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Hashimoto N, Ito S, Harazono A, Tsuchida A, Mouri Y, Yamamoto A, Okajima T, Ohmi Y, Furukawa K, Kudo Y, Kawasaki N, Furukawa K. Bidirectional signals generated by Siglec-7 and its crucial ligand tri-sialylated T to escape of cancer cells from immune surveillance. iScience 2024; 27:111139. [PMID: 39507251 PMCID: PMC11539641 DOI: 10.1016/j.isci.2024.111139] [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: 04/12/2024] [Revised: 08/05/2024] [Accepted: 10/07/2024] [Indexed: 11/08/2024] Open
Abstract
Siglec-7, an inhibitory receptor expressed on natural killer (NK) cells, recognizes sialic acid-containing glycans. However, the ligand glycan structures of Siglec-7 and its carrier proteins have not been comprehensively investigated. Here, we identified four sialyltransferases that are used for the synthesis of ligand glycans of Siglec-7 and two ligand O-glycan-carrier proteins, PODXL and MUC13, using a colon cancer line. Upon binding of these ligand glycans, Siglec-7-expressing immune cells showed reduced cytotoxic activity, whereas cancer cells expressing ligand glycans underwent signal activation, leading to enhanced invasion activity. To clarify the structure of the ligand glycan, podoplanin (PDPN) identified as a Siglec-7 ligand-carrier protein, was transfected into HEK293T cells using sialyltransferase cDNAs. Mass spectrometry of the products revealed a ligand glycan, tri-sialylated T antigen. These results indicate that Siglec-7 interaction with its ligand generates bidirectional signals in NK and cancer cells, leading to the efficient escape of cancers from host immune surveillance.
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Affiliation(s)
- Noboru Hashimoto
- Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan
- Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Shizuka Ito
- Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan
| | - Akira Harazono
- Biological Chemistry and Biologicals, National Institute of Health Sciences, Kanagawa 210-9501, Japan
| | - Akiko Tsuchida
- Laboratory of Glycobiology, The Noguchi Institute, Itabashi 173-0003, Japan
| | - Yasuhiro Mouri
- Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Akihito Yamamoto
- Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Tetsuya Okajima
- Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan
| | - Yuhsuke Ohmi
- Clinical Engineering, Chubu University College of Life and Health Science, Aichi 487-8501, Japan
| | - Keiko Furukawa
- Biomedical Sciences, Chubu University College of Life and Health Sciences, Aichi 487-8501, Japan
| | - Yasusei Kudo
- Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Nana Kawasaki
- Biopharmaceutical and Regenerative Sciences, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan
| | - Koichi Furukawa
- Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-0065, Japan
- Biomedical Sciences, Chubu University College of Life and Health Sciences, Aichi 487-8501, Japan
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2
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Chen X, Tu J, Yang M, Wang Y, Liu B, Qiu H, Yuan X. RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis. Int J Biol Sci 2024; 20:4999-5026. [PMID: 39309442 PMCID: PMC11414392 DOI: 10.7150/ijbs.98396] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/07/2024] [Indexed: 09/25/2024] Open
Abstract
Background: Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood. Objective: This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target. Methods: RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. In vitro and in vivo assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13. Results: RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1. Conclusion: RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.
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Affiliation(s)
| | | | | | | | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Arai J, Hayakawa Y, Tateno H, Fujiwara H, Kasuga M, Fujishiro M. The role of gastric mucins and mucin-related glycans in gastric cancers. Cancer Sci 2024; 115:2853-2861. [PMID: 39031976 PMCID: PMC11463072 DOI: 10.1111/cas.16282] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/22/2024] Open
Abstract
Gastric mucins serve as a protective barrier on the stomach's surface, protecting from external stimuli including gastric acid and gut microbiota. Their composition typically changes in response to the metaplastic sequence triggered by Helicobacter pylori infection. This alteration in gastric mucins is also observed in cases of gastric cancer, although the precise connection between mucin expressions and gastric carcinogenesis remains uncertain. This review first introduces the relationship between mucin expressions and gastric metaplasia or cancer observed in humans and mice. Additionally, we discuss potential pathogenic mechanisms of how aberrant mucins and their glycans affect gastric carcinogenesis. Finally, we summarize challenges to target tumor-specific glycans by utilizing lectin-drug conjugates that can bind to specific glycans. Understanding the correlation and mechanism between these mucin expressions and gastric carcinogenesis could pave the way for new strategies in gastric cancer treatment.
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Affiliation(s)
- Junya Arai
- Division of Gastroenterology, The Institute for Medical ScienceAsahi Life FoundationChuo‐ku, TokyoJapan
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo‐ku, TokyoJapan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo‐ku, TokyoJapan
| | - Hiroaki Tateno
- Cellular and Molecular Biotechnology Research InstituteNational Institute of Advanced Industrial Science and Technology (AIST)TsukubaJapan
| | - Hiroaki Fujiwara
- Division of Gastroenterology, The Institute for Medical ScienceAsahi Life FoundationChuo‐ku, TokyoJapan
| | - Masato Kasuga
- The Institute for Medical ScienceAsahi Life FoundationChuo‐ku, TokyoJapan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo‐ku, TokyoJapan
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4
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Malik S, Sikander M, Wahid M, Dhasmana A, Sarwat M, Khan S, Cobos E, Yallapu MM, Jaggi M, Chauhan SC. Deciphering cellular and molecular mechanism of MUC13 mucin involved in cancer cell plasticity and drug resistance. Cancer Metastasis Rev 2024; 43:981-999. [PMID: 38498072 DOI: 10.1007/s10555-024-10177-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 02/26/2024] [Indexed: 03/19/2024]
Abstract
There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.
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Affiliation(s)
- Shabnam Malik
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohammed Sikander
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohd Wahid
- Unit of Research and Scientific Studies, College of Nursing and Allied Health Sciences, University of Jazan, Jizan, Saudi Arabia
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Noida, India
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Everardo Cobos
- Department of Medicine, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA.
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA.
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5
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Liu Z, Zhang D, Chen S. Unveiling the gastric microbiota: implications for gastric carcinogenesis, immune responses, and clinical prospects. J Exp Clin Cancer Res 2024; 43:118. [PMID: 38641815 PMCID: PMC11027554 DOI: 10.1186/s13046-024-03034-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/29/2024] [Indexed: 04/21/2024] Open
Abstract
High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications.
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Affiliation(s)
- Zhiyi Liu
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Dachuan Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.
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Doxtater K, Tripathi MK, Sekhri R, Hafeez BB, Khan S, Zafar N, Behrman SW, Yallapu MM, Jaggi M, Chauhan SC. MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway. Life Sci Alliance 2023; 6:e202301975. [PMID: 37793774 PMCID: PMC10551643 DOI: 10.26508/lsa.202301975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
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Affiliation(s)
- Kyle Doxtater
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Radhika Sekhri
- Department of Pathology, Montefiore Medical Center College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Nadeem Zafar
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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Pan D, Chen H, Xu J, Lin X, Li L. Evaluation of vital genes correlated with CD8 + T cell infiltration as prognostic biomarkers in stomach adenocarcinoma. BMC Gastroenterol 2023; 23:399. [PMID: 37978443 PMCID: PMC10656896 DOI: 10.1186/s12876-023-03003-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 10/17/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Infiltration of CD8 + T cells in the tumor microenvironment is correlated with better prognosis in various malignancies. Our study aimed to investigate vital genes correlated with CD8 + T cell infiltration in stomach adenocarcinoma (STAD) and develop a new prognostic model. METHODS Using the STAD dataset, differentially expressed genes (DEGs) were analyzed, and co-expression networks were constructed. Combined with the CIBERSORT algorithm, the most relevant module of WGCNA with CD8 + T cell infiltration was selected for subsequent analysis. The vital genes were screened out by univariate regression analysis to establish the risk score model. The expression of the viral genes was verified by lasso regression analysis and in vitro experiments. RESULTS Four CD8 + T cell infiltration-related genes (CIDEC, EPS8L3, MUC13, and PLEKHS1) were correlated with the prognosis of STAD. Based on these genes, a risk score model was established. We found that the risk score could well predict the prognosis of STAD, and the risk score was positively correlated with CD8 + T cell infiltration. The validation results of the gene expression were consistent with TCGA. Furthermore, the risk score was significantly higher in tumor tissues. The high-risk group had poorer overall survival (OS) in each subgroup. CONCLUSIONS Our study constructed a new risk score model for STAD prognosis, which may provide a new perspective to explore the tumor immune microenvironment mechanism in STAD.
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Affiliation(s)
- Dun Pan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, No.20, ChaZhong Road, TaiJiang District, Fuzhou, 350000, Fujian Province, China
| | - Hui Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, No.20, ChaZhong Road, TaiJiang District, Fuzhou, 350000, Fujian Province, China
| | - Jiaxiang Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, No.20, ChaZhong Road, TaiJiang District, Fuzhou, 350000, Fujian Province, China
| | - Xin Lin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, No.20, ChaZhong Road, TaiJiang District, Fuzhou, 350000, Fujian Province, China
| | - Liangqing Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, No.20, ChaZhong Road, TaiJiang District, Fuzhou, 350000, Fujian Province, China.
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Patel NM, Geropoulos G, Patel PH, Bhogal RH, Harrington KJ, Singanayagam A, Kumar S. The Role of Mucin Expression in the Diagnosis of Oesophago-Gastric Cancer: A Systematic Literature Review. Cancers (Basel) 2023; 15:5252. [PMID: 37958425 PMCID: PMC10650431 DOI: 10.3390/cancers15215252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Survival in oesophago-gastric cancer (OGC) is poor due to early diagnostic challenges. Non-invasive risk stratification may identify susceptible patients with pre-malignant or benign disease. Following diagnostic confirmation with endoscopic biopsy, early OGC may be treated sooner. Mucins are transmembrane glycoproteins implicated in OGC with potential use as biomarkers of malignant transformation. This systematic review defines the role of mucins in OGC diagnosis. A literature search of MEDLINE, Web of Science, Embase and Cochrane databases was performed following PRISMA protocols for studies published January 1960-December 2022. Demographic data and data on mucin sampling and analysis methods were extracted. The review included 124 studies (n = 11,386 patients). Gastric adenocarcinoma (GAc) was the commonest OG malignancy (n = 101) followed by oesophageal adenocarcinoma (OAc, n = 24) and squamous cell carcinoma (OSqCc, n = 10). Mucins MUC1, MUC2, MUC5AC and MUC6 were the most frequently implicated. High MUC1 expression correlated with poorer prognosis and metastases in OSqCc. MUC2 expression decreases during progression from healthy mucosa to OAc, causing reduced protection from gastric acid. MUC5AC was upregulated, and MUC6 downregulated in GAc. Mucin expression varies in OGC; changes may be epigenetic or mutational. Profiling upper GI mucin expression in OGC, with pre-malignant, benign and healthy controls may identify potential early diagnostic biomarkers.
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Affiliation(s)
- Nikhil Manish Patel
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Georgios Geropoulos
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Pranav Harshad Patel
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Ricky Harminder Bhogal
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
| | - Kevin Joseph Harrington
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW7 3RP, UK
| | - Aran Singanayagam
- Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK
| | - Sacheen Kumar
- The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
- The Upper Gastrointestinal Surgical Oncology Research Group, The Institute of Cancer Research, London SW7 3RP, UK
- Department of Upper Gastrointestinal Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic London Hospital, London SW1X 7HY, UK
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McGuckin MA, Davies JM, Felgner P, Wong KY, Giri R, He Y, Moniruzzaman M, Kryza T, Sajiir H, Hooper JD, Florin TH, Begun J, Oussalah A, Hasnain SZ, Hensel M, Sheng YH. MUC13 Cell Surface Mucin Limits Salmonella Typhimurium Infection by Protecting the Mucosal Epithelial Barrier. Cell Mol Gastroenterol Hepatol 2023; 16:985-1009. [PMID: 37660948 PMCID: PMC10630632 DOI: 10.1016/j.jcmgh.2023.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND & AIMS MUC13 cell surface mucin is highly expressed on the mucosal surface throughout the intestine, yet its role against bacterial infection is unknown. We investigated how MUC13 impacts Salmonella typhimurium (S Tm) infection and elucidated its mechanisms of action. METHODS Muc13-/- and wild-type littermate mice were gavaged with 2 isogenic strains of S Tm after pre-conditioning with streptomycin. We assessed clinical parameters, cecal histology, local and systemic bacterial load, and proinflammatory cytokines after infection. Cecal enteroids and epithelial cell lines were used to evaluate the mechanism of MUC13 activity after infection. The interaction between bacterial SiiE and MUC13 was assessed by using siiE-deficient Salmonella. RESULTS S Tm-infected Muc13-/- mice had increased disease activity, histologic damage, and higher local and systemic bacterial loads. Mechanistically, we found that S Tm binds to MUC13 through its giant SiiE adhesin and that MUC13 acts as a pathogen-binding decoy shed from the epithelial cell surface after pathogen engagement, limiting bacterial invasion. In addition, MUC13 reduces epithelial cell death and intestinal barrier breakdown by enhancing nuclear factor kappa B signaling during infection, independent of its decoy function. CONCLUSIONS We show for the first time that MUC13 plays a critical role in antimicrobial defense against pathogenic S Tm at the intestinal mucosal surface by both acting as a releasable decoy limiting bacterial invasion and reducing pathogen-induced cell death. This further implicates the cell surface mucin family in mucosal defense from bacterial infection.
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Affiliation(s)
- Michael A McGuckin
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
| | - Julie M Davies
- Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Pascal Felgner
- CellNanOs, Center for Cellular Nanoanalytics, Osnabrueck, Germany; Division Microbiology, Universitaet Osnabrueck, Osnabrueck, Germany
| | - Kuan Yau Wong
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Rabina Giri
- Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Yaowu He
- Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia
| | - Md Moniruzzaman
- Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Thomas Kryza
- Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia
| | - Haressh Sajiir
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - John D Hooper
- Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia
| | - Timothy H Florin
- Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Jakob Begun
- Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Abderrahim Oussalah
- Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Nancy, France; University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France; Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy, France
| | - Sumaira Z Hasnain
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Michael Hensel
- CellNanOs, Center for Cellular Nanoanalytics, Osnabrueck, Germany; Division Microbiology, Universitaet Osnabrueck, Osnabrueck, Germany
| | - Yong H Sheng
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; Laboratory of B-Lymphocytes in Autoimmunity and Malignancies, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
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10
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Oosterlinck B, Ceuleers H, Arras W, De Man JG, Geboes K, De Schepper H, Peeters M, Lebeer S, Skieceviciene J, Hold GL, Kupcinskas J, Link A, De Winter BY, Smet A. Mucin-microbiome signatures shape the tumor microenvironment in gastric cancer. MICROBIOME 2023; 11:86. [PMID: 37085819 PMCID: PMC10120190 DOI: 10.1186/s40168-023-01534-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 03/22/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND AND AIMS We aimed to identify mucin-microbiome signatures shaping the tumor microenvironment in gastric adenocarcinomas and clinical outcomes. METHODS We performed high-throughput profiling of the mucin phenotypes present in 108 gastric adenocarcinomas and 20 functional dyspepsia cases using validated mucin-based RT-qPCRs with subsequent immunohistochemistry validation and correlated the data with clinical outcome parameters. The gastric microbiota was assessed by 16S rRNA gene sequencing, taxonomy, and community composition determined, microbial networks analyzed, and the metagenome inferred in association with mucin phenotypes and expression. RESULTS Gastric adenocarcinomas with an intestinal mucin environment or high-level MUC13 expression are associated with poor survival. On the contrary, gastric MUC5AC or MUC6 abundance was associated with a more favorable outcome. The oral taxa Neisseria, Prevotella, and Veillonella had centralities in tumors with intestinal and mixed phenotypes and were associated with MUC13 overexpression, highlighting their role as potential drivers in MUC13 signaling in GC. Furthermore, dense bacterial networks were observed in intestinal and mixed mucin phenotype tumors whereas the lowest community complexity was shown in null mucin phenotype tumors due to higher Helicobacter abundance resulting in a more decreased diversity. Enrichment of oral or intestinal microbes was mucin phenotype dependent. More specifically, intestinal mucin phenotype tumors favored the establishment of pro-inflammatory oral taxa forming strong co-occurrence networks. CONCLUSIONS Our results emphasize key roles for mucins in gastric cancer prognosis and shaping microbial networks in the tumor microenvironment. Specifically, the enriched oral taxa associated with aberrant MUC13 expression can be potential biomarkers in predicting disease outcomes. Video Abstract.
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Affiliation(s)
- Baptiste Oosterlinck
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Wout Arras
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Karen Geboes
- Pathology Department, Gent University Hospital, Ghent, Belgium
| | - Heiko De Schepper
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
- Division of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium
| | - Marc Peeters
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Sarah Lebeer
- Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium
| | - Jurgita Skieceviciene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Georgina L Hold
- Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von-Guericke University, Magdeburg, Germany
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
- Division of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium
| | - Annemieke Smet
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium.
- Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium.
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11
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Ren AH, Filippou PS, Soosaipillai A, Dimitrakopoulos L, Korbakis D, Leung F, Kulasingam V, Bernardini MQ, Diamandis EP. Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes. Clin Chem Lab Med 2023; 61:464-472. [PMID: 36380677 DOI: 10.1515/cclm-2022-0491] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 11/07/2022] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is a transmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. METHODS We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. RESULTS MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). CONCLUSIONS We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.
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Affiliation(s)
- Annie H Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Panagiota S Filippou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Antoninus Soosaipillai
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lampros Dimitrakopoulos
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Dimitrios Korbakis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Felix Leung
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Marcus Q Bernardini
- Division of Gynecologic Oncology, University Health Network, Toronto, ON, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
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12
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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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13
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Sojka L, Opattova A, Bartu L, Horak J, Korenkova V, Novosadova V, Krizkova V, Bruha J, Liska V, Schneiderova M, Kubecek O, Vodickova L, Urbanova M, Simsa J, Vodicka P, Vymetalkova V. MUC13-miRNA-4647 axis in colorectal cancer: Prospects to identifications of risk factors and clinical outcomes. Oncol Lett 2022; 25:72. [PMID: 36688110 PMCID: PMC9843305 DOI: 10.3892/ol.2022.13658] [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: 08/04/2022] [Accepted: 12/09/2022] [Indexed: 01/01/2023] Open
Abstract
MUC13, a transmembrane mucin glycoprotein, is overexpressed in colorectal cancer (CRC), however, its regulation and functions are not fully understood. It has been shown that MUC13 protects colonic epithelial cells from apoptosis. Therefore, studying MUC13 and MUC13-regulated pathways may reveal promising therapeutic approaches for CRC treatment. Growing evidence suggests that microRNAs (miRs) are involved in the development and progression of CRC. In the present study, the MUC13-miR-4647 axis was addressed in association with survival of patients. miR-4647 is predicted in silico to bind to the MUC13 gene and was analyzed by RT-qPCR in 187 tumors and their adjacent non-malignant mucosa of patients with CRC. The impact of previously mentioned genes on survival and migration abilities of cancer cells was validated in vitro. Significantly upregulated MUC13 (P=0.02) in was observed tumor tissues compared with non-malignant adjacent mucosa, while miR-4647 (P=0.05) showed an opposite trend. Higher expression levels of MUC13 (log-rank P=0.05) were associated with worse patient's survival. The ectopic overexpression of studied miR resulted in decreased migratory abilities and worse survival of cells. Attenuated MUC13 expression levels confirmed the suppression of colony forming of CRC cells. In summary, the present data suggested the essential role of MUC13-miR-4647 in patients' survival, and this axis may serve as a novel therapeutic target. It is anticipated MUC13 may hold significant potential in the screening, diagnosis and treatment of CRC.
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Affiliation(s)
- Ladislav Sojka
- Department of Surgery, Thomayer Hospital, 14200 Prague, Czech Republic,Institute of Experimental Medicine, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic
| | - Alena Opattova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Linda Bartu
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic
| | - Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Department of Medical Genetics, 3rd Medical Faculty, Charles University, 10000 Prague, Czech Republic
| | - Vlasta Korenkova
- Institute of Immunology and Microbiology, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
| | - Vendula Novosadova
- Centre for Phenogenomics, Institute of Molecular Genetics, BIOCEV, 25250 Vestec, Czech Republic
| | - Vera Krizkova
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Jan Bruha
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Vaclav Liska
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Michaela Schneiderova
- Department of Surgery, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, 10034 Prague, Czech Republic
| | - Ondrej Kubecek
- Department of Oncology and Radiotherapy, University Hospital and Faculty of Medicine in Hradec Kralove, Charles University, 50005 Hradec Kralove, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Marketa Urbanova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic
| | - Jaromir Simsa
- Department of Surgery, Thomayer Hospital, 14200 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Correspondence to: Dr Veronika Vymetalkova, Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czech Republic, E-mail:
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14
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Taillieu E, Chiers K, Amorim I, Gärtner F, Maes D, Van Steenkiste C, Haesebrouck F. Gastric Helicobacter species associated with dogs, cats and pigs: significance for public and animal health. Vet Res 2022; 53:42. [PMID: 35692057 PMCID: PMC9190127 DOI: 10.1186/s13567-022-01059-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/10/2022] [Indexed: 12/14/2022] Open
Abstract
This article focuses on the pathogenic significance of Helicobacter species naturally colonizing the stomach of dogs, cats and pigs. These gastric "non-Helicobacter (H.) pylori Helicobacter species" (NHPH) are less well-known than the human adapted H. pylori. Helicobacter suis has been associated with gastritis and decreased daily weight gain in pigs. Several studies also attribute a role to this pathogen in the development of hyperkeratosis and ulceration of the non-glandular stratified squamous epithelium of the pars oesophagea of the porcine stomach. The stomach of dogs and cats can be colonized by several Helicobacter species but their pathogenic significance for these animals is probably low. Helicobacter suis as well as several canine and feline gastric Helicobacter species may also infect humans, resulting in gastritis, peptic and duodenal ulcers, and low-grade mucosa-associated lymphoid tissue lymphoma. These agents may be transmitted to humans most likely through direct or indirect contact with dogs, cats and pigs. Additional possible transmission routes include consumption of water and, for H. suis, also consumption of contaminated pork. It has been described that standard H. pylori eradication therapy is usually also effective to eradicate the NHPH in human patients, although acquired antimicrobial resistance may occasionally occur and porcine H. suis strains are intrinsically less susceptible to aminopenicillins than non-human primate H. suis strains and other gastric Helicobacter species. Virulence factors of H. suis and the canine and feline gastric Helicobacter species include urease activity, motility, chemotaxis, adhesins and gamma-glutamyl transpeptidase. These NHPH, however, lack orthologs of cytotoxin-associated gene pathogenicity island and vacuolating cytotoxin A, which are major virulence factors in H. pylori. It can be concluded that besides H. pylori, gastric Helicobacter species associated with dogs, cats and pigs are also clinically relevant in humans. Although recent research has provided better insights regarding pathogenic mechanisms and treatment strategies, a lot remains to be investigated, including true prevalence rates, exact modes of transmission and molecular pathways underlying disease development and progression.
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Affiliation(s)
- Emily Taillieu
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
| | - Koen Chiers
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Irina Amorim
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Porto, Portugal.,Institute of Pathology and Molecular Immunology, University of Porto (IPATIMUP), Porto, Portugal.,School of Medicine and Biomedical Sciences, Porto University, Porto, Portugal
| | - Fátima Gärtner
- Instituto de Investigação E Inovação Em Saúde (i3S), Universidade Do Porto, Porto, Portugal.,Institute of Pathology and Molecular Immunology, University of Porto (IPATIMUP), Porto, Portugal
| | - Dominiek Maes
- Department of Internal Medicine, Reproduction and Population Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp University, Edegem, Belgium.,Department of Gastroenterology and Hepatology, General Hospital Maria Middelares, Ghent, Belgium
| | - Freddy Haesebrouck
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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15
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Keikha M, Karbalaei M. Clinical aspects of Helicobacter heilmannii-associated gastritis in patients with dyspepsia: A systematic review and meta-analysis. Microb Pathog 2022; 166:105518. [PMID: 35405277 DOI: 10.1016/j.micpath.2022.105518] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/01/2022] [Accepted: 04/05/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND The clinical relevance of Helicobacter heilmannii (H. heilmannii) infection in patients with upper gastrointestinal diseases is not yet fully understood. The main purpose of this study was to evaluate the clinical, endoscopic, histopathological, and therapeutic features of H. heilmannii. METHODS To retrieve the relevant studies, we conducted a comprehensive systematic search of global databases such as the ISI Web of Science, PubMed, Scopus, Embase, and Google Scholar. After confirming the studies based on the inclusion criteria statistical analysis was performed using Comprehensive Meta-Analysis software. RESULTS In our study, the prevalence of infection with H. heilmannii was measured at 1.9% (95% CI: 0.8-4.2). The prevalence of H. heilmannii in Asian population was higher than Western countries (3.1% vs. 1.2%, respectively). Interestingly, the frequency of coinfection with both H. pylori and H. heilmannii was 15.4% (95% CI: 5.2-37.6). The most common endoscopic findings were chronic gastritis, hyperplasia, and erosion. In addition, our results showed that in people infected with this bacterium, gastric inflammation is typically chronic, focal, and less active than Helicobacter pylori (H. pylori) gastritis. Conventional treatment of H. pylori can lead to the eradication of H. heilmannii. CONCLUSION In general, H. heilmannii infection is significantly associated with mild chronic gastritis and can be treated with standard anti-H. pylori treatment.
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Affiliation(s)
- Masoud Keikha
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran.
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16
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Cai T, Peng B, Hu J, He Y. Long noncoding RNA BBOX1-AS1 promotes the progression of gastric cancer by regulating the miR-361-3p/Mucin 13 signaling axis. Bioengineered 2022; 13:13407-13421. [PMID: 36700475 PMCID: PMC9275992 DOI: 10.1080/21655979.2022.2072629] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Gastric cancer (GC) places a heavy burden on global health, and the information on the molecular mechanism of the progression of GC is still inadequate. Long noncoding RNA (LncRNA) has been confirmed to be widely involved in regulating the progression of GC. Our aim in this study was to explore the role and potential regulatory mechanism of lncRNA BBOX1-AS1 in GC. The expression levels of BBOX1-AS1, miR-361-3p, and MUC13 in GC tissues and cells were evaluated using quantitative real-time polymerase chain reaction and western blotting. The silencer of BBOX1 antisense RNA 1 (BBOX1-AS1) and mucin 13 (MUC13), the mimics and inhibitor of miR-361-3p, and their negative controls were used to alter the expression of these genes. Luciferase reporter, pull-down, and RNA immunoprecipitation assays were performed to verify the correlation between miR-361-3p, BBOX1-AS1, and MUC13. GC cell proliferation, invasion, and apoptosis were detected by cell counting kit-8, transwell, and flow cytometry assays, respectively. An in vivo functional experiment was performed to assess the effect of BBOX1-AS1 on GC. The results showed that BBOX1-AS1 was significantly upregulated in GC tissues. Silencing of BBOX1-AS1 inhibited GC cell proliferation and invasion and inhibited tumor growth in vivo, whereas it promoted apoptosis. MiR-361-3p was significantly downregulated in GC and counteracted the inhibitory effects of BBOX1-AS1 on GC progression. MUC13, which is targeted by miR-361-3p, is significantly upregulated in GC. MUC13 silencing inhibited GC progression was aborgated by miR-361-3p inhibitor. Collectively, BBOX1-AS1 silencing inhibits GC progression by regulating the miR-361-3p/MUC13 axis, providing a potential therapeutic biomarker for GC.
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Affiliation(s)
- Tao Cai
- Department of Gastrointestinal Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Binyu Peng
- Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Jun Hu
- Department of Gastrointestinal Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Yan He
- Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China,CONTACT Yan He Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, No. 26 Zhongshan Avenue, Qiaokou District, Wuhan 430033, Hubei, China
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17
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Pang Y, Zhang Y, Zhang HY, Wang WH, Jin G, Liu JW, Zhu ZJ. MUC13 promotes lung cancer development and progression by activating ERK signaling. Oncol Lett 2021; 23:37. [PMID: 34966453 PMCID: PMC8669675 DOI: 10.3892/ol.2021.13155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 05/14/2021] [Indexed: 01/14/2023] Open
Abstract
Mucin 13 (MUC13) is a glycoprotein that is expressed on the cell surface and participates in the tumorigenesis of multiple malignancies, including pancreatic cancer, colorectal cancer and renal cancer. However, to the best of our knowledge, the expression levels and function of MUC13 in lung cancer progression have not yet been demonstrated. Therefore, the present study examined the expression pattern and regulatory role of MUC13 in lung cancer tumorigenesis. The results demonstrated that MUC13 was highly expressed in lung cancer tissues and cell lines compared with that in normal tissues and cell lines. Functionally, knockdown of MUC13 inhibited cell proliferation and enhanced the apoptosis of A549 and NCI-H1650 lung cancer cells. Furthermore, silencing of MUC13 suppressed the migration and invasion of lung cancer cells. Additionally, a xenograft tumor model demonstrated that knockdown of MUC13 delayed the development of the lung cancer xenograft and suppressed the expression of proliferation marker Ki-67 in tumor tissues. Mechanistically, MUC13 activated the ERK signaling pathway by enhancing the phosphorylation of ERK, JNK and p38 in lung cancer tissues compared with that in normal tissues. Knockdown of MUC13 inhibited the phosphorylation of ERK/JNK/p38 in A549 and NCI-H1650 cells. Overall, these findings suggested that MUC13 could act as an oncogenic glycoprotein to accelerate the progression of lung cancer via abnormal activation of the ERK/JNK/p38 signaling pathway and might serve as a therapeutic target for lung cancer treatment.
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Affiliation(s)
- Yao Pang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yu Zhang
- Department of Clinical Medicine, Gansu Health Vocational College, Lanzhou, Gansu 730000, P.R. China
| | - Hong-Yi Zhang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Wen-Hao Wang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Gang Jin
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Jia-Wei Liu
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zi-Jiang Zhu
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
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18
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Proteomics Analysis of Gastric Cancer Patients with Diabetes Mellitus. J Clin Med 2021; 10:jcm10030407. [PMID: 33494396 PMCID: PMC7866049 DOI: 10.3390/jcm10030407] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/15/2021] [Accepted: 01/16/2021] [Indexed: 12/13/2022] Open
Abstract
Proteomics is a powerful approach to study the molecular mechanisms of cancer. In this study, we aim to characterize the proteomic profile of gastric cancer (GC) in patients with diabetes mellitus (DM) type 2. Forty GC tissue samples including 19 cases from diabetic patients and 21 cases from individuals without diabetes (control group) were selected for the proteomics analysis. Gastric tissues were processed following the single-pot, solid-phase-enhanced sample preparation approach-SP3 and enzymatic digestion with trypsin. The resulting peptides were analyzed by LC-MS Liquid Chromatography-Mass Spectrometry (LC-MS). The comparison of protein expression levels between GC samples from diabetic and non-diabetic patients was performed by label-free quantification (LFQ). A total of 6599 protein groups were identified in the 40 samples. Thirty-seven proteins were differentially expressed among the two groups, with 16 upregulated and 21 downregulated in the diabetic cohort. Statistical overrepresentation tests were considered for different annotation sets including the Gene Ontology(GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Disease functional databases. Upregulated proteins in the GC samples from diabetic patients were particularly enriched in respiratory electron transport and alcohol metabolic biological processes, while downregulated proteins were associated with epithelial cancers, intestinal diseases, and cell-cell junction cellular components. Taken together, these results support the data already obtained by previous studies that associate diabetes with metabolic disorders and diabetes-associated diseases, such as Alzheimer's and Parkinson's, and also provide valuable insights into seven GC-associated protein targets, claudin-3, polymeric immunoglobulin receptor protein, cadherin-17, villin-1, transglutaminase-2, desmoglein-2, and mucin-13, which warrant further investigation.
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Zhou Y, Yang W, Ao M, Höti N, Gabrielson E, Chan DW, Zhang H, Li QK. Proteomic Analysis of the Air-Way Fluid in Lung Cancer. Detection of Periostin in Bronchoalveolar Lavage (BAL). Front Oncol 2020; 10:1072. [PMID: 32719746 PMCID: PMC7350406 DOI: 10.3389/fonc.2020.01072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/28/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Bronchoalveolar lavage (BAL) is a specific type of air-way fluid. It is a commonly used clinical specimen for the diagnosis of benign diseases and cancers of the lung. Although previous studies have identified several disease-associated proteins in the BAL, the potential utility of BAL in lung cancer is still not well-studied. Based upon the fact that the majority of secreted proteins are glycoproteins, we have profiled N-glycoproteins in BAL collected from lung cancers, and investigated the expression of glycoproteins such as the matrix N-glycoprotein, periostin, in lung cancers. Methods: BAL specimens (n = 16) were collected from lung cancer patients, and analyzed using mass spectrometry-based quantitative N-glycoproteomic technique. Additional BAL specimens (n = 39) were independently collected to further evaluate the expression of periostin by using an enzyme-linked immunosorbent assay (ELISA). Results: A total of 462 glycoproteins were identified in BAL samples using N-glycoproteomic technique, including 290 in lung adenocarcinoma (ADC, n = 5), 376 in squamous cell carcinoma (SQCC, n = 4), 309 in small cell lung carcinoma (SCLC, n = 4), and 316 in benign lung disease (n = 3). The expressions of several glycoproteins were elevated, including 8 in ADC, 12 in SQCC, and 17 in SCLC, compared to benign BALs. The expression of periostin was detected in all subtypes of lung cancers. To further investigate the expression of periostin, an ELISA assay was performed using additional independently collected BALs (n = 39) The normalized levels of periostin in benign disease, ADC, SQCC, and SCLC were 255 ± 104 (mean ± SE) and 4,002 ± 2,181, 3,496 ± 1,765, and 1,772 ± 1,119 ng/mg of total BAL proteins. Conclusion: Our findings demonstrate that proteomic analysis of BAL can be used for the study of cancer-associated extracellular proteins in air-way fluid from lung cancer patients.
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Affiliation(s)
- Yangying Zhou
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Weiming Yang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Minghui Ao
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Naseruddin Höti
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Edward Gabrielson
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.,Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.,Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Hui Zhang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.,Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD, United States
| | - Qing Kay Li
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.,Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD, United States
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MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways. J Hepatol 2020; 72:761-773. [PMID: 31837357 DOI: 10.1016/j.jhep.2019.11.021] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 10/31/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.
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Rajilic-Stojanovic M, Figueiredo C, Smet A, Hansen R, Kupcinskas J, Rokkas T, Andersen L, Machado JC, Ianiro G, Gasbarrini A, Leja M, Gisbert JP, Hold GL. Systematic review: gastric microbiota in health and disease. Aliment Pharmacol Ther 2020; 51:582-602. [PMID: 32056247 DOI: 10.1111/apt.15650] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/09/2020] [Accepted: 01/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori is the most infamous constituent of the gastric microbiota and its presence is the strongest risk factor for gastric cancer and other gastroduodenal diseases. Although historically the healthy stomach was considered a sterile organ, we now know it is colonised with a complex microbiota. However, its role in health and disease is not well understood. AIM To systematically explore the literature on the gastric microbiota in health and disease as well as the gut microbiota after bariatric surgery. METHODS A systematic search of online bibliographic databases MEDLINE/EMBASE was performed between 1966 and February 2019 with screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomised controlled trials, cohort studies and observational studies were included if they reported next-generation sequencing derived microbiota analysis on gastric aspirate/tissue or stool samples (bariatric surgical outcomes). RESULTS Sixty-five papers were eligible for inclusion. With the exception of H pylori-induced conditions, overarching gastric microbiota signatures of health or disease could not be determined. Gastric carcinogenesis induces a progressively altered microbiota with an enrichment of oral and intestinal taxa as well as significant changes in host gastric mucin expression. Proton pump inhibitors usage increases gastric microbiota richness. Bariatric surgery is associated with an increase in potentially pathogenic proteobacterial species in patient stool samples. CONCLUSION While H pylori remains the single most important risk factor for gastric disease, its capacity to shape the collective gastric microbiota remains to be fully elucidated. Further studies are needed to explore the intricate host/microbial and microbial/microbial interplay.
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MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity. Oncogene 2019; 38:7294-7310. [PMID: 31427737 DOI: 10.1038/s41388-019-0951-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 02/26/2019] [Accepted: 05/12/2019] [Indexed: 12/13/2022]
Abstract
Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103+ dendritic cells and CD8+ T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.
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Loss of Bcl-G, a Bcl-2 family member, augments the development of inflammation-associated colorectal cancer. Cell Death Differ 2019; 27:742-757. [PMID: 31296963 PMCID: PMC7206067 DOI: 10.1038/s41418-019-0383-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 06/06/2019] [Accepted: 06/17/2019] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal epithelial cells provide a selective barrier that segregates the host immune system from luminal microorganisms, thereby contributing directly to the regulation of homeostasis. We have shown that from early embryonic development Bcl-G, a Bcl-2 protein family member with unknown function, was highly expressed in gastrointestinal epithelial cells. While Bcl-G was dispensable for normal growth and development in mice, the loss of Bcl-G resulted in accelerated progression of colitis-associated cancer. A label-free quantitative proteomics approach revealed that Bcl-G may contribute to the stability of a mucin network, which when disrupted, is linked to colon tumorigenesis. Consistent with this, we observed a significant reduction in Bcl-G expression in human colorectal tumors. Our study identifies an unappreciated role for Bcl-G in colon cancer.
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Resistance to ETEC F4/F18-mediated piglet diarrhoea: opening the gene black box. Trop Anim Health Prod 2019; 51:1307-1320. [PMID: 31127494 DOI: 10.1007/s11250-019-01934-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 05/15/2019] [Indexed: 01/08/2023]
Abstract
Diarrhoea, a significant problem in pig rearing industry affecting pre- and post-weaning piglets is caused by enterotoxigenic Escherichia coli (ETEC). The ETEC are classified as per the fimbriae types which are responsible for bacterial attachment with enterocytes and release of toxins causing diarrhoea. However, genetic difference exists for susceptibility to ETEC infection in piglets. The different phenotypes found in pigs determine their (pigs') susceptibility or resistance towards fimbrial subtypes/variants (F4ab, F4ac, F4ad and F18). Specific receptors are present on intestinal epithelium for attachment of these fimbriae, which do not express to same level in all animals. This differential expression is genetically determined and thus their genetic causes (may be putative candidate gene or mutations) render some animals resistant or susceptible to one or more fimbrial subtypes. Genetic linkage studies have revealed the mapping location of the receptor loci for the two most frequent variants F4ab and F4ac to SSC13q41 (i.e. q arm of 13th chromosome of Sus scrofa). Some SNPs have been identified in mucin gene family, transferring receptor gene, fucosyltransferase 1 gene and swine leucocyte antigen locus that are proposed to be linked mutations for resistance/susceptibility towards ETEC diarrhoea. However, owing to the variety of fimbrial types and subtypes, it would be difficult to identify a single causative mutation and the candidate loci may involve more number of genes/regions. In this review, we focus on the genetic mutations in genes involved in imparting resistance/susceptibility to F4 or F18 ETEC diarrhoea and possibilities to use them as marker for selection against susceptible animals.
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Volstatova T, Marchica A, Hroncova Z, Bernardi R, Doskocil I, Havlik J. Effects of chlorogenic acid, epicatechin gallate, and quercetin on mucin expression and secretion in the Caco-2/HT29-MTX cell model. Food Sci Nutr 2019; 7:492-498. [PMID: 30847127 PMCID: PMC6392881 DOI: 10.1002/fsn3.818] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022] Open
Abstract
Mucins are a family of large glycoproteins that represent the major structural components of the mucus and are encoded by 20 different mucin genes. Mucin expression can be modulated by different stimuli. In this study, we analyzed four mucins (MUC2, MUC3, MUC13, and MUC17) in coculture of Caco-2/HT29-MTX cells to demonstrate the variation in gene expression in the presence of antioxidant compounds like chlorogenic acid, epicatechin gallate, and quercetin (apple, tea, and coffee polyphenols, respectively). coculture of Caco-2/HT29-MTX cells was treated with polyphenols, and the expression of four mucins was determined by reverse-transcriptase PCR. In addition, the secretion levels of MUC2 were established by enzyme-linked immunoassay (ELISA) analysis. The results showed that each polyphenol compound induces different expression patterns of the mucin genes. Statistically significant up-regulation of MUC17 was observed following incubation with epicatechin gallate and quercetin. ELISA results did not prove any significant differences in protein levels of MUC2 after treatment by the polyphenol compounds. The polyphenols considered in this study may influence mucin secretion and act on diverse salivary substrates to change the barrier properties of mucins for mucus secretion in different ways.
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Affiliation(s)
- Tereza Volstatova
- Department of Microbiology, Nutrition and DieteticsCzech University of Life Sciences PraguePragueCzech Republic
| | - Alessandra Marchica
- Department of Agricultural, Food and Agro‐Environmental SciencesUniversity of PisaPisaItaly
| | - Zuzana Hroncova
- Department of Microbiology, Nutrition and DieteticsCzech University of Life Sciences PraguePragueCzech Republic
- Department of Genetics and Breeding of Farm AnimalsInstitute of Animal SciencePragueCzech Republic
| | - Rodolfo Bernardi
- Department of Agricultural, Food and Agro‐Environmental SciencesUniversity of PisaPisaItaly
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”University of PisaPisaItaly
| | - Ivo Doskocil
- Department of Microbiology, Nutrition and DieteticsCzech University of Life Sciences PraguePragueCzech Republic
| | - Jaroslav Havlik
- Department of Quality of Agricultural ProductsCzech University of Life Sciences PraguePragueCzech Republic
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Filippou PS, Ren AH, Korbakis D, Dimitrakopoulos L, Soosaipillai A, Barak V, Frenkel S, Pe'er J, Lotem M, Merims S, Molina R, Blasutig I, Bogdanos DP, Diamandis EP. Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. Clin Chem Lab Med 2018; 56:1945-1953. [PMID: 29768245 DOI: 10.1515/cclm-2018-0139] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/10/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions. METHODS We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals. RESULTS MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease. CONCLUSIONS Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential.
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Affiliation(s)
- Panagiota S Filippou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Annie H Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Dimitrios Korbakis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lampros Dimitrakopoulos
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Antoninus Soosaipillai
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Vivian Barak
- Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Shahar Frenkel
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Jacob Pe'er
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michal Lotem
- Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Sharon Merims
- Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Rafael Molina
- Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Ivan Blasutig
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, University of Thessaly, Larissa, Greece
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St [Box 32], Flr 6 - Rm L6-201, Toronto, ON, M5T 3L9, Canada
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Xu Z, Liu Y, Yang Y, Wang J, Zhang G, Liu Z, Fu H, Wang Z, Liu H, Xu J. High expression of Mucin13 associates with grimmer postoperative prognosis of patients with non-metastatic clear-cell renal cell carcinoma. Oncotarget 2018; 8:7548-7558. [PMID: 27911274 PMCID: PMC5352342 DOI: 10.18632/oncotarget.13692] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 11/22/2016] [Indexed: 01/11/2023] Open
Abstract
Background Mucin13 (MUC13) is a transmembrane glycoprotein that is aberrantly expressed in ovarian and gastro-intestinal tumors, but its role in renal cell carcinoma remains elusive. The purpose of this study is to evaluate the prognostic value of MUC13 expression in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) after surgical resection. Results MUC13 high expression was associated with high Fuhrman grade (p < 0.001), high SSIGN score (p = 0.011), early recurrence (p < 0.001) and poor survival (p < 0.001). Multivariate Cox regression analysis identified MUC13 expression as an independent prognostic factor for RFS and OS of ccRCC patients. A nomogram integrating MUC13 expression and other independent prognosticators was established to predict RFS and OS of ccRCC patients. Optimal agreement was shown between the predictions and observations in calibration curves. Matrials and methods This study enrolled 410 postoperative non-metastatic ccRCC patients at a single institution. Clinicopathologic variables, recurrence-free survival (RFS), and overall survival (OS) were recorded. MUC13 expression was detected by immunohistochemical staining in tumor specimens. Association of MUC13 expression with clinicopathological factors was explored. Kaplan-Meier analysis was performed to compare survival curves. Univariate and multivariate Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. A prognostic nomogram was constructed based on the independent prognostic factors identified by multivariate analysis. Conclusions MUC13 high expression is a novel independent adverse prognostic factor of clinical outcome in non-metastatic ccRCC patients after surgery.
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Affiliation(s)
- Zhiying Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yidong Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yuanfeng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jieti Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Guodong Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zheng Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Hangcheng Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zewei Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Haiou Liu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:378-391. [DOI: 10.1016/j.ajpath.2017.10.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/25/2017] [Accepted: 10/19/2017] [Indexed: 12/27/2022]
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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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Cairns MT, Gupta A, Naughton JA, Kane M, Clyne M, Joshi L. Glycosylation-related gene expression in HT29-MTX-E12 cells upon infection by Helicobacter pylori. World J Gastroenterol 2017; 23:6817-6832. [PMID: 29085225 PMCID: PMC5645615 DOI: 10.3748/wjg.v23.i37.6817] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 06/09/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify glycosylation-related genes in the HT29 derivative cell line, HT29-MTX-E12, showing differential expression on infection with Helicobacter pylori (H. pylori). METHODS Polarised HT29-MTX-E12 cells were infected for 24 h with H. pylori strain 26695. After infection RNA was isolated from both infected and non-infected host cells. Sufficient infections were carried out to provide triplicate samples for microarray analysis and for qRT-PCR analysis. RNA was isolated and hybridised to Affymetrix arrays. Analysis of microarray data identified genes significantly differentially expressed upon infection. Genes were grouped into gene ontology functional categories. Selected genes associated with host glycan structure (glycosyltransferases, hydrolases, lectins, mucins) were validated by real-time qRT-PCR analysis. RESULTS Infection of host cells was confirmed by the isolation of live bacteria after 24 h incubation and by PCR amplification of bacteria-specific genes from the host cell RNA. H. pylori do not survive incubation under the adopted culture conditions unless they associate with the adherent mucus layer of the host cell. Microarray analysis identified a total of 276 genes that were significantly differentially expressed (P < 0.05) upon H. pylori infection and where the fold change in expression was greater than 2. Six of these genes are involved in glycosylation-related processes. Real-time qRT-PCR demonstrated significant downregulation (1.8-fold, P < 0.05) of the mucin MUC20. REG4 was heavily expressed and significantly downregulated (3.1-fold, P < 0.05) upon infection. Gene ontology analysis was consistent with previous studies on H. pylori infection. CONCLUSION Gene expression data suggest that infection with H. pylori causes a decrease in glycan synthesis, resulting in shorter and simpler glycan structures.
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Affiliation(s)
- Michael T Cairns
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Ananya Gupta
- School of Natural Sciences, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Julie A Naughton
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland
| | - Marian Kane
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Marguerite Clyne
- Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland
| | - Lokesh Joshi
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 CF50 Galway, Ireland
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Sheng Y, Ng CP, Lourie R, Shah ET, He Y, Wong KY, Seim I, Oancea I, Morais C, Jeffery PL, Hooper J, Gobe GC, McGuckin MA. MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance. Int J Cancer 2017; 140:2351-2363. [PMID: 28205224 DOI: 10.1002/ijc.30651] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/21/2016] [Accepted: 01/25/2017] [Indexed: 01/09/2023]
Abstract
Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti-apoptotic proteins, BCL-xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi-kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.
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Affiliation(s)
- Yonghua Sheng
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Choa Ping Ng
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Rohan Lourie
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Esha T Shah
- Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Yaowu He
- Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia
| | - Kuan Yau Wong
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Inge Seim
- Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Iulia Oancea
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Christudas Morais
- Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia
| | - Penny L Jeffery
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.,Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - John Hooper
- Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia
| | - Glenda C Gobe
- Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia
| | - Michael A McGuckin
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
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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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33
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Sheng YH, He Y, Hasnain SZ, Wang R, Tong H, Clarke DT, Lourie R, Oancea I, Wong KY, Lumley JW, Florin TH, Sutton P, Hooper JD, McMillan NA, McGuckin MA. MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target. Oncogene 2016; 36:700-713. [PMID: 27399336 PMCID: PMC5541270 DOI: 10.1038/onc.2016.241] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 05/24/2016] [Accepted: 06/01/2016] [Indexed: 02/07/2023]
Abstract
MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.
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Affiliation(s)
- Y H Sheng
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Y He
- Cancer Biology Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - S Z Hasnain
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - R Wang
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - H Tong
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - D T Clarke
- Molecular Basis of Disease Program, School of Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland, Australia
| | - R Lourie
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.,Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - I Oancea
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.,Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - K Y Wong
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - J W Lumley
- Wesley Hospital, Auchenflower, Australia
| | - T H Florin
- Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - P Sutton
- Mucosal Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.,Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Victoria, Australia
| | - J D Hooper
- Cancer Biology Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - N A McMillan
- Molecular Basis of Disease Program, School of Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland, Australia
| | - M A McGuckin
- Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
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Comparative genome-wide association studies of a depressive symptom phenotype in a repeated measures setting by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis. BMC Genet 2015; 16:118. [PMID: 26459564 PMCID: PMC4603946 DOI: 10.1186/s12863-015-0274-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 09/30/2015] [Indexed: 11/29/2022] Open
Abstract
Background Time-varying phenotypes have been studied less frequently in the context of genome-wide analyses across ethnicities, particularly for mood disorders. This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163). Methods This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163). Results Several novel variants were identified at the genome-wide suggestive level (5×10−8 < p-value ≤ 5×10−6) in each ethnicity for each approach to analyzing depressive symptoms. The repeated measures analyses resulted in typically smaller p-values and an increase in the number of single-nucleotide polymorphisms (SNP) reaching genome-wide suggestive level. Conclusions For phenotypes that vary over time, the detection of genetic predictors may be enhanced by repeated measures analyses. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0274-0) contains supplementary material, which is available to authorized users.
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35
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Steiner J, Davis J, McClellan J, Enos R, Carson J, Fayad R, Nagarkatti M, Nagarkatti P, Altomare D, Creek K, Murphy E. Dose-dependent benefits of quercetin on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer. Cancer Biol Ther 2015; 15:1456-67. [PMID: 25482952 DOI: 10.4161/15384047.2014.955444] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anti-carcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/SV40 Tag mice were randomized to one of four dietary treatments (n = 15-16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted 'U' dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 ± 0.9; C3-0.2%: 7.3 ± 0.9) and (C3-Con: 2061.8 ± 977.0 mm(3); and C3-0.2%: 462.9 ± 75.9 mm(3)). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 ± 305.9 mm(3); C3-0.02%: 1401.5 ± 555.6 mm(3)), as was tumor number (C3-2%: 10.7 ± 1.3 mm(3); C3-0.02%: 8.1 ± 1.1 mm(3)). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment.
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Key Words
- BW, body weight
- DCIS, ductal carcinoma in situ
- DEPTOR, DEP domain containing mTOR-interacting protein
- DEXA, dual-energy X-ray absorptiometry
- ERα, estrogen receptor alpha
- FABP7, fatty acid binding protein-7
- GREB1, growth regulation by estrogen in breast cancer
- MIN, mammary intraepithelial neoplasia
- Muc13, Mucin 13
- NGFR, nerve growth factor receptor
- TIMP4, tissue inhibitor of metalloproteinases-4
- TMPRSS4, transmembrane protease serine 4
- dose-response
- flavonoid
- gene expression microarray
- krt6a/b, keratin 6A/B
- mammary tumorigenesis
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Affiliation(s)
- Jl Steiner
- a Department of Pathology Microbiology and Immunology ; University of South Carolina School of Medicine ; Columbia , SC USA
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Nishii Y, Yamaguchi M, Kimura Y, Hasegawa T, Aburatani H, Uchida H, Hirata K, Sakuma Y. A newly developed anti-Mucin 13 monoclonal antibody targets pancreatic ductal adenocarcinoma cells. Int J Oncol 2015; 46:1781-7. [PMID: 25672256 DOI: 10.3892/ijo.2015.2880] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 01/05/2015] [Indexed: 11/06/2022] Open
Abstract
Pancreatic cancer is one of the most severe forms of malignancy. Patients with unresectable or metastatic pancreatic cancer usually receive chemotherapy that causes various adverse effects. Antibody-drug conjugates (ADCs), drugs developed by conjugating an anticancer agent to a monoclonal antibody (mAb), can alleviate the side effects of chemotherapy because ADCs selectively bind to cancer cells expressing a particular antigen. We recently developed the recombinant protein DT3C comprising diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of Streptococcus protein G (3C). The mAb-DT3C conjugates can be used to select mAbs that are internalized by cells, because the conjugates decrease cell viability only when they are internalized by cells through Ab-antigen reactions. We developed a new mAb to be internalized by TCC-PAN2 cells, a pancreatic carcinoma cell line. The mAb, designated TCC56, recognized Mucin 13 (MUC13), while TCC56‑DT3C conjugates induced cell death in TCC-PAN2 cells expressing MUC13. We found that MUC13 was expressed, at least partially, in all 40 pancreatic ductal carcinoma tissues and adjacent non-cancerous tissues analyzed. The expression levels of MUC13 in pancreatic cancer tissues were greater than those in normal tissues. Our findings suggest that MUC13 can be a target molecule for pancreatic cancer treatment. ADCs, including mAb TCC56, could be promising anticancer agents to alleviate the adverse effects of chemotherapy.
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Affiliation(s)
- Yukari Nishii
- Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Miki Yamaguchi
- Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Uchida
- Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Koichi Hirata
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuji Sakuma
- Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Functions and regulation of MUC13 mucin in colon cancer cells. J Gastroenterol 2014; 49:1378-91. [PMID: 24097071 PMCID: PMC3979492 DOI: 10.1007/s00535-013-0885-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 09/09/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND MUC13 is overexpressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. METHODS Stable cell lines with either overexpressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. RESULTS Overexpression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase, sonic hedgehog, B cell lymphoma murine like site 1, and GATA like transcription factor 1. Additionally, MUC13-overexpressing cells showed increased HER2 and P-ERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of the JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6-induced MUC13 expression. IHC analysis showed increased expression of both P-STAT5 and MUC13 in colon cancer as compared to adjacent normal tissue. CONCLUSIONS The results of this study, for the first time, suggest functional roles of MUC13 in colon cancer progression and provide information regarding the regulation of MUC13 expression via JAK2/STAT5 which may reveal promising therapeutic approaches for colon cancer treatment.
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Sung HY, Park AK, Ju W, Ahn JH. Overexpression of mucin 13 due to promoter methylation promotes aggressive behavior in ovarian cancer cells. Yonsei Med J 2014; 55:1206-13. [PMID: 25048476 PMCID: PMC4108803 DOI: 10.3349/ymj.2014.55.5.1206] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Recent discoveries suggest that aberrant DNA methylation provides cancer cells with advanced metastatic properties. However, the precise regulatory mechanisms controlling metastasis genes and their role in metastatic transformation are largely unknown. To address epigenetically-regulated gene products involved in ovarian cancer metastasis, we examined the mechanisms regulating mucin 13 (MUC13) expression and its influence on aggressive behaviors of ovarian malignancies. MATERIALS AND METHODS We injected SK-OV-3 ovarian cancer cells peritoneally into nude mice to mimic human ovarian tumor metastasis. Overexpression of MUC13 mRNA was detected in metastatic implants from the xenografts by expression microarray analysis and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The DNA methylation status within the MUC13 promoter region was determined using bisulfite sequencing PCR and quantitative methylation-specific PCR. We evaluated the effects of exogenous MUC13 on cell invasion and migration using in vitro transwell assays. RESULTS MUC13 mRNA expression was up-regulated, and methylation of specific CpG sites within the promoter was reduced in the metastatic implants relative to those in wild-type SK-OV-3 cells. Addition of a DNA methyltransferase inhibitor to SK-OV-3 cells induced MUC13 expression, thereby implying epigenetic regulation of MUC13 by promoter methylation. MUC13 overexpression increased migration and invasiveness, compared to control cells, suggesting aberrant up-regulation of MUC13 is strongly associated with progression of aggressive behaviors in ovarian cancer. CONCLUSION We provide novel evidence for epigenetic regulation of MUC13 in ovarian cancer. We suggest that the DNA methylation status within the MUC13 promoter region may be a potential biomarker of aggressive behavior in ovarian cancer.
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Affiliation(s)
- Hye Youn Sung
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea
| | - Ae Kyung Park
- College of Pharmacy, Sunchon National University, Suncheon, Korea
| | - Woong Ju
- Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, Korea.
| | - Jung-Hyuck Ahn
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea.
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Gastric de novo Muc13 expression and spasmolytic polypeptide-expressing metaplasia during Helicobacter heilmannii infection. Infect Immun 2014; 82:3227-39. [PMID: 24866791 DOI: 10.1128/iai.01867-14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Helicobacter heilmannii is a zoonotic bacterium that has been associated with gastric disease in humans. In this study, the mRNA expression of mucins in the stomach of BALB/c mice was analyzed at several time points during a 1-year infection with this bacterium, during which gastric disease progressed in severity. Markers for acid production by parietal cells and mucous metaplasia were also examined. In the first 9 weeks postinfection, the mRNA expression of Muc6 was clearly upregulated in both the antrum and fundus of the stomach of H. heilmannii-infected mice. Interestingly, Muc13 was upregulated already at 1 day postinfection in the fundus of the stomach. Its expression level remained high in the stomach over the course of the infection. This mucin is, however, not expressed in a healthy stomach, and high expression of this mucin has so far only been described in gastric cancer. In the later stages of infection, mRNA expression of H(+)/K(+)-ATPase α/β and KCNQ1 decreased, whereas the expression of Muc4, Tff2, Dmbt1, and polymeric immunoglobulin receptor (pIgR) increased starting at 16 weeks postinfection onwards, suggesting the existence of spasmolytic polypeptide-expressing metaplasia in the fundus of the stomach. Mucous metaplasia present in the mucosa surrounding low-grade mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions was also histologically confirmed. Our findings indicate that H. heilmannii infection causes severe gastric pathologies and alterations in the expression pattern of gastric mucins, such as Muc6 and Muc13, as well as disrupting gastric homeostasis by inducing the loss of parietal cells, resulting in the development of mucous metaplasia.
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40
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Sahasrabuddhe NA, Barbhuiya MA, Bhunia S, Subbannayya T, Gowda H, Advani J, Shrivastav BR, Navani S, Leal P, Roa JC, Chaerkady R, Gupta S, Chatterjee A, Pandey A, Tiwari PK. Identification of prosaposin and transgelin as potential biomarkers for gallbladder cancer using quantitative proteomics. Biochem Biophys Res Commun 2014; 446:863-9. [PMID: 24657443 DOI: 10.1016/j.bbrc.2014.03.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 03/04/2014] [Indexed: 01/11/2023]
Abstract
Gallbladder cancer is an uncommon but lethal malignancy with particularly high incidence in Chile, India, Japan and China. There is a paucity of unbiased large-scale studies investigating molecular basis of gallbladder cancer. To systematically identify differentially regulated proteins in gallbladder cancer, iTRAQ-based quantitative proteomics of gallbladder cancer was carried out using Fourier transform high resolution mass spectrometry. Of the 2575 proteins identified, proteins upregulated in gallbladder cancer included several lysosomal proteins such as prosaposin, cathepsin Z and cathepsin H. Downregulated proteins included serine protease HTRA1 and transgelin, which have been reported to be downregulated in several other cancers. Novel biomarker candidates including prosaposin and transgelin were validated to be upregulated and downregulated, respectively, in gallbladder cancer using tissue microarrays. Our study provides the first large scale proteomic characterization of gallbladder cancer which will serve as a resource for future discovery of biomarkers for gallbladder cancer.
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Affiliation(s)
| | - Mustafa A Barbhuiya
- Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior 474011, India; School of Studies in Zoology, Jiwaji University, Gwalior, India
| | - Shushruta Bhunia
- Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior 474011, India
| | - Tejaswini Subbannayya
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India; Amrita School of Biotechnology, Amrita University, Kollam, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Jayshree Advani
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | | | | | - Pamela Leal
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Juan Carlos Roa
- Department of Pathology, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Raghothama Chaerkady
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sanjeev Gupta
- Cancer Hospital and Research Institute, Gwalior, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Pramod K Tiwari
- Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior 474011, India; School of Studies in Zoology, Jiwaji University, Gwalior, India.
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Poon CE, Lecce L, Day ML, Murphy CR. Mucin 15 is lost but mucin 13 remains in uterine luminal epithelial cells and the blastocyst at the time of implantation in the rat. Reprod Fertil Dev 2014; 26:421-31. [DOI: 10.1071/rd12313] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 02/18/2013] [Indexed: 01/28/2023] Open
Abstract
The glycocalyx of the uterine luminal epithelium in the rat undergoes considerable reduction before implantation. In particular, the reduction of some mucins is necessary to facilitate blastocyst adhesion and subsequent implantation. The present study investigated the localisation, abundance and hormonal control of two mucin proteins, Muc13 and Muc15, in rat uterine epithelial cells during early pregnancy to determine whether they are likely to play a role in uterine receptivity for implantation. Muc13 and Muc15 are localised to the uterine luminal epithelium but show a presence and an absence, respectively, at the apical cell surface at the time of implantation. This localisation corresponds to changes in the molecular weights of Muc13 and Muc15, as shown with western blotting analysis. Furthermore, the localisation of Muc13 and Muc15 was shown to be controlled by the ovarian hormones, oestrogen and progesterone, and they were also localised in preimplantation rat blastocysts. Our results suggest that Muc15 may operate in an anti-adhesive capacity to prevent implantation while Muc13 potentially functions in either an adhesive or cell-signalling role in the events of implantation.
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Wang R, Yu C, Zhao D, Wu M, Yang Z. The mucin-type glycosylating enzyme polypeptide N-acetylgalactosaminyltransferase 14 promotes the migration of ovarian cancer by modifying mucin 13. Oncol Rep 2013; 30:667-76. [PMID: 23708057 DOI: 10.3892/or.2013.2493] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 04/10/2013] [Indexed: 11/05/2022] Open
Abstract
A high expression of O-glycosylated proteins is one of the prominent characteristics of ovarian carcinoma cells associated with cell migration, which would be attributed to the upregulated expression of glycosyltransferases. Therefore, elucidating glycosyltransferases and their substrates may improve our understanding of their roles in tumor metastasis. In the present study, we reported that knockdown of polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14) by small interfering RNA significantly suppressed the cell migration and altered cellular morphology. Immunoprecipitation and western blot analyses indicated that GALNT14 contributed to the glycosylation of transmembrane mucin 13 (MUC13), which was significantly higher in ovarian cancer cells compared with the normal/benign ovary tissues. Furthermore, interleukin-8 (IL-8), which could regulate the migration ability of epithelial ovarian cancer (EOC) cells, had no remarkable effect on the expression of GALNT14 and the tumor-associated carbohydrate epitope Tn antigen. In addition, extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor modulated the expression levels of GALNT14. Our findings provide evidence that GALNT14 may contribute to ovarian carcinogenesis through aberrant glycosylation of MUC13, but not through the IL-8 pathway. These data provide novel insights into understanding the function of MUC13 on neoplasm metastasis and may aid in the development of new anticancer drugs for EOC.
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MESH Headings
- Antigens, Tumor-Associated, Carbohydrate/genetics
- Antigens, Tumor-Associated, Carbohydrate/metabolism
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Carcinoma, Ovarian Epithelial
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Movement/physiology
- Female
- Glycosylation
- Humans
- Interleukin-8/genetics
- Interleukin-8/metabolism
- MAP Kinase Signaling System/genetics
- Mucins/genetics
- Mucins/metabolism
- N-Acetylgalactosaminyltransferases/genetics
- N-Acetylgalactosaminyltransferases/metabolism
- Neoplasm Metastasis
- Neoplasms, Glandular and Epithelial/enzymology
- Neoplasms, Glandular and Epithelial/genetics
- Neoplasms, Glandular and Epithelial/metabolism
- Neoplasms, Glandular and Epithelial/pathology
- Ovarian Neoplasms/enzymology
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Polypeptide N-acetylgalactosaminyltransferase
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Affiliation(s)
- Ranran Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China
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Toyoda T, Tsukamoto T, Yamamoto M, Ban H, Saito N, Takasu S, Shi L, Saito A, Ito S, Yamamura Y, Nishikawa A, Ogawa K, Tanaka T, Tatematsu M. Gene expression analysis of a Helicobacter pylori-infected and high-salt diet-treated mouse gastric tumor model: identification of CD177 as a novel prognostic factor in patients with gastric cancer. BMC Gastroenterol 2013; 13:122. [PMID: 23899160 PMCID: PMC3734037 DOI: 10.1186/1471-230x-13-122] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 07/22/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model. METHODS To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis. RESULTS The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival. CONCLUSIONS These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.
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44
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Mucins as diagnostic and prognostic biomarkers in a fish-parasite model: transcriptional and functional analysis. PLoS One 2013; 8:e65457. [PMID: 23776483 PMCID: PMC3680472 DOI: 10.1371/journal.pone.0065457] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 04/26/2013] [Indexed: 01/01/2023] Open
Abstract
Mucins are O-glycosylated glycoproteins present on the apex of all wet-surfaced epithelia with a well-defined expression pattern, which is disrupted in response to a wide range of injuries or challenges. The aim of this study was to identify mucin gene sequences of gilthead sea bream (GSB), to determine its pattern of distribution in fish tissues and to analyse their transcriptional regulation by dietary and pathogenic factors. Exhaustive search of fish mucins was done in GSB after de novo assembly of next-generation sequencing data hosted in the IATS transcriptome database (www.nutrigroup-iats.org/seabreamdb). Six sequences, three categorized as putative membrane-bound mucins and three putative secreted-gel forming mucins, were identified. The transcriptional tissue screening revealed that Muc18 was the predominant mucin in skin, gills and stomach of GSB. In contrast, Muc19 was mostly found in the oesophagus and Muc13 was along the entire intestinal tract, although the posterior intestine exhibited a differential pattern with a high expression of an isoform that does not share a clear orthologous in mammals. This mucin was annotated as intestinal mucin (I-Muc). Its RNA expression was highly regulated by the nutritional background, whereas the other mucins, including Muc2 and Muc2-like, were expressed more constitutively and did not respond to high replacement of fish oil (FO) by vegetable oils (VO) in plant protein-based diets. After challenge with the intestinal parasite Enteromyxum leei, the expression of a number of mucins was decreased mainly in the posterior intestine of infected fish. But, interestingly, the highest down-regulation was observed for the I-Muc. Overall, the magnitude of the changes reflected the intensity and progression of the infection, making mucins and I-Muc, in particular, reliable markers of prognostic and diagnostic value of fish intestinal health.
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Gupta BK, Maher DM, Ebeling MC, Sundram V, Koch MD, Lynch DW, Bohlmeyer T, Watanabe A, Aburatani H, Puumala SE, Jaggi M, Chauhan SC. Increased expression and aberrant localization of mucin 13 in metastatic colon cancer. J Histochem Cytochem 2012; 60:822-31. [PMID: 22914648 DOI: 10.1369/0022155412460678] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer.
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Affiliation(s)
- Brij K Gupta
- Cancer Biology Research Center, Sanford Research, University of South Dakota, Sioux Falls, SD, USA
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Ding XF, Huang GM, Shi Y, Li JA, Fang XD. Med19 promotes gastric cancer progression and cellular growth. Gene 2012; 504:262-7. [DOI: 10.1016/j.gene.2012.04.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Revised: 03/25/2012] [Accepted: 04/11/2012] [Indexed: 01/19/2023]
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Suh YS, Lee HJ, Jung EJ, Kim MA, Nam KT, Goldenring JR, Yang HK, Kim WH. The combined expression of metaplasia biomarkers predicts the prognosis of gastric cancer. Ann Surg Oncol 2011; 19:1240-9. [PMID: 22048633 DOI: 10.1245/s10434-011-2125-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer. METHODS The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers. RESULTS MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis. CONCLUSIONS The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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48
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Chauhan SC, Ebeling MC, Maher DM, Koch MD, Watanabe A, Aburatani H, Lio Y, Jaggi M. MUC13 mucin augments pancreatic tumorigenesis. Mol Cancer Ther 2011; 11:24-33. [PMID: 22027689 DOI: 10.1158/1535-7163.mct-11-0598] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell-cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target.
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Affiliation(s)
- Subhash C Chauhan
- Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
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Maher DM, Gupta BK, Nagata S, Jaggi M, Chauhan SC. Mucin 13: structure, function, and potential roles in cancer pathogenesis. Mol Cancer Res 2011; 9:531-537. [PMID: 21450906 DOI: 10.1158/1541-7786.mcr-10-0443] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mucin 13 (MUC13) is a high-molecular-weight transmembrane glycoprotein that is frequently and aberrantly expressed in a variety of epithelial carcinomas, including gastric, colorectal, and ovarian cancers. On the basis of the high expression of MUC13 in cancer cells as well as recent laboratory findings suggesting a malignant phenotype of MUC13-transfected cell lines, the oncogenic potential of MUC13 has emerged. The various functional domains of MUC13 may confer oncogenic potential to MUC13. For example, the bulky extracellular domain with extensive modification with glycan chains may prevent cell-cell and cell-extracellular matrix binding whereas the cytoplasmic tail containing serine and tyrosine residues for potential phosphorylation may participate in cell signaling. MUC13 exhibits the characteristics suitable as an early marker for cancer screening and presents a promising target for antibody-guided targeted therapy.
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Affiliation(s)
- Diane M Maher
- Cancer Biology Research Center, Sanford Research/USD
| | - Brij K Gupta
- Cancer Biology Research Center, Sanford Research/USD.,Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Sioux Falls, South Dakota
| | | | - Meena Jaggi
- Cancer Biology Research Center, Sanford Research/USD.,Department of Obstetrics and Gynecology, The University of South Dakota, Sioux Falls, South Dakota.,Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Sioux Falls, South Dakota
| | - Subhash C Chauhan
- Cancer Biology Research Center, Sanford Research/USD.,Department of Obstetrics and Gynecology, The University of South Dakota, Sioux Falls, South Dakota.,Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Sioux Falls, South Dakota
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Cui J, Li F, Wang G, Fang X, Puett JD, Xu Y. Gene-expression signatures can distinguish gastric cancer grades and stages. PLoS One 2011; 6:e17819. [PMID: 21445269 PMCID: PMC3060867 DOI: 10.1371/journal.pone.0017819] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Accepted: 02/09/2011] [Indexed: 12/13/2022] Open
Abstract
Microarray gene-expression data of 54 paired gastric cancer and adjacent noncancerous gastric tissues were analyzed, with the aim to establish gene signatures for cancer grades (well-, moderately-, poorly- or un-differentiated) and stages (I, II, III and IV), which have been determined by pathologists. Our statistical analysis led to the identification of a number of gene combinations whose expression patterns serve well as signatures of different grades and different stages of gastric cancer. A 19-gene signature was found to have discerning power between high- and low-grade gastric cancers in general, with overall classification accuracy at 79.6%. An expanded 198-gene panel allows the stratification of cancers into four grades and control, giving rise to an overall classification agreement of 74.2% between each grade designated by the pathologists and our prediction. Two signatures for cancer staging, consisting of 10 genes and 9 genes, respectively, provide high classification accuracies at 90.0% and 84.0%, among early-, advanced-stage cancer and control. Functional and pathway analyses on these signature genes reveal the significant relevance of the derived signatures to cancer grades and progression. To the best of our knowledge, this represents the first study on identification of genes whose expression patterns can serve as markers for cancer grades and stages.
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Affiliation(s)
- Juan Cui
- Computational Systems Biology Laboratory, Department of Biochemistry and Molecular Biology, and Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States of America
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