PMC4852113 DOI: 10.1155/2016/9421571] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 02/24/2016] [Indexed: 01/17/2023]
Abstract
MUC1, a member of the mucin family, is expressed in tumors of various human organs and may function as an antiadhesion molecule that inhibits cell-to-cell adhesion, inducing tumor metastasis, and served as a potential biomarker of tumor progression in early gastric cancer. However, its prognostic significance in gastric cancer is still in dispute. We performed a meta-analysis to evaluate the relationship between MUC1 expression and prognosis of gastric cancer. A total of ten eligible studies with 834 cases and 548 controls were included. MUC1 positive cases were highly positive in intestinal-type carcinomas (OR = 1.76, 95% CI: 1.27-2.44, P = 0.0008 fixed-effect), higher rate of vascular invasion (OR = 1.64, 95% CI: 1.13-2.39, P = 0.009 fixed-effect), and lymph node metastasis (OR = 2.10, 95% CI: 1.20-3.67, P = 0.01 random-effect), as well as lower 5-year survival rate (HR = 0.27, 95% CI: 0.11-0.66, P = 0.004 random-effect). However, the presence of MUC1 was not associated with gender, tumor size, histologic differentiation, and clinical stage. In summary, MUC1 is a prognostic factor in gastric cancer, which acts as a marker of poor outcome in patients with gastric cancer. Further clinical studies are needed to confirm the role of MUC1 in clinical practice.
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Affiliation(s)
- Xiao-Tong Wang
- Departments of Gastrointestinal and Peripheral Vascular Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Fan-Biao Kong
- Department of Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
| | - Wei Mai
- Departments of Gastrointestinal and Peripheral Vascular Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Lei Li
- Departments of Gastrointestinal and Peripheral Vascular Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Li-Ming Pang
- Department of Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
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Pyo JS, Ko YS, Kang G, Kim DH, Kim WH, Lee BL, Sohn JH. Bile acid induces MUC2 expression and inhibits tumor invasion in gastric carcinomas. J Cancer Res Clin Oncol 2015; 141:1181-8. [PMID: 25475007 DOI: 10.1007/s00432-014-1890-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 11/25/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Bile acids might induce mucin expression and regulate tumor behavior in esophageal and colon cancers. However, little is known about the effect of bile acids on tumor invasiveness of gastric carcinoma (GC). The aim of the current study was to elucidate the mechanisms by which bile acids regulate tumor invasion in GC. METHODS We investigated bile acid-induced MUC2 expression and cell invasion and migration in the cultured GC cell lines, SNU-216, and MKN45. In addition, immunohistochemical analysis of MUC2 and Snail was performed on 389 archival paraffin-embedded tissues of GC to evaluate the correlation of their expression with prognosis. RESULTS Deoxycholic acid (DCA), a secondary bile acid, had no effect on the viability of SNU-216 and MKN45 GC cells at low concentrations (0-100 μM), but decreased viability at a higher concentration (200 μM). MKN45 cells showed higher MUC2 expression than SNU-216 cells under basal conditions. DCA treatment upregulated MUC2 mRNA expression in both SNU-216 and MKN45 cells. Expression of Snail and MMP9 was markedly decreased by DCA treatment, and E-cadherin expression was subsequently increased. DCA significantly inhibited invasion and migration of SNU-216 and MKN45 cells. In human GC, MUC2 expression showed a negative correlation with Snail expression (P = 0.021) and a significantly positive correlation with better prognosis (P = 0.023). CONCLUSIONS Taken together, our data suggest that DCA induced MUC2 expression in GC cells and inhibited tumor invasion and migration. Additionally, MUC2-expressing GCs showed low rates of Snail expression and were associated with a favorable prognosis.
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Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 78 Saemunan-gil, Jongno-gu, Seoul, 110-746, South Korea
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20
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Lee TI, Jang JY, Kim S, Kim JW, Chang YW, Kim YW. Oxyntic gland adenoma endoscopically mimicking a gastric neuroendocrine tumor: A case report. World J Gastroenterol 2015; 21:5099-5104. [PMID: 25945027 PMCID: PMC4408486 DOI: 10.3748/wjg.v21.i16.5099] [Citation(s) in RCA: 7] [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] [Received: 09/23/2014] [Revised: 11/17/2014] [Accepted: 01/16/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric adenocarcinoma is one of the most common malignancies worldwide. Histochemical and immunohistologic analyses classify the phenotypes of gastric adenocarcinoma into several groups based on the variable clinical and pathologic features. A new and rare variant of gastric adenocarcinoma with chief cell differentiation (GA-CCD) has recently been recognized. Studies reporting the distinct clinicopathologic characteristics proposed the term oxyntic gland polyp/adenoma because of the benign nature of the GA-CCD. Typically, GA-CCD is a solitary mucosal lesion that develops either in the gastric cardia or fundus. Histologically, this lesion is characterized by tightly clustered glands and anastomosing cords of chief cells. Immunohistochemically, GA-CCD is diffusely positive for mucin (MUC) 6 and negative for MUC2 and MUC5AC. However, other gastric tumors such as a gastric neuroendocrine tumor or fundic gland polyp have been difficult to exclude. Because GA-CCD tends to be endoscopically misdiagnosed as a neuroendocrine tumor or fundic gland polyp, comprehensive assessment and observation by an endoscopist are strongly recommended. Herein, we report a rare case of oxyntic gland adenoma endoscopically mimicking a gastric neuroendocrine tumor that was successfully removed by endoscopic mucosal resection.
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21
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Corfield AP. Mucins: A biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta Gen Subj 2015; 1850:236-52. [PMID: 24821013 DOI: 10.1016/j.bbagen.2014.05.003] [Citation(s) in RCA: 375] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 04/05/2014] [Accepted: 05/02/2014] [Indexed: 02/08/2023]
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22
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García-Labastida L, Garza-Guajardo R, Barboza-Quintana O, Rodríguez-Sanchez IP, Ancer-Rodríguez J, Flores-Gutierrez JP, Gómez-Macías GS. CDX-2, MUC-2 and B-catenin as intestinal markers in pure mucinous carcinoma of the breast. Biol Res 2014; 47:43. [PMID: 25299496 PMCID: PMC4177067 DOI: 10.1186/0717-6287-47-43] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 07/28/2014] [Indexed: 01/08/2023] Open
Abstract
Background Pure mucinous adenocarcinoma of the breast is a rare entity characterized by the production of variable amounts of mucin comprising 1% to 6% of breast carcinomas. Some mucinous adenocarcinomas have shown expression of intestinal differentiation markers such as MUC-2. This study examines the expression of intestinal differentiation markers in this type of breast carcinoma. Results Twenty-two cases of pure mucinous adenocarcinoma of the breast were assessed. Immunochemistry was performed for beta-catenin, CDX-2 and MUC-2. All cases were positive for B-catenin. MUC-2 positivity was observed in all cases; 63. 6% were 3 plus positive. All cases were negative for CDX-2. Conclusions These results suggest that mucinous breast carcinomas express some markers of intestinal differentiation, such as MUC-2 and beta-catenin; however, future studies with a larger series of cases and using molecular techniques that help affirm these results are needed.
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Affiliation(s)
- Laura García-Labastida
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Raquel Garza-Guajardo
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Oralia Barboza-Quintana
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Irám Pablo Rodríguez-Sanchez
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Jesús Ancer-Rodríguez
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Juan Pablo Flores-Gutierrez
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
| | - Gabriela Sofía Gómez-Macías
- Universidad Autónoma de Nuevo León, Hospital Universitario "Dr. José Eleuterio González", Departamento de Anatomía Patológica y Citopatología, Madero and Gonzalitos S/N, Col. Mitras Centro, Monterrey, Nuevo Leon, 64460, Mexico.
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The changes in MUC5AC expression in gastric cancer before and after Helicobacter pylori eradication. Clin Res Hepatol Gastroenterol 2014; 38:235-40. [PMID: 23910060 DOI: 10.1016/j.clinre.2013.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 05/31/2013] [Accepted: 06/24/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE To investigate MUC5AC expression in gastric cancer before and after Hp eradication. METHODS The MUC5AC protein and mRNA were detected in gastric cancer tissue by western blot and real time PCR protocols before and after Hp eradication (Hp positive group). Gastric cancer tissue without Hp infection served as the control group (Hp negative group). RESULTS The MUC5AC protein and mRNA expression was more significantly increased in gastric cancer after Hp eradication as compared to that before Hp eradication, but it was significantly lower than of the control group. The relative amount of MUC5AC in the well-differentiated cancer was higher than that of the moderately or poorly-differentiated cancer, in either Hp positive or control groups. The relative amount of MUC5AC in cancer tissues with more than five metastatic lymph nodes was significantly lower than that of the cancer tissues with five or less metastatic lymph nodes, and was significantly lower in the Hp positive group as compared to that of the control group. CONCLUSIONS The reduction of the MUC5AC might be related to gastric carcinogenesis caused by Hp and the progression of gastric cancer.
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Choi JE, Bae JS, Lee JH, Jang KY, Chung MJ, Moon WS. Musashi-1 expression and clinicopathological significance in young gastric cancer patients: a matched case-control study. Int J Oncol 2014; 44:1185-92. [PMID: 24452324 DOI: 10.3892/ijo.2014.2263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/29/2013] [Indexed: 11/05/2022] Open
Abstract
Musashi-1 (Msi-1) is proposed to be a marker of progenitor cells in the human gastric mucosa. We examined Msi-1 expression and localization in surgical specimens of gastric cancer in young patients using immunohistochemistry and tested associations of Msi-1 expression with clinicopathological features. Patients (n=611) with gastric cancer who underwent radical gastrectomy were included in the present study. To minimize confounding effects, we matched 26 gastric cancer patients 30 years of age or younger (age ≤30) with 26 patients 60 years of age or older (age ≥60). The groups were matched by gender, tumor histological type and tumor stage. Gastric cancer in the younger patients was significantly associated with female gender and with diffuse histological type, compared with 585 gastric cancer patients older than 31 years. Msi-1 expression was more frequently upregulated in gastric cancer in young patients than in patients older than 60 years. Msi-1 expression was significantly associated with diffuse histological type, depth of tumor invasion, lymph node metastasis and tumor stage in the 26 young patients with gastric cancer. Univariate Kaplan-Meier survival analysis identified Msi-1 expression as a significantly negative factor in the survival of young gastric cancer patients. However, Msi-1 expression was not significantly associated with survival in the 26 matched older patients. According to mucin phenotype, the gastric foveolar type predominated in Msi-1-positive gastric cancers. Our principal findings included a significantly higher level of Msi-1 expression in younger gastric cancer patients compared to older ones, and a probable association of tumor Msi-1 expression in young gastric cancer patients with more aggressive tumor type.
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Affiliation(s)
- Ji Eun Choi
- Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
| | - Jun Sang Bae
- Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
| | - Ju Hyung Lee
- Preventive Medicine, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
| | - Myoung Ja Chung
- Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
| | - Woo Sung Moon
- Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea
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Chung WC, Jung SH, Joo KR, Kim MJ, Youn GJ, Kim Y, Lee JS, Lee H, Jung JH, Lee YK. An inverse relationship between the expression of the gastric tumor suppressor RUNX3 and infection with Helicobacter pylori in gastric epithelial dysplasia. Gut Liver 2013; 7:688-95. [PMID: 24312710 PMCID: PMC3848534 DOI: 10.5009/gnl.2013.7.6.688] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 06/13/2013] [Accepted: 06/17/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS This study was performed to determine the association between RUNX3 expression and Helicobacter pylori infection in premalignant gastric lesions. METHODS We examined 107 patients with gastric epithelial dysplasia who had undergone endoscopic mucosal resection or submucosal dissection. All tissue samples were evaluated by RUNX3 staining and subclassified by immunophenotype. H. pylori infection in dysplastic lesions and the normal surrounding tissue was examined by silver staining, and cagA status was assessed by polymerase chain reaction. RESULTS The loss of RUNX3 expression was observed in 62 cases (57.9%), and an association with H. pylori infection was found in 54 cases (50.5%). The infection rate with the cagA-positive H. pylori strain was 63.0%. In RUNX3-negative lesions, the rate of H. pylori infection (p=0.03) and the frequency of category 4 lesions (according to the revised Vienna classification) were high (p=0.02). In addition, the gastric mucin phenotype was predominant. In RUNX3-negative category 4 lesions, the rate of cagA-positive H. pylori infection rate was high but not significantly increased (p=0.08). CONCLUSIONS Infection with H. pylori is associated with inactivation of RUNX3 in early gastric carcinogenesis. This mechanism was prominent in gastric cancer with a gastric mucin phenotype.
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Affiliation(s)
- Woo Chul Chung
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
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Kim DH, Shin N, Kim GH, Song GA, Jeon TY, Kim DH, Lauwers GY, Park DY. Mucin expression in gastric cancer: reappraisal of its clinicopathologic and prognostic significance. Arch Pathol Lab Med 2013; 137:1047-1053. [PMID: 23899060 DOI: 10.5858/arpa.2012-0193-oa] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CONTEXT The clinical validity of mucin expression in gastric cancer is debated. Whereas several reports demonstrate a correlation between mucin expression and prognosis, others deny such an association. OBJECTIVES This survival analysis study aims to elucidate the prognostic significance of mucin expression in gastric cancer. DESIGN A retrospective survival analysis was done with 412 cases of gastric cancer characterized on the basis of MUC immunohistochemistry using MUC2, MUC5AC, MUC6, and CD10 antibodies; the cases were divided into those with a gastric, an intestinal, or a null mucin phenotype based on the predominant mucin. RESULTS There was no association between mucin expression and survival when considering overall gastric cancers or the advanced gastric cancer subtype. However, early gastric cancers with a gastric mucin phenotype showed longer survival than those with an intestinal mucin phenotype (P = .01) or a null phenotype (P = .01). In particular, MUC5AC-positive early gastric cancers resulted in longer survival than did those that did not express MUC5AC (P = .009). The loss of MUC5AC expression was identified as an independent, poor prognostic factor in early gastric cancers using the Cox regression proportional hazard model (hazard ratio, 3.50; P = .045). CONCLUSIONS MUC5AC expression is significantly associated with patient survival and can be used to predict outcomes in the gastric cancers, especially in the early gastric cancers.
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Affiliation(s)
- Dae Hwan Kim
- Department of Surgery, Pusan National University Hospital, Busan, Korea
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Shi D, Qiu XM, Bao YF. Effects of Helicobacter pylori infection on MUC5AC protein expression in gastric cancer. Future Oncol 2013; 9:115-20. [PMID: 23252568 DOI: 10.2217/fon.12.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
AIM To investigate the effects of the expression of the MUC5AC protein in gastric cancer depending on the Helicobacter pylori (Hp) infection status. MATERIALS & METHODS The MUC5AC protein and mRNA were detected using western blot and real-time PCR protocols in gastric cancer tissue and stratified for Hp infection. Gastric mucus membranes near the cancer site serve as the control group. RESULTS The expression of MUC5AC protein and mRNA is significantly decreased in gastric cancer tissue (p < 0.05). The decrease was more significant in the Hp-infected group than in the Hp-uninfected group (p < 0.05). CONCLUSION The infection of Hp is correlated with a decrease in MUC5AC protein amount in gastric cancer tissue. The current result suggests that there may be a potential necessary link between Hp, MUC5AC and gastric cancer.
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Affiliation(s)
- Ding Shi
- Department of Gastroenterology, The First People's Hospital of Yuhang District, Hangzhou 311100, Zhejiang Province, China.
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Liu YY, Chen HY, Zhang ML, Tian D, Li S, Lee JY. Loss of fragile histidine triad and amplification of 1p36.22 and 11p15.5 in primary gastric adenocarcinomas. World J Gastroenterol 2012; 18:4522-32. [PMID: 22969225 PMCID: PMC3435777 DOI: 10.3748/wjg.v18.i33.4522] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 02/01/2012] [Accepted: 04/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the genomic copy number alterations that may harbor key driver genes in gastric tumorigenesis.
METHODS: Using high-resolution array comparative genomic hybridization (CGH), we investigated the genomic alterations of 20 advanced primary gastric adenocarcinomas (seventeen tubular and three mucinous) of Chinese patients from the Jilin province. Ten matching adjacent normal regions from the same patients were also studied.
RESULTS: The most frequent imbalances detected in these cancer samples were gains of 3q26.31-q27.2, 5p, 8q, 11p, 18p, 19q and 20q and losses of 3p, 4p, 18q and 21q. The use of high-resolution array CGH increased the resolution and sensitivity of the observed genomic changes and identified focal genetic imbalances, which included 54 gains and 16 losses that were smaller than 1 Mb in size. The most interesting focal imbalances were the intergenic loss/homozygous deletion of the fragile histidine triad gene and the amplicons 11q13, 18q11.2 and 19q12, as well as the novel amplicons 1p36.22 and 11p15.5.
CONCLUSION: These regions, especially the focal amplicons, may harbor key driver genes that will serve as biomarkers for either the diagnosis or the prognosis of gastric cancer, and therefore, a large-scale investigation is recommended.
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Takami H, Sentani K, Matsuda M, Oue N, Sakamoto N, Yasui W. Cytokeratin expression profiling in gastric carcinoma: clinicopathologic significance and comparison with tumor-associated molecules. Pathobiology 2012; 79:154-61. [PMID: 22286119 DOI: 10.1159/000335694] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 12/12/2011] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the molecular basis that determines variations in CK patterns in gastric cancers (GCs). The aim of the present study was to analyze the CK expression patterns in a large number of GCs and to investigate how the CK patterns correlate with clinicopathologic parameters, histology, mucin phenotype or several tumor-related molecules. METHODS AND RESULTS We immunohistochemically examined the CK7/CK20 patterns, mucin expression profiles (MUC5AC, MUC6, MUC2 and CD10), and the cancer-related molecules (CDX2, p53, EGFR and β-catenin), using a tissue microarray with 870 GCs. The GCs were divided into four patterns; 17% of CK7+/CK20+, 57% of CK7+/CK20-, 9% of CK7-/CK20+ and 17% of CK7-/CK20. GCs with the CK7-/CK20- pattern demonstrated a close relation to undifferentiated adenocarcinoma. CK7 expression was significantly correlated with the expression of MUC5AC and MUC6, while CK20 expression was correlated with MUC2 and CDX2. There were statistically significant associations between CK expression patterns and mucin phenotypes. CONCLUSION These results indicate that the CK7/CK20 expression patterns in GCs demonstrated different clinicopathologic features and molecular signatures.
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Affiliation(s)
- Hokuto Takami
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
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Determining the site of origin of mucinous adenocarcinoma: an immunohistochemical study of 175 cases. Am J Surg Pathol 2012; 35:1830-6. [PMID: 21881489 DOI: 10.1097/pas.0b013e3182299c25] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Mucinous adenocarcinomas (MAs) of various origins may have a similar histologic appearance and frequently metastasize to distant sites, which often causes diagnostic problems in surgical pathology practice. The immunohistochemical profiles of MAs of various origins have not been well studied. We investigated the expression of 10 immunohistochemical markers (CK7, CK20, CDX-2, β-catenin, MUC-1, MUC-2, MUC-6, ER, WT-1, and PAX-8) in 175 cases of MA, including 69 cases from the lower gastrointestinal (GI) tract, 41 from the upper GI tract, 27 from gynecologic organs, 4 from the urinary bladder, 18 from the breast, and 16 from the lung. We found that lower GI MAs (colon, rectum, and anus) frequently expressed CDX-2 (42 of 42, 100%; 33 of 42 with homogenous positivity, 79%), MUC-2 (42 of 42; 100%), CK20 (41 of 42; 98%), and β-catenin (nuclear) (27 of 42; 64%) and rarely expressed MUC-6 (2 of 42; 5%) and CK7 (8 of 42; 19%). Most of the CK7-positive cases were from the rectum and anus (7 of 8; 88%). The expression of these markers in appendiceal MAs was similar to that of low GI tract MAs, except for a lower percentage of homogenous CDX-2 (3 of 27; 11%) and nuclear β-catenin (3 of 27; 11%) expression. Unlike their lower GI tract counterparts, the upper GI tract MAs (ampulla, pancreas/biliary tree, and stomach/esophagus) frequently expressed CK7 (38 of 41; 93%) and MUC-6 (31 of 41; 76%) and were rarely homogenously positive for CDX-2 (4 of 41; 10%) and nuclear positive for β-catenin (8 of 41; 19%). Breast MAs were frequently positive for CK7 (18 of 18; 100%), MUC-1 (18 of 18; 100%), MUC-2 (18 of 18; 100%), ER (16 of 18; 89%), MUC-6 (9 of 18; 50%), and WT-1 (9 of 18; 50%). Lung MAs were frequently positive for CK7 (16 of 16; 100%) and MUC-1 (15 of 16; 94%). Gynecologic MAs were positive for CK7 (25 of 27; 93%) and PAX-8 (13 of 27; 48%). We conclude that homogenous CDX-2 and nuclear β-catenin expressions are commonly seen in lower GI tract MAs. In contrast, appendiceal MAs are usually heterogenously positive for CDX-2 and show cytoplasmic positivity for β-catenin. Unlike lower GI tract MAs, upper GI tract MAs are frequently positive for CK7 and MUC-6. As is the case in appendiceal MAs, the upper GI tract MAs may also be heterogenously positive for CDX-2. Breast MAs are positive for ER and WT-1, whereas gynecologic MAs are positive for PAX-8 and negative for WT-1.
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Zheng L, Weng M, Qi M, Qi T, Tong L, Hou X, Tong Q. Aberrant expression of intelectin-1 in gastric cancer: its relationship with clinicopathological features and prognosis. J Cancer Res Clin Oncol 2012; 138:163-172. [PMID: 22083213 DOI: 10.1007/s00432-011-1088-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Accepted: 11/01/2011] [Indexed: 01/13/2023]
Abstract
PURPOSES Human intelectin-1 (ITLN-1) is a novel identified galactose-binding lectin that is expressed in the colonic goblet cells. Since gastric adenocarcinomas can arise through a process of intestinalization, we speculate that ITLN-1 may be aberrantly expressed in gastric cancer. This study was undertaken to examine the ITLN-1 expression in gastric cancer and correlate it with clinical outcomes. METHODS One hundred and ninety-six gastric cancer patients were evaluated for the ITLN-1 expression by immunohistochemistry. The ITLN-1 transcripts were measured by real-time quantitative PCR. RESULTS ITLN-1 expression was absent in normal gastric mucosa, whereas areas of intestinal metaplasia revealed ITLN-1 immunoreactivity. One hundred and forty-two gastric cancer patients (72.4%) were positive for ITLN-1 expression. In a subtotal of 20 patients, ITLN-1 transcripts were significantly enhanced in gastric cancer tissues than in normal gastric mucosa (P < 0.001). The expression rate of ITLN-1 was higher in intestinal-type carcinomas than in diffuse-type carcinomas (P = 0.003). ITLN-1 positivity in gastric cancer was positively correlated with tumor differentiation (P = 0.001) and CDX2 expression (P < 0.001), and inversely correlated with depth of invasion (P = 0.007), lymph node metastasis (P = 0.001), distant metastasis (P = 0.014), clinical stage (P = 0.006), Ki-67 expression (P = 0.001), and heparanase expression (P < 0.001), without correlation with age, gender, tumor location, or tumor size. In univariate and multivariate analyses, ITLN-1 was an independent prognostic factor for longer survival of gastric cancer patients (P = 0.001). CONCLUSION The aberrant ITLN-1 expression in gastric cancer is correlated with clinicopathological features and may be a useful prognostic factor for predicting the outcomes of gastric cancer patients.
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Affiliation(s)
- Liduan Zheng
- Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People's Republic of China
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32
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Koyama T, Sekine S, Taniguchi H, Tsuda H, Ikegami M, Hano H, Kushima R. Hepatocyte nuclear factor 4A expression discriminates gastric involvement by metastatic breast carcinomas from primary gastric adenocarcinomas. Hum Pathol 2011; 42:1777-84. [PMID: 21733563 DOI: 10.1016/j.humpath.2011.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2010] [Revised: 03/16/2011] [Accepted: 04/06/2011] [Indexed: 01/13/2023]
Abstract
Breast carcinomas sometimes metastasize to the stomach, and the histopathologic distinction of such metastases from primary gastric adenocarcinomas is often difficult. We characterized the clinicopathologic features of 21 breast carcinomas that had metastasized to the stomach and examined the use of a panel of antibodies, including hepatocyte nuclear factor 4A, for distinguishing the metastases from primary gastric diffuse-type adenocarcinomas. Histologically, all the metastatic breast carcinomas showed a poorly differentiated and/or signet ring cell morphology. Although most metastatic breast and primary gastric carcinomas contained signet ring cell components, the cases that were predominantly or exclusively composed of univacuolated-type signet ring cells were limited to metastatic breast carcinomas. Immunohistochemically, hepatocyte nuclear factor 4A was expressed in all 33 primary gastric carcinomas that were examined but was never expressed in metastatic breast carcinomas. Previously reported markers for breast and gastric carcinomas also showed a high specificity, but their sensitivities were quite variable. Estrogen receptor α, progesterone receptor, mammaglobin, and gross cystic disease fluid protein 15 were expressed in 76%, 33%, 52%, and 62%, respectively, of the metastatic breast carcinomas, whereas none of the primary gastric carcinomas expressed these antigens. CDX2, MUC5AC, MUC6, and CK20 were expressed in 36%, 85%, 27%, and 55%, respectively, of the primary gastric carcinomas. All the metastatic breast carcinomas were negative for these antibodies except for 1 case that expressed MUC5AC. Overall, the use of immunohistochemistry efficiently discriminated metastatic breast carcinomas from primary gastric carcinomas. In particular, the present study identified hepatocyte nuclear factor 4A as an excellent marker for differentiating the 2 lesions.
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Affiliation(s)
- Taiga Koyama
- Pathology and Clinical Laboratory Division, National Cancer Center Hospital, 104-0045 Tokyo, Japan
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33
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The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma. Mod Pathol 2011; 24:1177-90. [PMID: 21572404 DOI: 10.1038/modpathol.2011.77] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Adenocarcinoma of the distal esophagus and esophagogastric junction continues to rise in incidence. An intestinal metaplasia (Barrett esophagus)-dysplasia-carcinoma sequence induced by gastroesophageal reflux disease is well established. However, a significant number of adenocarcinomas in the vicinity of the esophagogastric junction are seen in the background of gastric/cardiac-type mucosa without intestinal metaplasia. Thus, the aim of this study was to investigate the role of Barrett esophagus (intestinal-type mucosa) in the classification and prognosis of tumors of the distal esophagus and esophagogastric junction. Clinicopathological and molecular characteristics were examined in 157 consecutively resected adenocarcinomas of the distal esophagus and esophagogastric junction and were compared between tumors arising in association with intestinal-type and cardiac-type mucosa. Intestinal-type mucosa-associated adenocarcinomas were more likely to be associated with younger age (P=0.0057), reflux symptoms (P<0.0001), proximal location (P=0.0009), lower T stage (P<0.0001), fewer nodal metastases (P=0.0001), absence of lymphatic (P<0.0001), venous (P=0.0060) or perineural (P<0.0001) invasion. Histologically, intestinal-type mucosa-associated tumors were more likely to be low-grade glandular tumors (P=0.0095) of intestinal or mixed immunophenotype (P=0.015) and express nuclear β-catenin (P=0.0080), whereas tumors arising in a background of cardiac-type mucosa were more frequently associated with EGFR amplification (P=0.0051). Five-year overall survival rate was significantly higher in patients with intestinal-type mucosa-associated tumors (28 vs 9%, P=0.0015), although no survival benefit was seen after adjusting for potential confounders. Our findings support the theory that multiple distinct pathways of tumorigenesis exist in the vicinity of the esophagogastric junction, including one in which tumors arise from dysplastic intestinal metaplasia (intestinal pathway), and one potentially involving dysplasia of the cardiac-type mucosa (non-intestinal pathway). Additional studies are warranted to further clarify their pathogenesis and the molecular mechanisms involved.
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Shin N, Kim HY, Kim WK, Park MG, Kim KB, Shin DH, Choi KU, Kim JY, Lee CH, Huh GY, Sol MY, Park DY. Molecular Biological Characteristics of Differentiated Early Gastric Cancer on the Basis of Mucin Expression. KOREAN JOURNAL OF PATHOLOGY 2011. [DOI: 10.4132/koreanjpathol.2011.45.1.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Nari Shin
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hye-Yeon Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Woo-Kyung Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Min-Gyung Park
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Kyung-Bin Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Dong Hoon Shin
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Kyung-Un Choi
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Jee-Yeon Kim
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Chang Hun Lee
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Gi Young Huh
- Department of Forensic Medicine, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Mee Young Sol
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Do Youn Park
- Department of Pathology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
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Khattab AZM, Nasif WA, Lotfy M. MUC2 and MUC6 apomucins expression in human gastric neoplasm: an immunohistochemical analysis. Med Oncol 2010; 28 Suppl 1:S207-13. [PMID: 20878553 DOI: 10.1007/s12032-010-9699-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Accepted: 09/17/2010] [Indexed: 01/16/2023]
Abstract
Apomucins play important biological roles in cell-cell and cell-extracellular matrix interactions, in cell signaling, and in biological properties of cancer cells. Their specific pattern of expression during the different steps of tumor progression toward adenocarcinoma suggests that they play significant roles in tumorigenesis. The family of secreted mucins, gel-forming components of viscoelastic mucus gels protecting the epithelia, includes mucins MUC2 and MUC6. Their principle function is to contribute in mucus formation by forming a tridimensional network via oligomerization domains to protect underlying epithelia against diverse injuries. The current study was investigated the expression of MUC2 and MUC6 in patients with gastric carcinoma. MUC2 and MUC6 expressions were detected immunohistochemically in gastric cancer biopsies using specific monoclonal antibodies. The results showed that in our gastric carcinoma cases, MUC2 expression was detected in 78.6% of cases. MUC2 expression is increased from well differentiated to moderately differentiated to poorly differentiated gastric adenocarcinoma. On the other hand, MUC6 was detected in 32% of cases. The expression of MUC2 is increasing, which is accompanied by an altered expression of MUC6 in gastric cancer. Therefore, it is concluded that the expression pattern of secreted mucins including MUC2 and MUC6 is altered apparently in gastric carcinoma.
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Liman N, Alan E, Küçük Bayram G. The differences between the localizations of MUC1, MUC5AC, MUC6 and osteopontin in quail proventriculus and gizzard may be a reflection of functional differences of stomach parts. J Anat 2010; 217:57-66. [PMID: 20492430 PMCID: PMC2913012 DOI: 10.1111/j.1469-7580.2010.01243.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2010] [Indexed: 11/30/2022] Open
Abstract
Mucins are high molecular weight glycoproteins which constitute the major component of the mucus layer and are produce by many epithelial tissues in vertebrates. Osteopontin (OPN) is an adhesive phosphorylated glycoprotein that is expressed by a broad range of tissues and cells. Although gastric mucins MUC1, MUC5AC, MUC6 and OPN have been widely used in histological studies and in diagnostic pathology in order to diagnose gastric carcinomas, their localizations in the stomach of quail have not yet been studied. In this study, the localizations of MUC1, MUC5AC, MUC6 and OPN in the proventriculus and gizzard of Japanese quail during the post-hatching period were compared at light microscope levels by applying immunohistochemical methods. In all ages studied, the immunoreactivity of MUC5AC was present in the lining epithelium of both folds and superficial proventricular glands in the proventriculus, whereas MUC1, MUC6 and OPN reactivity was found in the oxynticopeptic cells of profound proventricular glands. In addition, some cells in the fold epithelium of the proventriculus showed a positive reaction to OPN. The immunoreactivity of MUC1 in gizzard was different from that of MUC5AC. Although MUC5AC was expressed in the cells of both the surface epithelium and profound glands of the gizzard, MUC1 was only localized in the profound glands of the gizzard. However, MUC6 and OPN immunoreactivity was absent in the gizzard. The results indicated that the differences between the localizations of MUC1, MUC5AC, MUC6 and OPN in quail proventriculus and gizzard may be a reflection of functional differences of stomach parts. Although the biological significances of the expressions of MUC1, MUC5AC, MUC6 and OPN in the quail stomach remains unknown, these notable glycoproteins may be associated with barrier function, host defence, and/or secretion.
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Affiliation(s)
- Narin Liman
- Department of Histology and Embryology, Faculty of Veterinary Medicine, University of Erciyes, Kayseri, Turkey.
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Toki F, Takahashi A, Aihara R, Ogata K, Ando H, Ohno T, Mochiki E, Kuwano H. Relationship between clinicopathological features and mucin phenotypes of advanced gastric adenocarcinoma. World J Gastroenterol 2010; 16:2764-70. [PMID: 20533596 PMCID: PMC2883132 DOI: 10.3748/wjg.v16.i22.2764] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Revised: 01/15/2010] [Accepted: 01/22/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate a relationship between the clinicopathological features and mucin phenotypes in advanced gastric adenocarcinoma (AGA). METHODS Immunohistochemical staining was performed to determine the mucin phenotypes in 38 patients with differentiated adenocarcinomas (DACs), 9 with signet-ring cell carcinomas (SIGs), and 48 with other diffuse-type adenocarcinomas (non-SIGs) of AGA. The mucin phenotypes were classified into 4 types: gastric (G), gastrointestinal (GI), intestinal, and unclassified. RESULTS The G-related mucin phenotypes were highly expressed in all the histological subtypes of AGA. The expression of the GI phenotype in SIG patients was lower than that in DAC patients (P = 0.02), and this phenotype was observed in 56% of the non-SIG patients in the intramucosal layer. Among non-SIG cases, the expression of the GI phenotype was significantly higher in patients with extended adenocarcinomas and those with positive rates of lymph node metastasis. There was no difference between the expressions of the G and other GI phenotypes factors. Among DAC and non-SIG patients, there were no differences between the survival rates of the corresponding patient groups. CONCLUSION The GI phenotype might possess more invasive characteristics than the G phenotype in non-SIG. Neither of the phenotypes indicated a poor prognosis of DAC and non-SIG.
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Conze T, Carvalho AS, Landegren U, Almeida R, Reis CA, David L, Söderberg O. MUC2 mucin is a major carrier of the cancer-associated sialyl-Tn antigen in intestinal metaplasia and gastric carcinomas. Glycobiology 2009; 20:199-206. [PMID: 19815850 DOI: 10.1093/glycob/cwp161] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Changes in mucin protein expression and in glycosylation are common features in pre-neoplastic lesions and cancer and are therefore used as cancer-associated markers. De novo expression of intestinal mucin MUC2 and cancer-associated sialyl-Tn antigen are frequently observed in intestinal metaplasia (IM) and gastric cancer. However, despite that these antigens often co-localize, MUC2 has not been demonstrated to be a carrier of sialyl-Tn. By using the in situ proximity ligation assay (in situ PLA), we herein could show that MUC2 is a major carrier of the sialyl-Tn antigen in all IM cases and in most gastric carcinoma cases. The requirement by in situ PLA for the presence of both antigens in close proximity increases the selectivity compared to measurement of co-localization, as determined by immunohistochemistry. Identification of the mucin which is the carrier of a carbohydrate structure offers unique advantages for future development of more accurate diagnostic and prognostic markers.
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Affiliation(s)
- Tim Conze
- Department of Genetics and Pathology, University of Uppsala, Uppsala, Sweden
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Shinozaki A, Ushiku T, Morikawa T, Hino R, Sakatani T, Uozaki H, Fukayama M. Epstein-Barr virus-associated gastric carcinoma: a distinct carcinoma of gastric phenotype by claudin expression profiling. J Histochem Cytochem 2009; 57:775-85. [PMID: 19398608 DOI: 10.1369/jhc.2009.953810] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subtype with characteristic clinicopathological features. To better characterize its cellular characteristics, 43 cases of EBV-associated GC, 68 cases of EBV-negative GC, and non-neoplastic gastric mucosa in adults and fetuses were examined immunohistochemically. We quantified the expression of the major tight-junction protein claudin (CLDN) -1, -3, -4, -7, and -18 together with gastric mucins (MUC5AC and MUC6), intestinal mucin (MUC2), and CD10. EBV-associated GC showed a high frequency of CLDN18 expression (84%) and a low frequency of CLDN3 expression (5%). This expression profile corresponded to that of normal gastric epithelium in adults and fetuses. Almost half of the EBV-associated GC cases demonstrated gastric mucin expression, whereas the other half lacked mucin or CD10 expression. In contrast, as demonstrated by the expression profiles of CLDN3 and CLDN18, EBV-negative GC comprised a heterogeneous group of four different CLDN phenotypes: gastric, intestinal, mixed, and an undifferentiated type with variable expression patterns of mucins. These results indicate that EBV-associated GC is considerably homogenous with regard to cellular differentiation and that it preserves well the nature of the cells of origin. EBV-associated GC may undergo distinct carcinogenic processes, which differ from those of EBV-negative GC.
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Affiliation(s)
- Aya Shinozaki
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Silva EM, Begnami MD, Fregnani JHTG, Pelosof AG, Zitron C, Montagnini AL, Soares FA. Cadherin-catenin adhesion system and mucin expression: a comparison between young and older patients with gastric carcinoma. Gastric Cancer 2009; 11:149-59. [PMID: 18825309 DOI: 10.1007/s10120-008-0468-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Accepted: 05/05/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND Young patients are thought to develop gastric carcinomas with a molecular genetic profile that is distinct from that of gastric carcinomas occurring at a later age. The aim of this study was to compare the clinicopathological features and expression patterns of the markers E-cadherin and beta-catenin, and mucins (MUC1, MUC2, MUC5AC, and MUC6) in young and older patients. METHODS The clinicopathological features and overall survival data of 62 young patients (age <or=40 years) with gastric cancer were retrospectively reviewed from hospital records and compared with the data for 453 older patients (age >40 years). A tissue microarray method and immunohistochemistry were used in order to analyze marker expression in paraffin-embedded tissue blocks obtained from both groups. RESULTS The young group presented a higher percentage of diffuse-type tumors in comparison to the older group (P<0.01). The rates of positivity for E-cadherin and beta-catenin membranous expression patterns and mucin (MUC2, MUC5AC and MUC6) positivity were higher in the young group (P<0.01). Although young patients showed a lower frequency of alterations in marker expression and had significantly better survival rates than the older patients, neither age nor the marker expression pattern were found to be independent prognostic factors of survival. Only stage, tumor size, and tumor location persisted as prognostic factors for patients with gastric cancer. CONCLUSION Biological markers of cellular adhesion and gastric differentiation were differently expressed in young and older patients. Our findings support the hypothesis that young patients develop carcinomas with a different genetic pathway compared to the pathway of tumors occurring at a later age, and we suggest further investigations to assess the prognostic relevance of the markers to specific subgroups.
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Affiliation(s)
- Edaise M Silva
- Department of Anatomic Pathology, Hospital AC Camargo, Rua Antonio Prudente, 109-1o Andar, São Paulo 01509-010, Brazil
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Piazuelo MB, Haque S, Delgado A, Du JX, Rodriguez F, Correa P. Phenotypic differences between esophageal and gastric intestinal metaplasia. Mod Pathol 2008. [PMID: 14631367 DOI: 10.1038/modpathol.3800016] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Intestinal metaplasia is a cancer precursor in the esophagus and the stomach. Marked differences exist between the carcinogenic processes in the two locations in terms of natural history and clinical significance. We investigated biopsies from 52 patients with Barrett's esophagus and from 50 patients with gastric intestinal metaplasia in an attempt to throw light on their pathogenic processes. Morphologic characteristics, presence of Helicobacter pylori (H. pylori), and markers of differentiation, inflammation, and proliferation were evaluated by histochemical and immunohistochemical techniques. The area covered by incomplete type of intestinal metaplasia and the proportion of sulfomucins were significantly higher in the esophagus than in the stomach. Immunoreactivity with MUC1, MUC2, MUC5AC, Das-1, cytokeratins 7 and 20, inducible nitric oxide synthase and cyclooxygenase-2 antibodies was also significantly greater in Barrett's esophagus than in gastric intestinal metaplasia. In gastric intestinal metaplasia, the presence of MUC1, MUC5AC, Das-1 and cytokeratin 7 was restricted to areas with the incomplete type of metaplasia. Cell proliferation (Ki-67) was significantly higher in Barrett's esophagus than in gastric intestinal metaplasia. H. pylori was absent in all of the patients with Barrett's esophagus, while it was present in 70% of the patients with gastric intestinal metaplasia. Our observations made clear that Barrett's esophagus shares some phenotypic characteristics with gastric intestinal metaplasia, leading us to suggest that both could arise in response to injuries with eventual carcinogenic potential. However, the progression to more advanced lesions could be modulated by the nature of the carcinogenic insult.
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Affiliation(s)
- M Blanca Piazuelo
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
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Lee HW, Yang DH, Kim HK, Lee BH, Choi KC, Choi YH, Park YE. Expression of MUC2 in gastric carcinomas and background mucosae. J Gastroenterol Hepatol 2007; 22:1336-43. [PMID: 17559374 DOI: 10.1111/j.1440-1746.2007.04939.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Gastric carcinomas contain elements of both intestinal and diffuse types. Such heterogeneous components may distort the evaluation of the role of the mucin MUC2 in gastric carcinoma. The role of MUC2 expression in background mucosa is not yet clarified. METHODS We analyzed the expression of MUC2 in gastric mucosa and intestinal metaplasia adjacent to the tumoral area and carcinomas (n = 98) using immunohistochemistry. The immunoreactivity was quantified using an immunohistochemical scoring system. RESULTS In the intestinal metaplasia adjacent to the tumoral area, MUC2 was detected in 76 (97.4%) of 78 intestinal metaplasia, and MUC2 expression was inversely associated with the depth of wall penetration (P = 0.026) and tumor stage (P = 0.021). Although the expression rate of MUC2 antigens was higher in intestinal-type adenocarcinoma than in diffuse-type adenocarcinoma, a significant correlation with pathologic staging of the TNM system (pTNM staging) and MUC2 expression could not be found in each subtype of gastric carcinomas. CONCLUSION The expression of MUC2 in intestinal metaplasia was higher in tumors of earlier stages. These findings suggest that increased MUC2 expression in intestinal metaplasia in the neighborhood of the carcinomas may play an important role in gastric carcinomas. Further investigations regarding the role of MUC2 expression in gastric carcinoma and background mucosae are necessary.
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Affiliation(s)
- Hae-Wan Lee
- Department of Surgery, College of Medicine, Hallym University, Chunchon, Korea
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Sasaki M, Ikeda H, Nakanuma Y. Expression profiles of MUC mucins and trefoil factor family (TFF) peptides in the intrahepatic biliary system: physiological distribution and pathological significance. ACTA ACUST UNITED AC 2007; 42:61-110. [PMID: 17616258 DOI: 10.1016/j.proghi.2007.02.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mucin secreted by mucosal epithelial cells plays a role in the protection of the mucosal surface and also is involved in pathological processes. So far, MUC1-4, 5AC, 5B, 6-8, 11-13 and 15-17 genes coding the backbone mucin core protein have been identified in humans. Their diverse physiological distribution and pathological alterations have been reported. Trefoil factor family (TFF) peptides are mucin-associated molecules co-expressed with MUC mucins and involved in the maintenance of mucosal barrier and the biological behavior of epithelial and carcinoma cells. Intrahepatic biliary system is a route linking the bile canaliculi and the extrahepatic bile duct for the excretion of bile synthesized by hepatocytes. Biliary epithelial cells line in the intrahepatic biliary system, secreting mucin and other molecules involved in the maintenance and regulation of the system. In this review, the latest information regarding properties, expression profiles and regulation of MUC mucins and TFF peptides in the intrahepatic biliary system is summarized. In particular, we focus on the expression profiles and their significance of MUC mucins in developmental and normal livers, various hepatobiliary diseases and intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Takaramachi 13-1, Kanazawa 920-8640, Japan.
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Zheng H, Takahashi H, Nakajima T, Murai Y, Cui Z, Nomoto K, Tsuneyama K, Takano Y. MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays. J Cancer Res Clin Oncol 2006; 132:817-23. [PMID: 16807756 DOI: 10.1007/s00432-006-0135-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2006] [Accepted: 05/26/2006] [Indexed: 12/23/2022]
Abstract
PURPOSE MUC6 was first discovered by screening a gastric mucosa cDNA library and is expressed in the mucous cells of the neck zone and antral glands of the stomach. The aim of the present study was to clarify whether down-regulation has any clinicopathological or prognostic significance in gastric neoplasia. METHODS Expression of MUC6, MUC5AC and MUC2 was examined using tissue microarrays for immunohistochemistry in gastric carcinomas (n = 225), adenomas (n = 40), and normal mucosa (n = 89) and compared with clinicopathological parameters and survival data. RESULTS MUC6 expression was lower in gastric carcinomas than in adenomas or normal mucosa (P < 0.05) and inversely correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis and UICC staging (P < 0.05). Positive links with expression of MUC2 and MUC5AC were noted (P < 0.05). MUC6 expression was lower in diffuse-type than intestinal-type lesions (P < 0.05). Kaplan-Meier analysis indicated that cumulative survival of patients with no MUC6 expression was significantly lower than with weak, moderate or strong expression in all and even advanced gastric carcinoma (P < 0.05). Multivariate analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to concordantly affect the relationship between MUC6 expression and prognosis. CONCLUSIONS Down-regulation of MUC6 may contribute to malignant transformation of gastric epithelial cells and underlie the molecular bases of growth, invasion, metastasis and differentiation of gastric carcinoma. Altered expression might therefore be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinoma.
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Affiliation(s)
- Huachuan Zheng
- Department of Diagnostic Pathology, School of Medicine, University of Toyama, Sugitani, 2630, Toyama, Japan
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Abstract
CONTEXT Signet-ring cell carcinoma (SRCC) is a poorly differentiated mucin-producing adenocarcinoma that may arise from many different organs, but all SRCCs share identical morphology. It is not possible to differentiate sites of origin for metastatic SRCC based on morphology alone. Mucins are high-molecular-weight glycoproteins differentially expressed in glandular epithelia and in adenocarcinomas. OBJECTIVE To identify mucin profiles of primary and metastatic SRCCs using immunohistochemistry to determine whether mucin staining could help distinguish sites of origin. DESIGN Forty-seven SRCCs, including 38 primary (21 stomach, 11 colorectum, and 6 breast) and 9 metastases from these primary sites were retrieved from archival files. Consecutive tissue sections were immunostained with monoclonal antibodies against MUC1, MUC2, MUC4, MUC5AC (MUC5), and MUC6 on separate slides. Cytoplasmic staining was scored based on proportion of positive tumor cells as follows: 0+ (<5%), 1+ (5%-25%), 2+ (26%-50%), and 3+ (>50%). Mucin profiles were recorded as MUC+, MUCv, and MUC- for consistent, variable, and negative expression, respectively. RESULTS The mucin profiles for gastric, colorectum, and breast SRCCs are MUC1.2.4.5.6v, MUC2.4+/MUC5v/ MUC1.6-, and MUC1+/MUC2.5.6v/MUC4-, respectively. Mucin profiles of metastatic cases shared profiles with their respective primaries. CONCLUSIONS Signet-ring cell carcinomas of the stomach, colorectum, and breast have distinct mucin expression patterns that are maintained in metastases. Mucin profiling may be useful to identify the origin of a metastatic SRCC of unknown primary.
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Affiliation(s)
- Minh D Nguyen
- Department of Pathology, Ohio State University Medical Center, Columbus, USA
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Leteurtre E, Zerimech F, Piessen G, Wacrenier A, Leroy X, Copin MC, Mariette C, Aubert JP, Porchet N, Buisine MP. Relationships between mucinous gastric carcinoma, MUC2 expression and survival. World J Gastroenterol 2006; 12:3324-31. [PMID: 16733847 PMCID: PMC4087862 DOI: 10.3748/wjg.v12.i21.3324] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [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 expression of the four secreted gel-forming mucins (MUC2, MUC5AC, MUC5B and MUC6) in a series of gastric carcinomas, classified according Laurén’s, Mulligan’s, WHO and Goseki’s classifications, with special attention to all the different components (major and minor) present in tumors and to follow up clinical data.
METHODS: Expression of MUC2, MUC5AC, MUC5B and MUC6 was investigated using immunohistochemistry and in situ hybridization.
RESULTS: Expression of secreted gel-forming mucins in gastric carcinoma was particularly complex, each mucin being not restricted to any histopathological type even considering all components (major and minor) present in a given tumor. There was a worst survival in patients with a higher content of mucus (Goseki II or IV) and high positive MUC2 expression.
CONCLUSION: Complexity of mucin gene expression patterns in gastric cancer may reflect a precise state of differentiation at the cell level not recognized in used morphologic classification systems. High expression of MUC2 was nevertheless associated with mucinous subtype of the WHO classification and with group II of Goseki’s classification identified by the major component of a particular tumor. The quantity and quality of mucus were related to survival.
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Minematsu H, Saito Y, Kakinoki R, Andoh A, Kushima R, Fujiyama Y. Evaluation of mucin expression patterns in gastric borderline (group III) lesions. J Gastroenterol 2006; 41:547-53. [PMID: 16868802 DOI: 10.1007/s00535-006-1798-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2005] [Accepted: 02/14/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recommendations for diagnosis and treatment of gastric borderline (group III) lesions remain controversial. We examined mucin expression patterns in endoscopically resected and forceps biopsy samples. METHODS Sixty-three gastric lesions were histopathologically identified as belonging to group III on the basis of an endoscopic forceps biopsy. All of the patients underwent endoscopic resection, and the lesions were classified into group A (final diagnosis, adenocarcinoma) or group B (final diagnosis, adenoma). Immunostaining for MUC2, MUC5AC, MUC6, and CD10 was performed and the mucin phenotype determined. An additional 26 forceps biopsy samples from the above 63 patients were similarly evaluated. RESULTS The proportion of complete gastric (positive for MUC5AC and MUC6) plus gastric-predominant phenotypes was significantly higher in group A (58.0%) than in group B (18.7%) lesions (P < 0.05). The proportion of the complete intestinal (positive for MUC2 and CD10) phenotype was significantly higher in group B (68.8%) than in group A (19.4%) (P < 0.05). Similar results were also observed in the 26 forceps biopsy samples histopathologically diagnosed as group III lesions. The proportion of samples with a diffuse Ki-67 immunostaining pattern was significantly higher in group A than in group B (P < 0.05). p53 expression was significantly higher in group A (29.2%) than in group B (4.3%) (P < 0.05). CONCLUSIONS Immunostaining of forceps biopsy samples for the mucin phenotype may be helpful for diagnosing gastric borderline (group III) lesions.
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Affiliation(s)
- Hideki Minematsu
- Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan
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Wang RQ, Fang DC. Effects of Helicobacter pylori infection on mucin expression in gastric carcinoma and pericancerous tissues. J Gastroenterol Hepatol 2006; 21:425-31. [PMID: 16509869 DOI: 10.1111/j.1440-1746.2005.04006.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Helicobacter pylori infection is one of the major causes of human gastric carcinoma and can disturb the gastric mucosa barrier. Mucins have not only lubricating and protecting functions, but are also related to signal transduction, turnover of gastric epithelium and carcinogenesis of gastric mucosa. The aim of this study was to investigate the relationship between H. pylori infection and aberrant mucin expression in patients with gastric carcinoma. METHODS H. pylori infection was diagnosed by the Warthin-Starry staining method. Different kinds of mucins were detected using an immunohistochemical method. RESULTS Of 46 patients with gastric carcinoma, there were 26 patients who had H. pylori infection (56.5%). Of 21 pericancerous mucosas from the H. pylori-positive patients, 14 had MUC2 expression (66.7%), seven had strong MUC1 expression (+ + +) (33.7%), seven had strong MUC6 expression (+ + +) (33.3%), and five had strong MUC5AC expression (+ + +) (23.8%). In contrast, only six of 18 H. pylori-negative pericancerous mucosas had MUC2 expression (33.3%) (P < 0.05 compared with H. pylori-positive pericancerous mucosas), 12 had strong MUC1 expression (+ + +) in 16 H. pylori-negative pericancerous mucosas (75%) (P < 0.05), 11 had strong MUC6 expression (+ + +) in 16 H. pylori-negative pericancerous mucosas (68.8%) (P < 0.05), and 10 had strong MUC5AC expression (+ + +) in 14 H. pylori-negative pericancerous mucosas (71.4%) (P < 0.01). Of the H. pylori-positive cancerous tissues, 50% (13/26) had MUC1 expression and 38.5% (10/26) had MUC6 expression. In comparison, of the H. pylori-negative cancerous tissues, 80% (16/20) had MUC1 expression (P < 0.05) and 80% (16/20) had MUC6 expression (P < 0.01). CONCLUSIONS The results indicate that H. pylori infection can alter the expression of some mucin genes in pericancerous mucosa and cancerous tissues of gastric carcinoma, then destroy the gastric mucosa barrier.
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Affiliation(s)
- Rong-Quan Wang
- Department of Gastroenterology, Southwestern Hospital, Third Military Medical University, Chongqing, China.
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Goldstein NS, Bosler DS. Immunohistochemistry of the Gastrointestinal Tract, Pancreas, Bile Ducts, Gallbladder and Liver. DIAGNOSTIC IMMUNOHISTOCHEMISTRY 2006:442-508. [DOI: 10.1016/b978-0-443-06652-8.50019-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Kim GH, Song GA, Park DY, Lee DH, Kim TO, Lee SH, Heo J, Kang DH, Cho M. Clinicopathologic significance of gastric and intestinal phenotypic marker expression in gastric carcinomas. Korean J Intern Med 2005; 20:191-197. [PMID: 16295776 PMCID: PMC3891152 DOI: 10.3904/kjim.2005.20.3.191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2004] [Accepted: 02/22/2005] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND It is well known that both gastric and intestinal phenotypic cell markers are expressed in gastric cancers. This study was aimed at investigating the correlation between gastric and intestinal phenotypic marker expression patterns of tumors and the clinicopathologic characteristics of gastric carcinomas. METHODS We evaluated phenotypic marker expression by immunohistochemical staining with monoclonal antibodies. All tumors were classified as gastric (G), gastric and intestinal mixed (GI), intestinal (I), or null (N) phenotype. RESULTS The tumors were phenotypically divided into G-phenotype tumors (33.2%), GI-phenotype tumors (25.7%), I-phenotype tumors (26.8%), and N-phenotype tumors (14.3%). N-phenotype tumors were associated with more corporeal location than GI- and I-phenotype tumors (o=0.009 and p=0.007, respectively), a larger size than I-phenotype tumors (0=0.007), a higher proportion of advanced gastric cancers than G-, GI-, and I-phenotype tumors (0=0.003, p<0.001, and p<0.001, respectively), more perineural invasion than G-, GI-, and I-phenotype tumors (p=0.076, p=0.003, and p=0.003, respectively), and more lymph node metastasis than GI-phenotype tumors (p=0.017). I-phenotype tumors were associated with a higher proportion of intestinal-type tumors than G-, GI-, and N-phenotype tumors (p<0.001, p=0.011, and p<0.001, respectively). CONCLUSION Our results indicate that the gastric and intestinal phenotypic marker expression pattern of tumors is prognostically useful for patients with gastric carcinoma.
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Affiliation(s)
- Gwang Ha Kim
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Geun Am Song
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Do Youn Park
- Department of Pathology, Pusan National University College of Medicine, Busan, Korea
| | - Dong Hyun Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Tae Oh Kim
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Seong Hun Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Jeong Heo
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Dae Hwan Kang
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Mong Cho
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
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