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Yu J, Meng Z, Liu X, Zheng Y, Xue D, Hao C, Wang L. Lipopolysaccharide in Bile Promotes the Neutrophil Extracellular Traps-Induced Gallstone Formation by Activating the Gallbladder Immune Barrier. Immunotargets Ther 2024; 13:789-803. [PMID: 39712952 PMCID: PMC11662912 DOI: 10.2147/itt.s495095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 12/03/2024] [Indexed: 12/24/2024] Open
Abstract
Background Cholelithiasis areis a common digestive system disorder, with cholesterol gallstones being the most prevalent type. Gallstones lead to many severe complications, posing a significant burden on global healthcare systems. Many studies have shown associations between biliary microbiota, gallbladder immune microenvironment, and gallstone formation. However, the specific immune mechanisms underlying the cholesterol gallstone formation have not been fully elucidated. Methods In this study, gallbladderand bile samples from 8 asymptomatic patients with cholelithiasis undergoing cholecystectomy and 11 healthy liver transplant donors were collected for tissue transcriptome sequencing and differential analysis. Male C57BL/6J mice were fed a normal or lithogenic diet for 6 weeks. Starting from the third week, lipopolysaccharide (LPS) or specific regulators were injected intraperitoneally once a week for a total of 3 times. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence were employed for quantitative, qualitative or localization analysis of LPS, neutrophil extracellular traps (NETs), inflammatory factors, proteins, and mRNAs using samples collected from mice. Results In patients with cholelithiasis, the gallbladder mechanical barrier is impaired, resulting in an immune-activated state. LPS induces damage to the gallbladder mucosal mechanical barrier through the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, it stimulates the continuous production of NETs through the TLR4/Phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, aggravating the formation of gallstones. Conclusion With the biliary dysbiosis, excessive LPS can invade the submucosa of the gallbladder, leading to chronic inflammation that recruits neutrophils to form NETs, which are ultimately expelled into bile, thereby promoting the formation of gallstones.
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Affiliation(s)
- Jingjing Yu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Ziang Meng
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Xuxu Liu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Yi Zheng
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Chenjun Hao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Liyi Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’ s Republic of China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
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Erickson A, Jackson LR, Camphausen K, Krauze AV. Mucins as Precision Biomarkers in Glioma: Emerging Evidence for Their Potential in Biospecimen Analysis and Outcome Prediction. Biomedicines 2024; 12:2806. [PMID: 39767713 PMCID: PMC11673638 DOI: 10.3390/biomedicines12122806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/06/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Despite attempts at improving survival by employing novel therapies, progression in glioma is nearly universal. Precision biomarkers are critical to advancing outcomes; however, biomarkers for glioma are currently unknown. Most data on which the field can draw for biomarker identification comprise tissue-based analysis requiring the biospecimen to be removed from the tumor. Non-invasive specimen-based precision biomarkers are needed. Mucins are captured in tissue and blood and are increasingly studied in cancer, with several studies exploring their role as biomarkers to detect disease and monitor disease progression. CA125, also known as MUC16, is implemented as a biomarker in the clinic for ovarian cancer. Similarly, several mucins are membrane-bound, facilitating downstream signaling associated with tumor resistance and hallmarks of cancer. Evidence supports mucin expression in glioma cells with relationships to tumor detection, progression, resistance, and patient outcomes. The differential expression of mucins across tissues and organs could also provide a means of attributing signals measured in serum or plasma. In this review, we compiled existing research on mucins as candidate precision biomarkers in glioma, focusing on promising mucins in relationship to glioma and leading to a framework for mucin analysis in biospecimens as well as avenues for validation as data evolve.
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Han F, Xu Y, Li X, Song Z, Xie J, Yao J. Clinicopathological features and prognosis analysis of proximal colonic mucinous adenocarcinoma. Sci Rep 2024; 14:18682. [PMID: 39134655 PMCID: PMC11319726 DOI: 10.1038/s41598-024-69916-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 08/09/2024] [Indexed: 08/15/2024] Open
Abstract
Mucinous adenocarcinoma (MAC) is a distinct subtype of colorectal cancer. Previous studies have confirmed the poor prognosis of rectal or left-sided colon MAC, while the prognosis and response to chemotherapy in proximal colon MAC remains controversial. The aim of this study was to investigate the clinicopathological characteristics, prognosis, response to chemotherapy, and risk prediction factors of proximal colon MAC. Patients with proximal colon MAC and non-mucinous adenocarcinoma (NMAC) were retrospectively analyzed in this study. The analyzed variables included gender, age, smoking, drinking, chemotherapy, metastasis, pathological stage, and tumor size. Overall survival (OS) was the primary outcome. Kaplan-Meier analysis was used to assess the impact of mucinous subtype and chemotherapy on OS. We conducted univariate and multivariate Cox regression analyses to determine prognosis factors for proximal colon MAC and NMAC. A total of 284 cases of proximal colon MAC and 1384 cases of NMAC were included in the study. Compared to NMAC, proximal colon MAC was diagnosed at a younger age. The proportion of synchronous and metachronous metastasis was also higher, as well as the pathological stage and tumor size. Proximal colon MAC had a worse prognosis than NMAC, especially in stage 3. Moreover, the prognosis of proximal colon NMAC improved after chemotherapy, while MAC showed no improvement in prognosis after chemotherapy. Advanced age, N1 and N2 stage were independent prognostic factors for adverse outcomes in MAC. For proximal colon adenocarcinoma, the independent predictors of adverse outcomes included mucinous subtype, order age, N1 and N2 stages, and pathological stage 4. Proximal colon MAC had a worse prognosis compared to NMAC. Chemotherapy did not improve the prognosis of proximal colon mucinous adenocarcinoma.
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Affiliation(s)
- Fei Han
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Yue Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangyu Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Zhaoxiang Song
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jinlin Xie
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jianning Yao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China.
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Laskou A, Znalesniak EB, Harder S, Schlüter H, Jechorek D, Langer K, Strecker C, Matthes C, Tchaikovski SN, Hoffmann W. Different Forms of TFF3 in the Human Endocervix, including a Complex with IgG Fc Binding Protein (FCGBP), and Further Aspects of the Cervico-Vaginal Innate Immune Barrier. Int J Mol Sci 2024; 25:2287. [PMID: 38396964 PMCID: PMC10888570 DOI: 10.3390/ijms25042287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
TFF3 is a typical secretory poplypeptide of mucous epithelia belonging to the trefoil factor family (TFF) of lectins. In the intestine, respiratory tract, and saliva, TFF3 mainly exists as a high-molecular-mass complex with IgG Fc binding protein (FCGBP), which is indicative of a role in mucosal innate immunity. For the first time, we identified different forms of TFF3 in the endocervix, i.e., monomeric and homodimeric TFF3, as well as a high-molecular-mass TFF3-FCGBP complex; the latter also exists in a hardly soluble form. Immunohistochemistry co-localized TFF3 and FCGBP. Expression analyses of endocervical and post-menopausal vaginal specimens revealed a lack of mucin and TFF3 transcripts in the vaginal specimens. In contrast, genes encoding other typical components of the innate immune defense were expressed in both the endocervix and vagina. Of note, FCGBP is possibly fucosylated. Endocervical specimens from transgender individuals after hormonal therapy showed diminished expression, particularly of FCGBP. Furthermore, mucus swabs from the endocervix and vagina were analyzed concerning TFF3, FCGBP, and lysozyme. It was the aim of this study to illuminate several aspects of the cervico-vaginal innate immune barrier, which is clinically relevant as bacterial and viral infections are also linked to infertility, pre-term birth and cervical cancer.
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Affiliation(s)
- Aikaterini Laskou
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Eva B. Znalesniak
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Sönke Harder
- Section Mass Spectrometric Proteomics, Diagnostic Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Hartmut Schlüter
- Section Mass Spectrometric Proteomics, Diagnostic Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Dörthe Jechorek
- Institute of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Kathrin Langer
- Institute of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Carina Strecker
- Department of Gynecology and Obstetrics, Otto-von-Guericke University Magdeburg, Gerhart-Hauptmann-Str. 35, 39108 Magdeburg, Germany
| | - Claudia Matthes
- Department of Gynecology and Obstetrics, Otto-von-Guericke University Magdeburg, Gerhart-Hauptmann-Str. 35, 39108 Magdeburg, Germany
| | - Svetlana N. Tchaikovski
- Department of Gynecology and Obstetrics, Otto-von-Guericke University Magdeburg, Gerhart-Hauptmann-Str. 35, 39108 Magdeburg, Germany
| | - Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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Kumar Murmu A, Pal A, Debnath M, Chakraborty A, Pal S, Banerjee S, Pal A, Ghosh N, Karmakar U, Samanta R. Role of mucin 2 gene for growth in Anas platyrhynchos: a novel report. Front Vet Sci 2023; 10:1089451. [PMID: 38026626 PMCID: PMC10666069 DOI: 10.3389/fvets.2023.1089451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 07/17/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction The mucin gene is expressed in the mucous membrane of the inner layer of the internal organs. Intestinalmucin 2 (MUC2), amajor gel-formingmucin, represents a primary barrier component of mucus layers. Materials and methods This is the first report on the role of mucin genes in growth traits in animals. In this study, we randomly studied Bengal ducks (Anas platyrhynchos) reared from day old to 10 weeks of age under an organized farm and studied the growth parameters as well as body weight and average daily body weight gain. Result and discussion We characterized the mucin gene for Bengal ducks and observed glycosylation and EGF1 (EGF-like domain signature) as important domains for growth traits in ducks. We observed a better expression profile for the mucin gene in high-growing ducks in comparison to that of low-growing ducks with real-time PCR. Hence, the mucin gene may be employed as a marker for growth traits.
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Affiliation(s)
- Anuj Kumar Murmu
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Aruna Pal
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Manti Debnath
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Argha Chakraborty
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Subhamoy Pal
- Department of Animal Science, Visva-Bharati University, Santiniketan, West Bengal, India
| | - Samiddha Banerjee
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Abantika Pal
- Department of Computer Science, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
- University of California, San Francisco, San Francisco, CA, United States
| | - Nilotpal Ghosh
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Utpal Karmakar
- Department of Animal Resource Development, Government of West Bengal, Kolkata, India
| | - Rajarshi Samanta
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
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Saraswathula A, Liu MM, Kulaga H, Lane AP. Chronic interleukin-13 expression in mouse olfactory mucosa results in regional aneuronal epithelium. Int Forum Allergy Rhinol 2023; 13:230-241. [PMID: 35950767 PMCID: PMC9918612 DOI: 10.1002/alr.23073] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/22/2022] [Accepted: 08/08/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Olfactory dysfunction is highly associated with chronic rhinosinusitis with nasal polyps (CRSwNP), and the severity of loss has been linked with biomarkers of type 2 inflammation. The ability of dupilumab to rapidly improve the sense of smell prior to improvement in polyp size suggests a direct role of IL-4/IL-13 receptor signaling in the olfactory epithelium (OE). METHODS We created a transgenic mouse model in which IL-13 is inducibly expressed specifically within the OE. Gene expression analysis and immunohistology were utilized to characterize the effect of IL-13 on the structure of the OE. RESULTS After induction of olfactory IL-13 expression, there is a time-dependent loss of neurons from OE regions, accompanied by a modest inflammatory infiltrate. Horizontal basal cells undergo morphologic changes consistent with activation and demonstrate proliferation. Mucus production and increased expression of eotaxins is observed, with marked expression of Ym2 by sustentacular cells. DISCUSSION Chronic IL-13 exposure has several effects on the OE that are likely to affect function. The neuronal loss is in keeping with other models of allergic type 2 nasal inflammation. Future studies are needed to correlate cellular and molecular alterations in olfactory cell populations with findings in human CRSwNP, as well as to assess olfactory function in behavioral model systems.
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Affiliation(s)
- Anirudh Saraswathula
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Melissa M Liu
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Heather Kulaga
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Dhanisha SS, Guruvayoorappan C. Pathological Implications of Mucin Signaling in Metastasis. Curr Cancer Drug Targets 2023; 23:585-602. [PMID: 36941808 DOI: 10.2174/1568009623666230320121332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 01/11/2023] [Accepted: 01/25/2023] [Indexed: 03/23/2023]
Abstract
The dynamic mucosal layer provides a selective protective barrier for the epithelial cells lining the body cavities. Diverse human malignancies exploit their intrinsic role to protect and repair epithelia for promoting growth and survival. Aberrant expression of mucin has been known to be associated with poor prognosis of many cancers. However, the emergence of new paradigms in the study of metastasis recognizes the involvement of MUC1, MUC4, MUC5AC, MUC5B, and MUC16 during metastasis initiation and progression. Hence mucins can be used as an attractive target in future diagnostic and therapeutic strategies. In this review, we discuss in detail about mucin family and its domains and the role of different mucins in regulating cancer progression and metastasis. In addition, we briefly discuss insights into mucins as a therapeutic agent.
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Affiliation(s)
| | - Chandrasekharan Guruvayoorappan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
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Kufe DW. Emergence of MUC1 in Mammals for Adaptation of Barrier Epithelia. Cancers (Basel) 2022; 14:cancers14194805. [PMID: 36230728 PMCID: PMC9564314 DOI: 10.3390/cancers14194805] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
The mucin 1 (MUC1) gene was discovered based on its overexpression in human breast cancers. Subsequent work demonstrated that MUC1 is aberrantly expressed in cancers originating from other diverse organs, including skin and immune cells. These findings supported a role for MUC1 in the adaptation of barrier tissues to infection and environmental stress. Of fundamental importance for this evolutionary adaptation was inclusion of a SEA domain, which catalyzes autoproteolysis of the MUC1 protein and formation of a non-covalent heterodimeric complex. The resulting MUC1 heterodimer is poised at the apical cell membrane to respond to loss of homeostasis. Disruption of the complex releases the MUC1 N-terminal (MUC1-N) subunit into a protective mucous gel. Conversely, the transmembrane C-terminal (MUC1-C) subunit activates a program of lineage plasticity, epigenetic reprogramming and repair. This MUC1-C-activated program apparently evolved for barrier tissues to mount self-regulating proliferative, inflammatory and remodeling responses associated with wound healing. Emerging evidence indicates that MUC1-C underpins inflammatory adaptation of tissue stem cells and immune cells in the barrier niche. This review focuses on how prolonged activation of MUC1-C by chronic inflammation in these niches promotes the cancer stem cell (CSC) state by establishing auto-inductive nodes that drive self-renewal and tumorigenicity.
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Affiliation(s)
- Donald W Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, D830, Boston, MA 02215, USA
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Yan X, Cheng Y, Zhang X, Hu Y, Huang H, Ren J, Wen B, Yang Y, Xiao K, Hu W, Wang W. NICD3 regulates the expression of MUC5AC and MUC2 by recruiting SMARCA4 and is involved in the differentiation of mucinous colorectal adenocarcinoma. Mol Oncol 2022; 16:3509-3532. [PMID: 35900231 PMCID: PMC9533685 DOI: 10.1002/1878-0261.13296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/08/2022] [Accepted: 07/27/2022] [Indexed: 12/24/2022] Open
Abstract
Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA‐sequencing results indicated a common targeting effect on the transcriptional activity of mucin‐5AC (MUC5AC) and mucin‐2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4‐dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.
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Affiliation(s)
- Xiaodong Yan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.,Department of Gastrointestinal Surgery, Changzhi People's Hospital, The Affiliated Hospital of Shanxi Medical University, Changzhi, Shanxi Province, 046000, China
| | - Yuan Cheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Xia Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yi Hu
- Fuxing Hospital, Capital Medical University, Beijing, 100038, China
| | - Haixia Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Jie Ren
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Boye Wen
- School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yuhui Yang
- School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Keyuan Xiao
- Central laboratory, Changzhi People's Hospital, The Affiliated Hospital of Shanxi Medical University, Changzhi, Shanxi Province, 046000, China
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People's Hospital, The Affiliated Hospital of Shanxi Medical University, Changzhi, Shanxi Province, 046000, China
| | - Wei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.,Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, 100069, China
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Novel Perspectives in Pseudomyxoma Peritonei Treatment. Cancers (Basel) 2021; 13:cancers13235965. [PMID: 34885075 PMCID: PMC8656832 DOI: 10.3390/cancers13235965] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/11/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Pseudomyxoma Peritonei (PMP) represents a rare entity which greatly benefits from Cytoreductive Surgery (CRS) associated with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). In fact, CRS-HIPEC represents the treatment with potential chances of cure and long-term disease control of patients affected by PMP. This therapeutic strategy should be performed in referral centers, where a consolidated know-how of this locoregional treatment and a multidisciplinary approach are available. CRS-HIPEC provides excellent results for PMP patients in terms of postoperative outcome, overall and disease-free survival, and quality of life. However, in patients with an extensive or recurrent disease, few therapeutic opportunities are available. This review is focused on the most recent clinical evidence and provides a better understanding of the molecular prognostic factors and potential therapeutic targets in this rare malignancy. Abstract Pseudomyxoma Peritonei (PMP) is an anatomo-clinical condition characterized by the implantation of neoplastic cells on peritoneal surfaces with the production of a large amount of mucin. The rarity of the disease precludes the evaluation of treatment strategies within randomized controlled trials. Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has proven to be the only therapeutic option with potential chances of cure and long-term disease control. The present review discusses the epidemiology, pathogenesis, clinical presentation and treatment of PMP, focusing on the molecular factors involved in tumor progression and mucin production that could be used, in the upcoming future, to improve patient selection for surgery and to expand the therapeutic armamentarium.
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Shi D, Xi XX. Regulation of MUC6 Methylation Correlates with Progression of Gastric Cancer. Yonsei Med J 2021; 62:1005-1015. [PMID: 34672134 PMCID: PMC8542475 DOI: 10.3349/ymj.2021.62.11.1005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 07/04/2021] [Accepted: 07/23/2021] [Indexed: 12/27/2022] Open
Abstract
PURPOSE This study aimed to investigate the mechanistic downregulation of mucin 6 (MUC6) and its influence on the progression of gastric cancer (GC). MATERIALS AND METHODS The expression of MUC6 was examined in 40 GC patients. The methylation status of the MUC6 promoter region was investigated using GC cell lines and GC tissue specimens by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR). MUC6 was knocked down in the gastric epithelial cells (GES-1) cell and overexpressed in the SGC7901 cell. The effects of MUC6 knockdown and overexpression on cell migration and invasion were examined using Transwell assays. The effects of demethylation and methylation on MUC6 expression were examined by western blot, qPCR, or double luciferase reporter assays. RESULTS The expression of MUC6 in GC with lymph node metastasis and poor pathological stage was significantly lower than that in GC without lymph node metastasis and good pathological stage, respectively. While cell migration and invasion were significantly decreased after overexpression of MUC6, these abilities significantly increased after the knockdown of MUC6. The methylation levels of MUC6 in GC tissues and GC cell lines were significantly higher than those in para-cancerous tissues and normal GES. Promoter methylation could significantly reduce the binding of related transcription factors to the MUC6 promoter. The expression of MUC6 increased with the concentration and time of action of demethylation drugs. CONCLUSION Expression of MUC6 was regulated by promotor methylation. This methylation of the MUC6 promoter may lead to significant downregulation of MUC6 in GC and promote the progression of GC.
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Affiliation(s)
- Ding Shi
- Department of Gastroenterology, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Xiao-Xia Xi
- Department of Gastroenterology, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
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12
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Koseki Y, Kamimura K, Tanaka Y, Ohkoshi-Yamada M, Zhou Q, Matsumoto Y, Mizusawa T, Sato H, Sakamaki A, Umezu H, Yokoyama J, Terai S. Rapid progression of colonic mucinous adenocarcinoma with immunosuppressive condition: A case report and review of literature. World J Clin Cases 2021; 9:9182-9191. [PMID: 34786403 PMCID: PMC8567511 DOI: 10.12998/wjcc.v9.i30.9182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/29/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal mucinous adenocarcinoma is a rare subtype of colorectal cancer and is characterized by an abundance of mucin in the tumor. In addition, the colorectal mucinous adenocarcinoma often demonstrates poor differentiation in the histology of tumor cells and poor prognosis compared with those with adenocarcinoma. Here, we present the case of a young woman with colonic mucinous adenocarcinoma showing significantly rapid progression within four months of immunosuppressant therapy for Henoch-Schönlein purpura. CASE SUMMARY Here we report a rare case of ascending colon mucinous adenocarcinoma with lymph node and liver metastases which developed and progressed rapidly within four months during the treatment of Henoch-Schönlein purpura using corticosteroids. The systemic screening examinations showed no tumors before the immunosuppressant therapy. Fortunately, the patient was successfully treated with chemotherapy. CONCLUSION While no direct evidence that the immunosuppressants accelerated the tumor development, the case presenta tion and review of the literature demonstrated that surveillance for malignancies before and during treatment with immunosuppressive agents is essential.
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Affiliation(s)
- Youhei Koseki
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
- Department of General Medicine, Niigata University, Niigata 9518510, Japan
| | - Yuto Tanaka
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Marina Ohkoshi-Yamada
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Qiliang Zhou
- Department of Medical Oncology, Niigata University, Niigata 9518510, Japan
| | | | - Takeshi Mizusawa
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Hiroki Sato
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Hajime Umezu
- Division of Pathology, Niigata University, Niigata 9518510, Japan
| | - Junji Yokoyama
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University, Niigata 9518510, Japan
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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: 25] [Impact Index Per Article: 6.3] [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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14
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Characterization of the regulatory 5'-flanking region of bovine mucin 2 (MUC2) gene. Mol Cell Biochem 2021; 476:2847-2856. [PMID: 33730299 DOI: 10.1007/s11010-021-04133-1] [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: 09/02/2020] [Accepted: 03/06/2021] [Indexed: 10/21/2022]
Abstract
Throughout the intestinal epithelium surface there is an intricate polymer network composed by gel-forming mucins, which plays a protective role due to the formation of a physical, chemical and immunological barrier between the organism and the environment. Mucin 2 (MUC2) is the main mucin in the small and large intestine, and it is expressed specifically in the gastrointestinal tract (GIT), which makes its promoter region an important candidate for expression of heterologous genes of biotechnological interest in the GIT of bovine and other ruminants. In order to characterize the bovine MUC2 promoter we designed primers to amplify and isolate a candidate region for this promoter. The amplified sequence was confirmed by sequencing and cloned into a plasmid vector containing the luciferase (LUC) reporter gene. The regulatory sites of the MUC2 promoter already described in the literature were used to find the putative regulatory sites in the bovine MUC2 promoter region. With these data, some deletions were performed in order to find the promoter sequence with greatest expression capacity and specificity. The constructions were tested by transient transfection assays in LoVo cells (human colorectal adenocarcinoma) and bovine fibroblasts. The quantification of the relative expression of the promoter was measured using dual-luciferase assays. Real-time PCR was performed to analyze the expression of endogenous MUC2. The results presented herein prove that the isolated sequence corresponds to the promoter of bovine MUC2 gene, since it was able to induce expression of a reporter gene in an in vitro cell culture experimental platform.
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15
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Yu F, Huang L, Shen F, Wu S, Chen J. Prognostic implications of mucinous histology in stage III colon cancer with the receipt of adjuvant chemotherapy. J Gastrointest Oncol 2020; 11:858-869. [PMID: 33209482 DOI: 10.21037/jgo-20-160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background There is still a debate about the survival benefit of chemotherapy in stage III mucinous colon cancer, we then conduct a comprehensive assessment of the efficacy of adjuvant chemotherapy in this population. Methods The data used in the current study were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Chi-squared (χ2) test was used to compared patient characteristics according to the histology. The outcome of the survival analysis used in the current study was cancer-specific survival (CSS). Univariable and multivariable analyses were carried out using the Cox proportional hazards regression models to evaluate the prognostic characteristics associated with CSS of colon cancer. And the risks of mortality were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Results A total of 68,976 patients diagnosed with stage III colon cancer were included in our analyses, including mucinous adenocarcinoma (MAC, N=6,592) and non-mucinous adenocarcinoma (NMA, N=62,384). In NMA, the receipt of chemotherapy had 46.0% independently decreased risk of colon cancer-specific mortality compared to non-chemotherapy group (HR =0.540, 95% CI: 0.523-0.558, P<0.001). In MAC, the receipt of chemotherapy had 37.7% independently decreased risk of colon cancer-specific mortality compared to non-chemotherapy group (HR =0.623, 95% CI: 0.566-0.685, P<0.001). Conclusions MAC was associated with worse prognosis and was less responsive to chemotherapy compared with NMA in stage III colon cancer. However, stage III mucinous colon cancer still need to be treated with chemotherapy because of the significant survival benefit and specialized treatment plans for MAC were quite necessary in the future.
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Affiliation(s)
- Feng Yu
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Luqiao Huang
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Feng Shen
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shuang Wu
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Jian Chen
- Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
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16
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Kennel C, Gould EA, Larson ED, Salcedo E, Vickery T, Restrepo D, Ramakrishnan VR. Differential Expression of Mucins in Murine Olfactory Versus Respiratory Epithelium. Chem Senses 2020; 44:511-521. [PMID: 31300812 DOI: 10.1093/chemse/bjz046] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mucins are a key component of the surface mucus overlying airway epithelium. Given the different functions of the olfactory and respiratory epithelia, we hypothesized that mucins would be differentially expressed between these 2 areas. Secondarily, we evaluated for potential changes in mucin expression with radiation exposure, given the clinical observations of nasal dryness, altered mucus rheology, and smell loss in radiated patients. Immunofluorescence staining was performed to evaluate expression of mucins 1, 2, 5AC, and 5B in nasal respiratory and olfactory epithelia of control mice and 1 week after exposure to 8 Gy of radiation. Mucins 1, 5AC, and 5B exhibited differential expression patterns between olfactory and respiratory epithelium (RE) while mucin 2 showed no difference. In the olfactory epithelium (OE), mucin 1 was located in a lattice-like pattern around gaps corresponding to dendritic knobs of olfactory sensory neurons, whereas in RE it was intermittently expressed by surface goblet cells. Mucin 5AC was expressed by subepithelial glands in both epithelial types but to a higher degree in the OE. Mucin 5B was expressed by submucosal glands in OE and by surface epithelial cells in RE. At 1-week after exposure to single-dose 8 Gy of radiation, no qualitative effects were seen on mucin expression. Our findings demonstrate that murine OE and RE express mucins differently, and characteristic patterns of mucins 1, 5AC, and 5B can be used to define the underlying epithelium. Radiation (8 Gy) does not appear to affect mucin expression at 1 week. LEVEL OF EVIDENCE N/A (Basic Science Research).IACUC-approved study [Protocol 200065].
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Affiliation(s)
- Christopher Kennel
- Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Elizabeth A Gould
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA.,Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine, Aurora, CO, USA.,Neuroscience Program, University of Colorado School of Medicine, Aurora, CO, USA
| | - Eric D Larson
- Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ernesto Salcedo
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Thad Vickery
- Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Diego Restrepo
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO, USA.,Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine, Aurora, CO, USA.,Neuroscience Program, University of Colorado School of Medicine, Aurora, CO, USA
| | - Vijay R Ramakrishnan
- Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA.,Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine, Aurora, CO, USA.,Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
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17
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An LCM-based genomic analysis of SPEM, Gastric Cancer and Pyloric Gland Adenoma in an Asian cohort. Mod Pathol 2020; 33:2075-2086. [PMID: 32269290 DOI: 10.1038/s41379-020-0520-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/01/2020] [Accepted: 03/02/2020] [Indexed: 12/26/2022]
Abstract
Spasmolytic polypeptide-expressing metaplasia (SPEM) and pyloric gland adenoma (PGA) in the stomach are metaplastic and neoplastic lesions, respectively, in which gastric body glands are replaced by pyloric glands. The aim of this study was to evaluate the genomic profile of SPEM and compare it with intestinal-type gastric cancer (GC) and PGA. Thirteen gastrectomies showing PGA with or without dysplasia, GC and SPEM were retrospectively selected. MUC5AC, MUC6, gastrin, and TFF2 IHC were performed. Lesions were subjected to laser capture microdissection followed by DNA extraction. Forty-three DNA samples were extracted from PGA without cytological dysplasia, PGA with low-grade and high-grade dysplasia and pyloric gland adenocarcinoma, GC, SPEM, and adjacent normal tissue from the body of the stomach and were subjected to exome sequencing for 49 genes that are commonly dysregulated in GC. Sanger sequencing was performed for confirmation. Twenty nonsynonymous mutations were identified in SPEM, and none of these were frameshifts or indels. PGA with or without cytological dysplasia showed a significantly higher number of mutations compared with SPEM. As cytological dysplasia increased from no dysplasia to dysplasia in PGA, the percentage of frameshift mutations, indels, and missense variations increased. Further missense or frameshift mutations were observed in the KRAS, APC, TP53, and CTNNB1 genes in the PGA group. In GC, mutations were observed in the TP53 gene (p.Arg248Gln). Missense mutations in the MUC5AC, KRAS, BRAF, and EZH2 genes were common between SPEM and GC. SPEM showed fewer genomic variations than GC and PGA, and was genomically distinct from the pyloric epithelium in PGA. Stepwise progression of PGA from PGA without dysplasia to PGA with dysplasia/adenocarcinoma was associated an increase in mutations. SPEM appears to be more genomically similar to GC than PGA.
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18
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Gan GL, Liu J, Chen WJ, Ye QQ, Xu Y, Wu HT, Li W. The Diverse Roles of the Mucin Gene Cluster Located on Chromosome 11p15.5 in Colorectal Cancer. Front Cell Dev Biol 2020; 8:514. [PMID: 32695780 PMCID: PMC7338833 DOI: 10.3389/fcell.2020.00514] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/28/2020] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC), the third most common malignant tumor in the world, shows multiple complex and pathologies based on the impaired structure and function of the intestinal mucosal barrier. Goblet cells secrete mucins, which are involved in the formation of the intestinal mucosal barrier and not only lubricate and protect the intestinal mucosa but also participate in the processes of cell adhesion, intercellular signal transduction, and immune regulation. It is accepted that the disordered expression and dysfunction of mucins are associated with the occurrence and development of CRC. This article focuses on the secretory mucins encoded by a gene cluster located on chromosome 11p15.5 and systematically reviews their composition, regulation, function, and role in CRC, to deepen the understanding of the pathogeneses of CRC and to provide a new basis and ideas for the treatment of CRC.
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Affiliation(s)
- Guo-Lian Gan
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Jing Liu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Wen-Jia Chen
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Qian-Qian Ye
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Ya Xu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wei Li
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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19
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Wang Y, Li L, Yang Y, Feng J, Wang L, Zhang H. Copy Number Variation in MUC5AC and Susceptibility to Allergic Rhinitis: A Low-Coverage Whole-Genome Sequencing and Validation Cohort Study. Genet Test Mol Biomarkers 2020; 24:173-180. [PMID: 32208937 DOI: 10.1089/gtmb.2019.0166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: The contribution of genetic copy number variations (CNVs) to allergic rhinitis (AR) remains unknown. The aim of this study was to identify genetic CNVs related to AR in the Han Chinese population. Methods: A case/parent trio of patients of Han Chinese descent affected with AR was examined using low-coverage whole-genome sequencing. Select CNVs were also explored for AR association in a validation cohort of 696 diagnosed AR patients and 528 matched controls. AccuCopy™, a multiplex fluorescence competitive polymerase chain reaction (PCR) assay, was used for genotyping of the CNV and was further validated with real-time PCR. Results: In the case/parent trio study, 67 CNVs were found in the Database of Genomic Variants and shared by patients within the family; 7 of these CNVs had a frequency higher than 0.05. A duplication at 11P15.5 was found involving three mucin-encoding genes (MUC2, MUC5AC, and MUC5B) previously identified as candidate genes for asthma and other chronic inflammatory upper airway diseases. In the validation cohort, no CNVs for MUC2 or MUC5B were identified. However, in the case group, 36.21% of individuals had a duplication of MUC5AC, and 28.03% of controls had MUC5AC duplication (χ2 = 9.123; p = 0.0025). The association of MUC5AC copy number with AR was significant in a multivariable logistic regression analysis after adjusting for age and sex (Padj = 0.0010; OR = 2.073; 95% CI, 1.625-2.805). Real-time PCR validation confirmed duplication of MUC5AC, and the CNV genotype detected with the AccuCopy assay was validated for 58 (96.67%) individuals. Furthermore, individuals with a high MUC5AC copy number showed enhanced total blood eosinophil counts in both the total sample group and the case group (Spearman's ρ: 0.162, p < 0.001; Spearman's ρ: 0.240, p < 0.001). Conclusions: MUC5AC copy number is associated with AR susceptibility. Additional validation and functional studies are warranted to elucidate the effect of MUC5AC CNV on gene expression and AR risk.
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Affiliation(s)
- Yan Wang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Linge Li
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yuping Yang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Juan Feng
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Lingling Wang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua Zhang
- Department of Otolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Abstract
Dysregulation of gel-forming mucins is associated with many airway diseases. Better knowledge of the pathophysiological mechanisms linking mucins and respiratory diseases will advance the understanding of their pathogenesis and should provide opportunities to develop new therapeutic compounds for treatment. MUC5B and MUC5AC are the two main gel-forming mucins in the respiratory tract. The organization in domains and the expression profile of mouse Muc5b are very similar to those in humans, which makes the mouse a relevant model for studies of the translational activities of human mucins. To assess the in vivo biological functions of Muc5b, a mouse reporter tagged in frame with the green fluorescent protein marker has been engineered by homologous recombination. The proof of concept that this reporter model may be informative for translational studies was confirmed by the finding that interleukin-13 administration in living mice upregulated Muc5b production.
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Abstract
This review describes the organization and importance of mucus in the intestine and lungs in relation to the diseases cystic fibrosis (CF), ulcerative colitis and chronic obstructive pulmonary disease (COPD). The inner surfaces of the body are protected by mucus built around polymeric glycoproteins called mucins. In the disease CF, the small intestinal mucus is in contrast the normal attached to the epithelium, explaining the intestinal problems at this disease. The inner of the two mucus layers of colon is normally impenetrable to bacteria, keeping the commensals away from and protecting the epithelium. This impenetrable property is dependent on the bacterial composition and the host diet, observations that can explain the increased incidence of inflammatory bowel diseases in the western world as bacteria reach the epithelial cells in active ulcerative colitis. The respiratory tract is normally cleared by thick mucus bundles that moved by the cilia sweep the epithelial surface. In CF, the bundles are nonmoving already at birth. Cholinergic stimulations stop the bundle movement explaining some of the beneficial effect of anticholinergic treatment in COPD. In this disease as well as in more developed CF, an attached mucus layer is formed. This mucus has features similar to the protective inner colon mucus and is by this able to separate bacteria from the epithelial surface. When formed in healthy individuals this mucus can be coughed up, but in chronically diseased lungs, bacteria colonizing the mucus will remain in the lungs and the resulting inflammation contribute to the destruction of the lungs.
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Affiliation(s)
- G. C. Hansson
- Department of Medical BiochemistryUniversity of GothenburgGothenburgSweden
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22
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Luo C, Cen S, Ding G, Wu W. Mucinous colorectal adenocarcinoma: clinical pathology and treatment options. Cancer Commun (Lond) 2019; 39:13. [PMID: 30922401 PMCID: PMC6440160 DOI: 10.1186/s40880-019-0361-0] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 03/21/2019] [Indexed: 02/07/2023] Open
Abstract
Mucinous colorectal adenocarcinoma is a distinct subtype of colorectal cancer (CRC) characterized by the presence of abundant extracellular mucin which accounts for at least 50% of the tumor volume. Mucinous colorectal adenocarcinoma is found in 10%–20% of CRC patients and occurs more commonly in female and younger patients. Moreover, mucinous colorectal adenocarcinoma is more frequently located in the proximal colon and diagnosed at an advanced stage. Based on its molecular context, mucinous colorectal adenocarcinoma is associated with the overexpression of mucin 2 (MUC2) and mucin 5AC (MUC5AC) proteins. At the same time, it shows higher mutation rates in the fundamental genes of the RAS/MAPK and PI3K/Akt/mTOR pathways. Mucinous colorectal adenocarcinoma also shows higher rates of microsatellite instability (MSI) than non-mucinous colorectal adenocarcinoma which might correlate it with Lynch syndrome and the CpG island methylator phenotype. The prognosis of mucinous colorectal adenocarcinoma as to non-mucinous colorectal adenocarcinoma is debatable. Further, the impaired responses of mucinous colorectal adenocarcinoma to palliative or adjuvant chemotherapy warrant more studies to be performed for a specialized treatment for these patients. In this review, we discuss the molecular background and histopathology of mucinous colorectal adenocarcinoma, and provide an update on its prognosis and therapeutics from recent literatures.
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Affiliation(s)
- Cong Luo
- Department of Abdominal Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, P. R. China.
| | - Shuyi Cen
- School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, P. R. China
| | - Guojun Ding
- Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, P. R. China
| | - Wei Wu
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, P. R. China
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23
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Svensson F, Lang T, Johansson MEV, Hansson GC. The central exons of the human MUC2 and MUC6 mucins are highly repetitive and variable in sequence between individuals. Sci Rep 2018; 8:17503. [PMID: 30504806 PMCID: PMC6269512 DOI: 10.1038/s41598-018-35499-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 11/07/2018] [Indexed: 12/22/2022] Open
Abstract
The DNA sequence of the two human mucin genes MUC2 and MUC6 have not been completely resolved due to the repetitive nature of their central exon coding for Proline, Threonine and Serine rich sequences. The exact nucleotide sequence of these exons has remained unknown for a long time due to limitations in traditional sequencing techniques. These are still very poorly covered in new whole genome sequencing projects with the corresponding protein sequences partly missing. We used a BAC clone containing both these genes and third generation sequencing technology, SMRT sequencing, to obtain the full-length contiguous MUC2 and MUC6 tandem repeat sequences. The new sequences span the entire repeat regions with good coverage revealing their length, variation in repeat sequences and their internal organization. The sequences obtained were used to compare with available sequences from whole genome sequencing projects indicating variation in number of repeats and their internal organization between individuals. The lack of these sequences has limited the association of genetic alterations with disease. The full sequences of these mucins will now allow such studies, which could be of importance for inflammatory bowel diseases for MUC2 and gastric ulcer diseases for MUC6 where deficient mucus protection is assumed to play an important role.
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Affiliation(s)
- Frida Svensson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Tiange Lang
- Big Data Decision Institute, Jinan University, Tianhe, Guangzhou, P. R. China
| | - Malin E V Johansson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar C Hansson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden.
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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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Geerlings SY, Kostopoulos I, de Vos WM, Belzer C. Akkermansia muciniphila in the Human Gastrointestinal Tract: When, Where, and How? Microorganisms 2018; 6:microorganisms6030075. [PMID: 30041463 PMCID: PMC6163243 DOI: 10.3390/microorganisms6030075] [Citation(s) in RCA: 308] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/03/2018] [Accepted: 07/12/2018] [Indexed: 02/06/2023] Open
Abstract
Akkermansia muciniphila is a mucin-degrading bacterium of the phylum Verrucomicrobia. Its abundance in the human intestinal tract is inversely correlated to several disease states. A. muciniphila resides in the mucus layer of the large intestine, where it is involved in maintaining intestinal integrity. We explore the presence of Akkermansia-like spp. based on its 16S rRNA sequence and metagenomic signatures in the human body so as to understand its colonization pattern in time and space. A. muciniphila signatures were detected in colonic samples as early as a few weeks after birth and likely could be maintained throughout life. The sites where Akkermansia-like sequences (including Verrucomicrobia phylum and/or Akkermansia spp. sequences found in the literature) were detected apart from the colon included human milk, the oral cavity, the pancreas, the biliary system, the small intestine, and the appendix. The function of Akkermansia-like spp. in these sites may differ from that in the mucosal layer of the colon. A. muciniphila present in the appendix or in human milk could play a role in the re-colonization of the colon or breast-fed infants, respectively. In conclusion, even though A. muciniphila is most abundantly present in the colon, the presence of Akkermansia-like spp. along the digestive tract indicates that this bacterium might have more functions than those currently known.
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Affiliation(s)
- Sharon Y Geerlings
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708WE Wageningen, The Netherlands.
| | - Ioannis Kostopoulos
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708WE Wageningen, The Netherlands.
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708WE Wageningen, The Netherlands.
- Immunobiology Research Program, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708WE Wageningen, The Netherlands.
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Gonul II, Cakir A, Sozen S. Immunohistochemical expression profiles of MUC1 and MUC2 mucins in urothelial tumors of bladder. INDIAN J PATHOL MICR 2018; 61:350-355. [PMID: 30004053 DOI: 10.4103/ijpm.ijpm_12_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Mucins may show aberrant expression, localization, and/or glycosylation in multiple malignancies. However, information regarding expression of these mucins is mostly unknown in urothelial tumors. Aim This study was conducted for examining the expressions of membrane associated and secreted mucin (MUC1) and a secreted gel-forming mucin (MUC2) in urothelial tumors of the urinary bladder. Subjects and Methods Archival transurethral resection materials of 97 urothelial carcinoma cases were reexamined light microscopically and graded according to the 2004 WHO Classification. Pathological stage was given as pTa, pT1, and pT2. Demonstrative sections were recut for immunohistochemistry for MUC1 and MUC2. The results were statistically analyzed, and P < 0.05 was considered statistically significant. Results The positivity for MUC1 and MUC2 was 89.7% and 44.3%, respectively. Independent from pathological stage of the tumor, MUC1 expression showed statistically significant correlation with tumor grade (P < 0.05). We did not find any correlation between pathological stage and MUC1 and MUC2 expression (P > 0.05). MUC1 staining pattern in papillary urothelial neoplasm of low malignant potential cases was more commonly apical and superficial (luminal cell layer only). Intermediate cells ± basal cells or isolated cells or islands of tumor cells with cytoplasmic and/or circumferential membrane positivity for MUC1 and MUC2 were more commonly observed in both low- and high-grade carcinomas. The difference between groups in terms of MUC1 and MUC2 staining was statistically significant (P < 0.05). Conclusions The staining patterns of both mucins are different between urothelial papillary tumors and may be used to make a differentiation, especially for low-grade papillary urothelial lesions. This difference may also be important in the carcinomatous transformation of urothelial neoplastic and preneoplastic lesions.
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Affiliation(s)
- Ipek Isik Gonul
- Department of Pathology, Gazi University Medical School, Ankara, Turkey
| | - Asli Cakir
- Department of Pathology, Istanbul Medipol University Medical School, Istanbul, Turkey
| | - Sinan Sozen
- Department of Urology, Gazi University Medical School, Ankara, Turkey
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Role of mucins in lung homeostasis: regulated expression and biosynthesis in health and disease. Biochem Soc Trans 2018; 46:707-719. [PMID: 29802217 DOI: 10.1042/bst20170455] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 01/02/2023]
Abstract
In humans and mice, the first line of innate defense against inhaled pathogens and particles in the respiratory tract is airway mucus. The primary solid components of the mucus layer are the mucins MUC5AC and MUC5B, polymeric glycoproteins whose changes in abundance and structure can dramatically affect airway defense. Accordingly, MUC5AC/Muc5ac and MUC5B/Muc5b are tightly regulated at a transcriptional level by tissue-specific transcription factors in homeostasis and in response to injurious and inflammatory triggers. In addition to modulated levels of mucin gene transcription, translational and post-translational biosynthetic processes also exert significant influence upon mucin function. Mucins are massive macromolecules with numerous functional domains that contribute to their structural composition and biophysical properties. Single MUC5AC and MUC5B apoproteins have molecular masses of >400 kDa, and von Willebrand factor D-like as well as other cysteine-rich domain segments contribute to mucin polymerization and flexibility, thus increasing apoprotein length and complexity. Additional domains serve as sites for O-glycosylation, which increase further mucin mass several-fold. Glycosylation is a defining process for mucins that is specific with respect to additions of glycans to mucin apoprotein backbones, and glycan additions influence the physical properties of the mucins via structural modifications as well as charge interactions. Ultimately, through their tight regulation and complex assembly, airway mucins follow the biological rule of 'form fits function' in that their structural organization influences their role in lung homeostatic mechanisms.
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Demouveaux B, Gouyer V, Gottrand F, Narita T, Desseyn JL. Gel-forming mucin interactome drives mucus viscoelasticity. Adv Colloid Interface Sci 2018; 252:69-82. [PMID: 29329667 DOI: 10.1016/j.cis.2017.12.005] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/14/2017] [Accepted: 12/15/2017] [Indexed: 12/31/2022]
Abstract
Mucus is a hydrogel that constitutes the first innate defense in all mammals. The main organic component of mucus, gel-forming mucins, forms a complex network through both reversible and irreversible interactions that drive mucus gel formation. Significant advances in the understanding of irreversible gel-forming mucins assembly have been made using recombinant protein approaches. However, little is known about the reversible interactions that may finely modulate mucus viscoelasticity, which can be characterized using rheology. This approach can be used to investigate both the nature of gel-forming mucins interactions and factors that influence hydrogel formation. This knowledge is directly relevant to the development of new drugs to modulate mucus viscoelasticity and to restore normal mucus functions in diseases such as in cystic fibrosis. The aim of the present review is to summarize the current knowledge about the relationship between the mucus protein matrix and its functions, with emphasis on mucus viscoelasticity.
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Affiliation(s)
| | - Valérie Gouyer
- Univ. Lille, Inserm, CHU Lille, LIRIC UMR 995, F-59000 Lille, France
| | - Frédéric Gottrand
- Univ. Lille, Inserm, CHU Lille, LIRIC UMR 995, F-59000 Lille, France
| | - Tetsuharu Narita
- Laboratoire Sciences et Ingénierie de la Matière Molle, PSL Research University, UPMC Univ Paris 06, ESPCI Paris, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France; Global Station for Soft Matter, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
| | - Jean-Luc Desseyn
- Univ. Lille, Inserm, CHU Lille, LIRIC UMR 995, F-59000 Lille, France.
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Dhanisha SS, Guruvayoorappan C, Drishya S, Abeesh P. Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Crit Rev Oncol Hematol 2017; 122:98-122. [PMID: 29458795 DOI: 10.1016/j.critrevonc.2017.12.006] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 10/28/2017] [Accepted: 12/12/2017] [Indexed: 12/25/2022] Open
Abstract
Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization have been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.
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Affiliation(s)
- Suresh Sulekha Dhanisha
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Chandrasekharan Guruvayoorappan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India.
| | - Sudarsanan Drishya
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Prathapan Abeesh
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
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Duruisseaux M, Antoine M, Rabbe N, Rodenas A, Mc Leer-Florin A, Lacave R, Poulot V, Duchêne B, Van Seuningen I, Cadranel J, Wislez M. Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers. Lung Cancer 2017; 109:92-100. [PMID: 28577958 DOI: 10.1016/j.lungcan.2017.05.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 04/30/2017] [Accepted: 05/09/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVES To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers. MATERIALS AND METHODS MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements. RESULTS MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression. CONCLUSIONS LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes.
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Affiliation(s)
- Michaël Duruisseaux
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France
| | - Martine Antoine
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France; AP-HP, GH HUEP, Hôpital Tenon, Service d'Anatomie pathologique, 4 rue de la Chine, F-75970 Paris, France
| | - Nathalie Rabbe
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France
| | - Anita Rodenas
- AP-HP, GH HUEP, Hôpital Tenon, Service d'Anatomie pathologique, 4 rue de la Chine, F-75970 Paris, France
| | - Anne Mc Leer-Florin
- Plateforme de Génétique Moléculaire des Tumeurs, Pôle de Biologie et Pathologie CHU Grenoble et INSERM U 823-Institut A Bonniot-Université J Fourier, F-Grenoble, France
| | - Roger Lacave
- AP-HP, GH HUEP, Hôpital Tenon, Unité de Génomique des Tumeurs Solides, Pôle de Biologie Médicale et Pathologie, 4 rue de la Chine, F-75970, Paris, France
| | - Virginie Poulot
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France; AP-HP, GH HUEP, Hôpital Tenon, Unité de Génomique des Tumeurs Solides, Pôle de Biologie Médicale et Pathologie, 4 rue de la Chine, F-75970, Paris, France
| | - Belinda Duchêne
- Inserm, UMR-S 1172, JPARC, Team « Mucins, differentiation and epithelial carcinogenesis », Bâtiment G. Biserte, Rue Polonovski, 59045 Lille cedex, France
| | - Isabelle Van Seuningen
- Inserm, UMR-S 1172, JPARC, Team « Mucins, differentiation and epithelial carcinogenesis », Bâtiment G. Biserte, Rue Polonovski, 59045 Lille cedex, France
| | - Jacques Cadranel
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France; AP-HP, GH HUEP, Hôpital Tenon, Service de Pneumologie, 4 rue de la Chine, F-75970 Paris, France
| | - Marie Wislez
- Sorbonne Universités, UPMC Univ. Paris 06, GRC no 04, Theranoscan, 4 rue de la Chine, F-75252 Paris, France; AP-HP, GH HUEP, Hôpital Tenon, Service de Pneumologie, 4 rue de la Chine, F-75970 Paris, France.
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Abstract
Mucins are heavily O-glycosylated proteins primarily produced by glandular and ductal epithelial cells, either in membrane-tethered or secretory forms, for providing lubrication and protection from various exogenous and endogenous insults. However, recent studies have linked their aberrant overexpression with infection, inflammation, and cancer that underscores their importance in tissue homeostasis. In this review, we present current status of the existing mouse models that have been developed to gain insights into the functional role(s) of mucins under physiological and pathological conditions. Knockout mouse models for membrane-associated (Muc1 and Muc16) and secretory mucins (Muc2) have helped us to elucidate the role of mucins in providing effective and protective barrier functions against pathological threats, participation in disease progression, and improved our understanding of mucin interaction with biotic and abiotic environmental components. Emphasis is also given to available transgenic mouse models (MUC1 and MUC7), which has been exploited to understand the context-dependent regulation and therapeutic potential of human mucins during inflammation and cancer.
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Wen R, Gao F, Zhou CJ, Jia YB. Polymorphisms in mucin genes in the development of gastric cancer. World J Gastrointest Oncol 2015; 7:328-337. [PMID: 26600932 PMCID: PMC4644855 DOI: 10.4251/wjgo.v7.i11.328] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/01/2015] [Accepted: 09/07/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well-characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high-molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC.
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Zhou CJ, Zhang LW, Gao F, Zhang B, Wang Y, Chen DF, Jia YB. Association analysis of common genetic variations in MUC5AC gene with the risk of non-cardia gastric cancer in a Chinese population. Asian Pac J Cancer Prev 2015; 15:4207-10. [PMID: 24935372 DOI: 10.7314/apjcp.2014.15.10.4207] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Several lines of evidence suggest that genetic variation in MUC5AC gene might contribute to the risk of gastric cancer. We conducted a case-control study to evaluate the relationship between common genetic variations in MUC5AC gene and non-cardia gastric cancer using an LD-based tagSNP approach in Baotou, north-western China. We genotyped 12 tagSNPs by TaqMan method among 288 cases with non-cardia gastric cancer and 281 normal controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for non-cardia gastric cancer risk in association with alleles, genotypes and haplotypes. We observed that the frequencies of rs3793964 C allele and rs11040869 A allele were significantly lower in cases than in controls. Meanwhile, minor allele homozygotes of rs3793964 and rs11040869 were significantly associated with a decreased risk of non-cardia gastric cancer when compared with their major allele homozygotes. Furthermore, a statistically significantly protective effect of rs885454 genotypes on non-cardia gastric cancer was also observed (for CT vs. CC: OR=0.581, 95%CI=0.408-0.829; for CT/TT vs. CC: OR=0.623, 95%CI=0.451-0.884). Our results indicated that some common genetic variations in the MUC5AC gene might have effects on the risk of non-cardia gastric cancer in our studied population.
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Affiliation(s)
- Cheng-Jiang Zhou
- School of Basic Medicine, Baotou Medical College, Baotou, China E-mail :
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Intestinal barrier function and the brain-gut axis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 817:73-113. [PMID: 24997030 DOI: 10.1007/978-1-4939-0897-4_4] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The luminal-mucosal interface of the intestinal tract is the first relevant location where microorganism-derived antigens and all other potentially immunogenic particles face the scrutiny of the powerful mammalian immune system. Upon regular functioning conditions, the intestinal barrier is able to effectively prevent most environmental and external antigens to interact openly with the numerous and versatile elements that compose the mucosal-associated immune system. This evolutionary super system is capable of processing an astonishing amount of antigens and non-immunogenic particles, approximately 100 tons in one individual lifetime, only considering food-derived components. Most important, to develop oral tolerance and proper active immune responses needed to prevent disease and inflammation, this giant immunogenic load has to be managed in a way that physiological inflammatory balance is constantly preserved. Adequate functioning of the intestinal barrier involves local and distant regulatory networks integrating the so-called brain-gut axis. Along this complex axis both brain and gut structures participate in the processing and execution of response signals to external and internal changes coming from the digestive tract, using multidirectional pathways to communicate. Dysfunction of brain-gut axis facilitates malfunctioning of the intestinal barrier, and vice versa, increasing the risk of uncontrolled immunological reactions that may trigger mucosal and brain low-grade inflammation, a putative first step to the initiation of more permanent gut disorders. In this chapter, we describe the structure, function and interactions of intestinal barrier, microbiota and brain-gut axis in both healthy and pathological conditions.
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Jevtov I, Samuelsson T, Yao G, Amsterdam A, Ribbeck K. Zebrafish as a model to study live mucus physiology. Sci Rep 2014; 4:6653. [PMID: 25323747 PMCID: PMC4200417 DOI: 10.1038/srep06653] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 09/10/2014] [Indexed: 12/13/2022] Open
Abstract
Dysfunctional mucus barriers can result in important pulmonary and gastrointestinal conditions, but model systems to study the underlying causes are largely missing. We identified and characterized five mucin homologues in zebrafish, and demonstrated a strategy for fluorescence labeling of one selected mucin. These tools can be used for in vivo experiments and in pharmacological and genetic screens to study the dynamics and mechanisms of mucosal physiology.
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Affiliation(s)
- Irena Jevtov
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Tore Samuelsson
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
| | - Grace Yao
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Adam Amsterdam
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
| | - Katharina Ribbeck
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Kusafuka K, Muramatsu K, Iida Y, Mori K, Miki T, Suda T, Fuke T, Kamijo T, Onitsuka T, Nakajima T. MUC expression in adenosquamous carcinoma of the head and neck regions of Japanese patients: Immunohistochemical analysis. Pathol Int 2014; 64:104-14. [DOI: 10.1111/pin.12144] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 02/02/2014] [Indexed: 11/27/2022]
Affiliation(s)
- Kimihide Kusafuka
- Pathology Division; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Koji Muramatsu
- Pathology Division; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Yoshiyuki Iida
- Division of Head and Neck Surgery; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Keita Mori
- Clinical Trial Coordination Office; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Tomoko Miki
- Pathology Division; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Toshihito Suda
- Division of Head and Neck Surgery; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Tomohito Fuke
- Division of Head and Neck Surgery; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Tomoyuki Kamijo
- Division of Head and Neck Surgery; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Tetsuro Onitsuka
- Division of Head and Neck Surgery; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
| | - Takashi Nakajima
- Pathology Division; Shizuoka Cancer Center; Sunto-gun Shizuoka Japan
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Walsh MD, Clendenning M, Williamson E, Pearson SA, Walters RJ, Nagler B, Packenas D, Win AK, Hopper JL, Jenkins MA, Haydon AM, Rosty C, English DR, Giles GG, McGuckin MA, Young JP, Buchanan DD. Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Mod Pathol 2013; 26:1642-56. [PMID: 23807779 DOI: 10.1038/modpathol.2013.101] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 05/02/2013] [Accepted: 05/03/2013] [Indexed: 12/11/2022]
Abstract
Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.
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Affiliation(s)
- Michael D Walsh
- 1] Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia [2] Department of Histopathology, Sullivan Nicolaides Pathology, Taringa, QLD, Australia
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Abstract
Gallstone disease (GSD) is one of the most common biliary tract disorders worldwide. The prevalence, however, varies from 5.9-21.9% in Western society to 3.1-10.7% in Asia. Most gallstones (75%) are silent. Approximately half of symptomatic gallstone carriers experience a second episode of biliary pain within 1 year. These individuals are at increased risk of developing acute cholecystitis, acute cholangitis, and biliary pancreatitis. As can be expected, these complications burden health care systems because of their invasive nature and surgical cost. Factors that contribute to gallstone formation include supersaturation of cholesterol in bile, gallbladder hypomotility, destabilization of bile by kinetic protein factors, and abnormal mucins. Epidemiologic studies have implicated multiple environmental factors and some common genetic elements in gallstone formation. Genetic factors that influence gallstone formation have been elaborated from linkage studies of twins, families, and ethnicities. Accumulating evidence suggests that genetic factors play a role in GSD.
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Affiliation(s)
- Shih-Chang Chuang
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Imai Y, Yamagishi H, Fukuda K, Ono Y, Inoue T, Ueda Y. Differential mucin phenotypes and their significance in a variation of colorectal carcinoma. World J Gastroenterol 2013; 19:3957-3968. [PMID: 23840140 PMCID: PMC3703182 DOI: 10.3748/wjg.v19.i25.3957] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 04/20/2013] [Accepted: 05/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate mucin expression profiles in colorectal carcinoma (CRC) histological subtypes with regard to clinicopathologic variables and prognosis. METHODS Mucin (MUC)2 and MUC5AC expressions were assessed by immunohistochemistry for a total of 250 CRC cases that underwent surgical resection. CRCs included 63 well-to-moderately differentiated adenocarcinomas (WMDAs), 91 poorly differentiated adenocarcinomas (PDAs), 81 mucinous adenocarcinoma (MUAs), and 15 signet-ring cell carcinomas (SRCCs). MUC2 and MUC5AC were scored as positive when ≥ 25% and ≥ 1% of cancer cells were stained positive, respectively. The human mutL homolog 1 and human mutS homolog 2 expressions were assessed by immunohistochemistry in PDAs to investigate mismatch-repair (MMR) status. Tumors that did not express either of these two were considered MMR-deficient. Results were analyzed for associations with clinicopathologic variables and the prognosis in individual histological CRC subtypes. RESULTS MUC2-positive and MUC5AC-positive WMDA percentages were 49.2% and 30.2%, respectively. In contrast, MUC2-positive and MUC5AC-positive PDA percentages were 9.5% and 51.6%, respectively. MUC2 levels tended to decrease and MUC5AC levels tended to increase from WMDA to PDA. In 21 tumors comprising both adenoma and adenocarcinoma components in a single tumor (4 WMDAs, 7 PDAs, and 10 MUAs), MUC2 was significantly downregulated in PDA and MUC5AC was downregulated in PDA and MUA in the adenoma-carcinoma sequence. These results suggested that MUC2 levels might be associated with malignant potential and that MUC5AC expression was an early event in tumorigenesis. Despite worse prognoses than WMDA, high MUC2 expression levels were maintained in MUA (95.1%) and SRCC (71.5%), which suggested a pathogenesis for these subtypes distinct from that of WMDA. No significant associations were found between MUC2 expression and any clinicopathologic variables in any histological subtype. MUC5AC expression in PDA was closely associated with right-sided location (P = 0.017), absence of nodal metastasis (P = 0.010), low tumor node metastasis stage (P = 0.010), and MMR deficiency (P = 0.003). MUC2 expression in WMDA was a marginal prognostic factor for recurrence/metastasis-free survival (RFS) by univariate Cox analysis (P = 0.077) but not by multivariate Cox analysis (P = 0.161). MUC5AC expression in PDA was a significant prognostic factor for RFS by univariate Cox analysis (P = 0.007) but not by multivariate Cox analysis (P = 0.104). Kaplan-Meier curves and log-rank tests revealed that MUC2 expression was marginally associated with a better WMDA prognosis [P = 0.064 for RFS and P = 0.172 for overall survival (OS)] but not for PDA. In contrast, MUC5AC expression was significantly and marginally associated with a better PDA prognosis in terms of RFS and OS, respectively (P = 0.004 for RFS and P = 0.100 for OS), but not for WMDA and MUA. CONCLUSION Mucin core protein expression profiles and clinical significance differ according to histological CRC subtypes. This may reflect different pathogeneses for these tumors.
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Gosalia N, Leir SH, Harris A. Coordinate regulation of the gel-forming mucin genes at chromosome 11p15.5. J Biol Chem 2013; 288:6717-25. [PMID: 23303185 DOI: 10.1074/jbc.m112.437400] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Four of the genes that encode gel-forming mucins, which are major components of the mucus layer protecting many epithelial surfaces, are clustered at chromosome 11p15.5 and show both cell- and tissue-specific expression patterns. We aimed to determine whether the individual genes were coordinately regulated by mechanisms involving higher order chromatin structure. CCCTC-binding factor (CTCF) sites were predicted in silico and CTCF occupancy then evaluated by chromatin immunoprecipitation. CTCF was found at many sites across the gene cluster, and its binding was correlated with mucin gene expression. Next, siRNA-mediated depletion of CTCF was shown to increase MUC2 expression in A549 lung carcinoma cells and both MUC6 and MUC5AC expression in LS180 colon carcinoma cells. These changes correlated with loss of CTCF binding at multiple sites, although others retained occupancy. In cells actively expressing the mucins, the gene cluster was shown by chromosome conformation capture to form looped three-dimensional structures with direct interactions between the MUC2 promoter region, regions 30 kb 5' to it, close to the MUC6 promoter and others near the 3' end of MUC5AC, >170 kb away. Finally, to demonstrate the importance of CTCF binding to mucin gene expression, Calu-3 lung carcinoma cells were exposed to lipopolysaccharide (LPS). LPS increased the expression of MUC2 and MUC5AC and reduced MUC5B. CTCF occupancy was concurrently depleted at specific binding sites close to these genes. These data suggest that CTCF binding and cell type-specific long-range interactions across the 11p15.5 gene cluster are critical mechanisms for coordinating gel-forming mucin gene expression.
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Affiliation(s)
- Nehal Gosalia
- Human Molecular Genetics Program, Children's Memorial Research Center and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614, USA
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Hasnain SZ, Gallagher AL, Grencis RK, Thornton DJ. A new role for mucins in immunity: insights from gastrointestinal nematode infection. Int J Biochem Cell Biol 2012; 45:364-74. [PMID: 23107603 DOI: 10.1016/j.biocel.2012.10.011] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Revised: 10/21/2012] [Accepted: 10/23/2012] [Indexed: 12/26/2022]
Abstract
The body's mucosal surfaces are protected from pathogens and physical and chemical attack by the gel-like extracellular matrix, mucus. The framework of this barrier is provided by polymeric, gel-forming mucins. These enormous O-linked glycoproteins are synthesised, stored and secreted by goblet cells that are also the source of other protective factors. Immune regulation of goblet cells during the course of infection impacts on mucin production and properties and ultimately upon barrier function. The barrier function of mucins in protection of the host is well accepted as an important aspect of innate defence. However, it is becoming increasingly clear that mucins have a much more direct role in combating pathogens and parasites and are an important part of the coordinated immune response to infection. Of particular relevance to this review is the finding that mucins are essential anti-parasitic effector molecules. The current understanding of the roles of these multifunctional glycoproteins, and other goblet cell products, in mucosal defence against intestinal dwelling nematodes is discussed.
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Affiliation(s)
- Sumaira Z Hasnain
- Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, Brisbane, QLD 4029, Australia
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Ahn MH, Bae KB, Kwon JA, Choi HJ, Lee SR, Kim SH, Jung TD, Kim SH, An MS, Hong KH, Heo J, Kang TH, Chung JW, Leem SH. Association of MUC6-minisatellite variants with susceptibility to rectal carcinoma. Mol Biol Rep 2012; 40:303-8. [PMID: 23054008 DOI: 10.1007/s11033-012-2062-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 10/03/2012] [Indexed: 01/08/2023]
Abstract
A secreted MUC6 mucin is reported to be expressed highly in the stomach and gall bladder. In previous our study, the five minisatellites were identified and a significant association between MUC6-MS5 alleles and gastric cancer was reported. Because of aberrant MUC6 expression is often found in gastrointestinal diseases, we evaluated a relationship between MUC6-MS5 and susceptibility to colorectal cancers. Case-control study was performed with 1,103 cancer-free controls and 414 rectal cancer cases. A significant association (OR = 2.70) between short rare MUC6-MS5 alleles (7, 9 repeats) and the occurrence of cancer was observed in rectal cancer [95 % confidence interval (CI), 1.12-6.54; p = 0.022]. Furthermore, a comparison by gender showed the differences in the association ratios between rectal cancer and short rare MUC6-MS5 alleles: male, 3.97 (CI: 1.36-11.5; p = 0.006) versus female 0.91 (CI: 0.18-4.75; p = 0.913). We also examined the association according to lymphovascular invasion (LVI). The frequency of LVI positive rectal cancer was increased in short rare allele cases than in the total rectal cases: 16.2 % versus 42.9 %. Therefore, we suggest that the short rare MUC6-MS5 alleles may be related to cancer development in male and these cancer cases may be related the bad prognosis.
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Affiliation(s)
- Myoung-Hyun Ahn
- Department of Biological Science, Dong-A University, 840 Hadan-2-dong, Saha-gu, Busan 604-714, Korea
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GATA-4/-6 and HNF-1/-4 families of transcription factors control the transcriptional regulation of the murine Muc5ac mucin during stomach development and in epithelial cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2012; 1819:869-76. [DOI: 10.1016/j.bbagrm.2012.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 04/13/2012] [Accepted: 04/17/2012] [Indexed: 02/07/2023]
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Chuang SC, Hsi E, Lee KT. Mucin genes in gallstone disease. Clin Chim Acta 2012; 413:1466-71. [PMID: 22705400 DOI: 10.1016/j.cca.2012.06.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 06/04/2012] [Accepted: 06/07/2012] [Indexed: 01/27/2023]
Abstract
Gallstone disease is a complex disorder that can be caused by environmental influences, common genetic factors and their interactions. Three major pathogenic abnormalities are considered to involve in gallstone formation: cholesterol supersaturation in bile, precipitation and nucleation of excess cholesterol, and gallbladder hypomotility, while, mucin takes part in the cholesterol nucleation process. Up to date, more than 20 mucin genes have been reported, 9 of them are identified at the mRNA and/or protein level in native gallbladder and its associated diseases. In the gallbladder, mucin is essential for best protection against detergent effect of high concentration of bile acids. Over the past decade, the properties, expressions and functions of the gallbladder mucins are delineated in animal and human studies. Alteration expressions of mucins are thought to response during the pathogenesis of gallstone formation. Moreover, recent genetic association study demonstrated mucin gene polymorphisms may also influence susceptibility to gallstone disease. This review is not to provide a complete coverage of all the aspects of mucin glycoproteins, but focus on the role and expression of mucins involve in the regulation of cholelithogenesis.
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Affiliation(s)
- Shih-Chang Chuang
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Rousseau K, Swallow DM. Mucin methods: genes encoding mucins and their genetic variation with a focus on gel-forming mucins. Methods Mol Biol 2012; 842:1-26. [PMID: 22259127 DOI: 10.1007/978-1-61779-513-8_1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Mucin genes encode the polypeptide backbone of the mucin glycoproteins which are expressed on all epithelial surfaces and are major constituents of the mucus layer. Mucins are, thus, expressed at the interface between the external and the internal environment of the organism, and represent the first line of defence of our body. These genes often have an extensive region of repetitive exonic sequence which codes for the heavily glycosylated domain, whose roles include bacterial interactions and gel hydration. This region shows, in several of the genes, considerable inter-individual variation in repeat number and sequence. Because of their site of expression and their high variability in this important domain, mucin genes are good candidates for conferring differences in genetic susceptibility to multifactorial epithelial and inflammatory disease. However, progress in characterizing the genes has been considerably slower than the rest of the genome because of their size and the GC-rich content of the large, repetitive variable region. Some of the issues relating to the study of these genes are discussed in this chapter. In addition, methods and approaches that have been used successfully are described.
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Affiliation(s)
- Karine Rousseau
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
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Abstract
The colonic human MUC2 mucin forms a polymeric gel by covalent disulfide bonds in its N- and C-termini. The middle part of MUC2 is largely composed of two highly O-glycosylated mucin domains that are interrupted by a CysD domain of unknown function. We studied its function as recombinant proteins fused to a removable immunoglobulin Fc domain. Analysis of affinity-purified fusion proteins by native gel electrophoresis and gel filtration showed that they formed oligomeric complexes. Analysis of the individual isolated CysD parts showed that they formed dimers both when flanked by two MUC2 tandem repeats and without these. Cleavages of the two non-reduced CysD fusion proteins and analysis by MS revealed the localization of all five CysD disulfide bonds and that the predicted C-mannosylated site was not glycosylated. All disulfide bonds were within individual peptides showing that the domain was stabilized by intramolecular disulfide bonds and that CysD dimers were of non-covalent nature. These observations suggest that CysD domains act as non-covalent cross-links in the MUC2 gel, thereby determining the pore sizes of the mucus.
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Yonezawa S, Higashi M, Yamada N, Yokoyama S, Kitamoto S, Kitajima S, Goto M. Mucins in human neoplasms: clinical pathology, gene expression and diagnostic application. Pathol Int 2011; 61:697-716. [PMID: 22126377 DOI: 10.1111/j.1440-1827.2011.02734.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. Our immunohistochemical studies demonstrated that MUC1 or MUC4 expression is related to the aggressive behavior and poor outcome of human neoplasms. MUC2 is expressed in indolent pancreatobiliary neoplasms, but these tumors sometimes show invasive growth with MUC1 expression in invasive areas. MUC5AC shows de novo high expression in many types of precancerous lesions of pancreatobiliary cancers and is an effective marker for early detection of the neoplasms. The combination of MUC1, MUC2, MUC4 and MUC5AC expression may be useful for early detection and evaluation of the potential for malignancy of pancreatobiliary neoplasms. Regarding the mechanism of mucin expression, we have recently reported that expression of the mucin genes is regulated epigenetically in cancer cell lines, using quantitative MassARRAY analysis, methylation-specific polymerase chain reaction analysis and chromatin immunoprecipitation analysis, with confirmation by the treatment with 5-aza-2'-deoxycytidine and trichostatin A. We have also developed a monoclonal antibody against the MUC1 cytoplasmic tail domain, which has many biological roles. Based on all of the above findings, we suggest that translational research into mucin gene expression mechanisms, including epigenetics, may provide new tools for early and accurate detection of human neoplasms.
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Affiliation(s)
- Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
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Simian immunodeficiency virus from the sooty mangabey and rhesus macaque is modified with O-linked carbohydrate. J Virol 2010; 85:582-95. [PMID: 20962077 DOI: 10.1128/jvi.01871-10] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Although stretches of serine and threonine are sometimes sites for O-linked carbohydrate attachment, specific sequence and structural determinants for O-linked attachment remain ill defined. The gp120 envelope protein of SIVmac239 contains a serine-threonine-rich stretch of amino acids at positions 128 to 139. Here we show that lectin protein from jackfruit seed (jacalin), which binds to non- and monosialylated core 1 O-linked carbohydrate, potently inhibited the replication of SIVmac239. Selection of a jacalin-resistant SIVmac239 variant population resulted in virus with specific substitutions within amino acids 128 to 139. Cloned simian immunodeficiency virus (SIV) variants with substitutions in the 128-to-139 region had infectivities equivalent to, or within 1 log unit of, that of SIVmac239 and were resistant to the inhibitory effects of jacalin. Characterization of the SIVmac239 gp120 O-linked glycome showed the presence of core 1 and core 2 O-linked carbohydrate; a 128-to-139-substituted variant gp120 from jacalin-resistant SIV lacked O-linked carbohydrate. Unlike that of SIVmac239, the replication of HIV-1 strain NL4-3 was resistant to inhibition by jacalin. Purified gp120s from four SIVmac and SIVsm strains bound jacalin strongly in an enzyme-linked immunosorbent assay, while nine different HIV-1 gp120s, two SIVcpz gp120s, and 128-to-139-substituted SIVmac239 gp120 did not bind jacalin. The ability or inability to bind jacalin thus correlated with the presence of the serine-threonine-rich stretch in the SIVmac and SIVsm gp120s and the absence of such stretches in the SIVcpz and HIV-1 gp120s. Consistent with sequence predictions, two HIV-2 gp120s bound jacalin, while one did not. These data demonstrate the presence of non- and monosialylated core 1 O-linked carbohydrate on the gp120s of SIVmac and SIVsm and the lack of these modifications on HIV-1 and SIVcpz gp120s.
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Molaei M, Mansoori BK, Mashayekhi R, Vahedi M, Pourhoseingholi MA, Fatemi SR, Zali MR. Mucins in neoplastic spectrum of colorectal polyps: can they provide predictions? BMC Cancer 2010; 10:537. [PMID: 20929551 PMCID: PMC2958948 DOI: 10.1186/1471-2407-10-537] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2009] [Accepted: 10/07/2010] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The significance of expression of different mucins in succession of malignant transformation of colorectal polyps is not determined yet. The aim of the present study was to determine the pattern of expression of MUC1, MUC2, MUC5AC and MUC6 in colorectal polyps and to evaluate the applicability of using mucin expression in predicting the extent of malignant transformation in colorectal polyps. METHODS A total of 454 polyp specimens comprising 36 hyperplastic polyps, 15 serrated adenomas, 258 tubular adenomas, 114 tubulovillous adenomas, and 31 villous adenomas were included in this study, and were immunostained for MUC1, MUC2, MUC5AC and MUC6 by using mucin specific antibodies. RESULTS MUC1 and MUC6 were absent in all hyperplastic polyps and their expression was higher in serrated and traditional adenomas. Only 5 cases including 2 serrated adenomas, 1 tubulovillous adenoma, and 2 villous adenomas stained negative for MUC2. The highest expression of MUC5AC was observed in serrated adenomas followed by tubular adenomas. Binary logistic regression analysis indicated that positive staining for MUC1, and MUC6, and negative staining for MUC2 would increase the risk of invasion to mucosa or the muscularis mucosae in colorectal polyps. Ordinal regression analysis demonstrated a positive association between the level of staining for MUC1 and risk of being of high configuration/grade in colorectal polyps. CONCLUSIONS MUC1, MUC2, MUC5AC, and MUC6 have the potential to be used as predictors of malignant transformation and invasion to mucosa or the muscularis mucosae in colorectal polyps. The most reliable predictions can be achieved by determining the level of expression of MUC1.
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Affiliation(s)
- Mahsa Molaei
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Babak Khoshkrood Mansoori
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Reza Mashayekhi
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Mohsen Vahedi
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Mohamad Amin Pourhoseingholi
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Seyed Reza Fatemi
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
| | - Mohammad Reza Zali
- Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University, M.C., Tehran, Iran
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Pearson JP, Brownlee IA. The interaction of large bowel microflora with the colonic mucus barrier. Int J Inflam 2010; 2010:321426. [PMID: 21152122 PMCID: PMC2989700 DOI: 10.4061/2010/321426] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 07/14/2010] [Accepted: 08/04/2010] [Indexed: 12/20/2022] Open
Abstract
The colonic mucus barrier is the first line of defence that the underlying mucosa has against the wide range of potentially damaging agents of microbial, endogenous, and dietary origin that occur within the colonic lumen. The functional component of mucus is the secreted, polymeric glycoprotein mucin. The mucus barrier can either act as an energy source or a support medium for growth to the intestinal microflora. The mucus barrier appears to effectively partition the vast number of microbial cells from the underlying epithelium. The normal functionality and biochemistry of this mucus barrier appears to be lost in diseases of the colorectal mucosa. Germ-free animal studies have highlighted the necessity of the presence of the colonic microflora to drive the maturation of the colonic mucosa and normal mucus production. A number of by-products of the microflora have been suggested to be key luminal drivers of colonic mucus secretion.
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Affiliation(s)
- Jeffrey P. Pearson
- Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Iain A. Brownlee
- Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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