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1
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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Li Y, Chen J, Li T, Lin J, Zheng H, Johnson N, Yao X, Ding X. Modeling gastric intestinal metaplasia in 3D organoids using nitrosoguanidine. J Mol Cell Biol 2024; 16:mjae030. [PMID: 39153963 PMCID: PMC11744189 DOI: 10.1093/jmcb/mjae030] [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: 02/01/2024] [Revised: 07/18/2024] [Accepted: 08/16/2024] [Indexed: 08/19/2024] Open
Abstract
Gastric intestinal metaplasia (GIM) represents a precancerous stage characterized by morphological and pathophysiological changes in the gastric mucosa, where gastric epithelial cells transform into a phenotype resembling that of intestinal cells. Previous studies have demonstrated that the intragastric administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces both gastric carcinoma and intestinal metaplasia in mice. Here, we show that MNNG induces GIM in three-dimensional (3D) mouse organoids. Our histological analyses reveal that MNNG-induced gastric organoids undergo classical morphological alterations, exhibiting a distinct up-regulation of CDX2 and MUC2, along with a down-regulation of ATP4B and MUC6. Importantly, metaplastic cells observed in MNNG-treated organoids originate from MIST1+ cells, indicating their gastric chief cell lineage. Functional analyses show that activation of the RAS signaling pathway drives MNNG-induced metaplasia in 3D organoids, mirroring the characteristics observed in human GIM. Consequently, modeling intestinal metaplasia using 3D organoids offers valuable insights into the molecular mechanisms and spatiotemporal dynamics of the gastric epithelial lineage during the development of intestinal metaplasia within the gastric mucosa. We conclude that the MNNG-induced metaplasia model utilizing 3D organoids provides a robust platform for developing preventive and therapeutic strategies to mitigate the risk of gastric cancer before precancerous lesions occur.
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Affiliation(s)
- Yuan Li
- National Institute of Traditional Chinese Medicine Constitution and Preventive Treatment of Diseases, Beijing University of Chinese Medicine, Beijing 100029, China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
- Research Center for Spleen and Stomach Diseases of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jiena Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Tao Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jie Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Haocheng Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Nadia Johnson
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xuebiao Yao
- MOE Key Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
- Research Center for Spleen and Stomach Diseases of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
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3
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Wei H, Li W, Zeng L, Ding N, Li K, Yu H, Jiang F, Yin H, Xia Y, Deng C, Cai N, Chen X, Gu L, Chen H, Zhang F, He Y, Li J, Zhang C. OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3β/β-catenin pathway. Mol Cancer 2024; 23:124. [PMID: 38849840 PMCID: PMC11157765 DOI: 10.1186/s12943-024-02016-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/04/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.
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Affiliation(s)
- Hongfa Wei
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Jinping, Shantou, Guangdong, 515041, P.R. China
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Wenchao Li
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
- The Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Leli Zeng
- Scientific Research Center, The Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, P.R. China
| | - Ni Ding
- Scientific Research Center, The Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, P.R. China
- The Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Kuan Li
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Hong Yu
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Fei Jiang
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Haofan Yin
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
- Department of Laboratory Medicine, Shenzhen People's Hospital, (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Yu Xia
- Scientific Research Center, The Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, P.R. China
| | - Cuncan Deng
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Nan Cai
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Xiancong Chen
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Liang Gu
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Huanjie Chen
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Jinping, Shantou, Guangdong, 515041, P.R. China
| | - Feiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Jinping, Shantou, Guangdong, 515041, P.R. China.
| | - Yulong He
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Jia Li
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
- Scientific Research Center, The Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, P.R. China.
| | - Changhua Zhang
- Department of Gastrointestinal Surgery, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China.
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Zhang X, Chen YC, Yao M, Xiong R, Liu B, Zhu X, Ao P. Potential therapeutic targets of gastric cancer explored under endogenous network modeling of clinical data. Sci Rep 2024; 14:13127. [PMID: 38849404 PMCID: PMC11161650 DOI: 10.1038/s41598-024-63812-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024] Open
Abstract
Improvement in the survival rate of gastric cancer, a prevalent global malignancy and the leading cause of cancer-related mortality calls for more avenues in molecular therapy. This work aims to comprehend drug resistance and explore multiple-drug combinations for enhanced therapeutic treatment. An endogenous network modeling clinic data with core gastric cancer molecules, functional modules, and pathways is constructed, which is then transformed into dynamics equations for in-silicon studies. Principal component analysis, hierarchical clustering, and K-means clustering are utilized to map the attractor domains of the stochastic model to the normal and pathological phenotypes identified from the clinical data. The analyses demonstrate gastric cancer as a cluster of stable states emerging within the stochastic dynamics and elucidate the cause of resistance to anti-VEGF monotherapy in cancer treatment as the limitation of the single pathway in preventing cancer progression. The feasibility of multiple objectives of therapy targeting specified molecules and/or pathways is explored. This study verifies the rationality of the platform of endogenous network modeling, which contributes to the development of cross-functional multi-target combinations in clinical trials.
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Affiliation(s)
- Xile Zhang
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Yong-Cong Chen
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China.
| | - Mengchao Yao
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Ruiqi Xiong
- Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai, 200444, China
| | - Bingya Liu
- Department of General Surgery, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Cancer, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaomei Zhu
- Shanghai Key Laboratory of Modern Optical Systems, School of Optoelectronic Information and Computer Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Ping Ao
- School of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
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5
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Liu M, Fan G, Liu H. Integrated bioinformatics and network pharmacology identifying the mechanisms and molecular targets of Guipi Decoction for treatment of comorbidity with depression and gastrointestinal disorders. Metab Brain Dis 2024; 39:183-197. [PMID: 37847347 DOI: 10.1007/s11011-023-01308-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/04/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND Guipi decoction (GPD) not only improves gastrointestinal (GI) function, but also depressive mood. The bioinformatics study aimed to reveal potential crosstalk genes and related pathways between depression and GI disorders. A network pharmacology approach was used to explore the molecular mechanisms and potential targets of GPD for the simultaneous treatment of depression comorbid GI disorders. METHODS Differentially expressed genes (DEGs) of major depressive disorder (MDD) were identified based on GSE98793 and GSE19738, and GI disorders-related genes were screened from the GeneCards database. Overlapping genes between MDD and GI disorders were obtained to identify potential crosstalk genes. Protein-protein interaction (PPI) network was constructed to screen for hub genes, signature genes were identified by LASSO regression analysis, and single sample gene set enrichment analysis (ssGSEA) was performed to analyze immune cell infiltration. In addition, based on the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, we screened the active ingredients and targets of GPD and identified the intersection targets of GPD with MDD and GI disorder-related genes, respectively. A "component-target" network was constructed using Cytoscape, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. RESULTS The MDD-corrected dataset contained 2619 DEGs, and a total of 109 crosstalk genes were obtained. 14 hub genes were screened, namely SOX2, CRP, ACE, LEP, SHH, CDH2, CD34, TNF, EGF, BDNF, FN1, IL10, PPARG, and KIT. These genes were identified by LASSO regression analysis for 3 signature genes, including TNF, EGF, and IL10. Gamma.delta.T.cell was significantly positively correlated with all three signature genes, while Central.memory.CD4.T.cell and Central.memory.CD8.T.cell were significantly negatively correlated with EGF and TNF. GPD contained 134 active ingredients and 248 targets, with 41 and 87 relevant targets for the treatment of depression and GI disorders, respectively. EGF, PPARG, IL10 and CRP overlap with the hub genes of the disease. CONCLUSION We found that GPD may regulate inflammatory and oxidative stress responses through EGF, PPARG, IL10 and CRP targets, and then be involved in the treatment of both depression and GI disorders.
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Affiliation(s)
- Menglin Liu
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Genhao Fan
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Huayi Liu
- Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.
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He Q, Liu L, Wei J, Jiang J, Rong Z, Chen X, Zhao J, Jiang K. Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review. Cell Death Dis 2022; 8:158. [PMID: 35379788 PMCID: PMC8979943 DOI: 10.1038/s41420-022-00962-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/11/2022] [Accepted: 03/17/2022] [Indexed: 12/13/2022]
Abstract
Gastric intestinal metaplasia (IM) is a precancerous lesion that increases the risk of subsequent gastric cancer (GC) development. Therefore, the mechanism of IM has been the focus of basic and clinical research. Helicobacter pylori (H. pylori) infection has been recognized as the main pathogenesis of gastric IM. However, more and more studies have shown that chronic inflammation of gastric mucosa caused by bile reflux is the key pathogenic factor of gastric IM. Bile reflux activates the expression of IM biomarkers via the bile acid receptor. In addition, microRNAs, exosomes, and epigenetics are also involved in the occurrence and development of bile acid-induced gastric IM. Currently, the relevant research is still very few. The molecular mechanism of the phenotypic transformation of gastrointestinal epithelial cells induced by bile acids has not been fully understood. This article mainly reviews the physiology and pathology of bile acid, mechanism of gastric IM induced by bile acid, bile acid receptors, and so on, in order to provide reference for further research.
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Affiliation(s)
- Qijin He
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Limin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Jiaying Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Zheng Rong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
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Yang H, Yang WJ, Hu B. Gastric epithelial histology and precancerous conditions. World J Gastrointest Oncol 2022; 14:396-412. [PMID: 35317321 PMCID: PMC8919001 DOI: 10.4251/wjgo.v14.i2.396] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/08/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
The most common histological type of gastric cancer (GC) is gastric adenocarcinoma arising from the gastric epithelium. Less common variants include mesenchymal, lymphoproliferative and neuroendocrine neoplasms. The Lauren scheme classifies GC into intestinal type, diffuse type and mixed type. The WHO classification includes papillary, tubular, mucinous, poorly cohesive and mixed GC. Chronic atrophic gastritis (CAG) and intestinal metaplasia are recommended as common precancerous conditions. No definite precancerous condition of diffuse/poorly/undifferentiated type is recommended. Chronic superficial inflammation and hyperplasia of foveolar cells may be the focus. Presently, the management of early GC and precancerous conditions mainly relies on endoscopy including diagnosis, treatment and surveillance. Management of precancerous conditions promotes the early detection and treatment of early GC, and even prevent the occurrence of GC. In the review, precancerous conditions including CAG, metaplasia, foveolar hyperplasia and gastric hyperplastic polyps derived from the gastric epithelium have been concluded, based on the overview of gastric epithelial histological organization and its renewal.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Juan Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Businello G, Angerilli V, Parente P, Realdon S, Savarino E, Farinati F, Grillo F, Vanoli A, Galuppini F, Paccagnella S, Pennelli G, Mastracci L, Saragoni L, Fassan M. Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:9950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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Affiliation(s)
- Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Stefano Realdon
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Fabio Farinati
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy; (E.S.); (F.F.)
| | - Federica Grillo
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Italy;
| | - Francesca Galuppini
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Silvia Paccagnella
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Gianmaria Pennelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
| | - Luca Mastracci
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, 16132 Genova, Italy; (F.G.); (L.M.)
- Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, 16132 Genova, Italy
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, 47121 Forlì, Italy;
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (V.A.); (F.G.); (S.P.); (G.P.)
- Veneto Institute of Oncology (IOV-IRCCS), 35128 Padua, Italy;
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9
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The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation. Int J Mol Sci 2021; 22:ijms22105359. [PMID: 34069715 PMCID: PMC8160799 DOI: 10.3390/ijms22105359] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.
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10
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Fang X, Wu X, Xiang E, Luo F, Li Q, Ma Q, Yuan F, Chen P. Expression profiling of CPS1 in Correa's cascade and its association with gastric cancer prognosis. Oncol Lett 2021; 21:441. [PMID: 33868479 PMCID: PMC8045184 DOI: 10.3892/ol.2021.12702] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
Carbamoyl phosphate synthetase 1 (CPS1), which is the antigen for the hepatocyte paraffin 1 antibody, exhibits focal immunoreactivity in adenocarcinoma from the gastrointestinal tract, but its expression profiles and roles in gastric cancer (GC) remain largely unknown. The present study aimed to determine the expression pattern and prognostic value of CPS1 in Correa's cascade using tissues from 32 patients with chronic atrophic gastritis with intestinal metaplasia (IM), 62 patients with low- or high-grade intraepithelial neoplasia (IN) and 401 patients with GC. The expression of CPS1 was diffuse and strongly positive in 32 cases (100%) of IM of the glandular epithelium, and gradually downregulated in Correa's cascade, with a strongly positive ratio of 21 (70%) in low-grade IN and 4 (12.5%) in high-grade IN. The levels of CPS1 expression were significantly higher in diffuse-type GC, with 37 (26%) cases strongly positive for CPS1, compared with 14 (8%) in intestinal-type and 11 (13%) cases in mixed-type GC. In intestinal-type GC, CPS1 expression was completely lost in 107 (62%) of cases, which was associated with an advanced Tumor-Node-Metastasis stage (P=0.031) and depth of invasion (P=0.037). Kaplan-Meier analysis suggested that low CPS1 expression levels were independently associated with a short overall survival (OS) time in the three types of GC (P<0.001 in intestinal-type, P=0.003 in diffuse-type and P=0.018 in mixed-type GC). Furthermore, low levels of CPS1 mRNA and high methylation levels in the CPS1 promoter were associated with a short OS time in patients with GC. These results suggested that the expression of CPS1 was progressively downregulated in Correa's cascade, and that CPS1 may serve as a prognostic marker for patients with GC, regardless of tumor type.
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Affiliation(s)
- Xuqian Fang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Xiaoqiong Wu
- Department of Clinical Laboratory, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Enfei Xiang
- Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Fangxiu Luo
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Qinqin Li
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Qianchen Ma
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
| | - Peizhan Chen
- Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, P.R. China
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11
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The role of SOX family transcription factors in gastric cancer. Int J Biol Macromol 2021; 180:608-624. [PMID: 33662423 DOI: 10.1016/j.ijbiomac.2021.02.202] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/26/2021] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is a leading cause of death worldwide. GC is the third-most common cause of cancer-related death after lung and colorectal cancer. It is also the fifth-most commonly diagnosed cancer. Accumulating evidence has revealed the role of signaling networks in GC progression. Identification of these molecular pathways can provide new insight into therapeutic approaches for GC. Several molecular factors involved in GC can play both onco-suppressor and oncogene roles. Sex-determining region Y (Sry)-box-containing (SOX) family members are transcription factors with a well-known role in cancer. SOX proteins can bind to DNA to regulate cellular pathways via a highly conserved domain known as high mobility group (HMG). In the present review, the roles of SOX proteins in the progression and/or inhibition of GC are discussed. The dual role of SOX proteins as tumor-promoting and tumor-suppressing factors is highlighted. SOX members can affect upstream mediators (microRNAs, long non-coding RNAs and NF-κB) and down-stream mediators (FAK, HIF-1α, CDX2 and PTEN) in GC. The possible role of anti-tumor compounds to target SOX pathway members in GC therapy is described. Moreover, SOX proteins may be used as diagnostic or prognostic biomarkers in GC.
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12
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Koulis A, Busuttil RA, Boussioutas A. Premalignant lesions of the stomach and management of early neoplastic lesions. RESEARCH AND CLINICAL APPLICATIONS OF TARGETING GASTRIC NEOPLASMS 2021:185-216. [DOI: 10.1016/b978-0-323-85563-1.00013-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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13
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Differentially Expressed mRNAs and Their Long Noncoding RNA Regulatory Network with Helicobacter pylori-Associated Diseases including Atrophic Gastritis and Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3012193. [PMID: 33282942 PMCID: PMC7686847 DOI: 10.1155/2020/3012193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/28/2020] [Accepted: 10/31/2020] [Indexed: 02/08/2023]
Abstract
Background Helicobacter pylori (Hp) infection is the strongest risk factor for gastric cancer (GC). However, the mechanisms of Hp-associated GC remain to be explored. Methods The gene expression profiling (GSE111762) data were downloaded from the GEO database. Differentially expressed genes (DEGs) between normal samples (NO) and Hp-atrophic gastritis (GA) or Hp-GA and Hp-GC were identified by GEO2R. Gene Ontology and pathway enrichment analysis were performed using the DAVID database. lncRNA-TF-mRNA and ceRNA regulation networks were constructed using Cytoscape. The cross-networks were obtained by overlapping molecules of the above two networks. GSE27411 and GSE116312 datasets were employed for validation. Results DEGs between NO and Hp-GA are linked to the activity of inward rectifying potassium channels, digestion, etc. DEGs between Hp-GA and Hp-GC were associated with digestion, positive regulation of cell proliferation, etc. According to the lncRNA-TF-mRNA network, 63 lncRNAs, 12 TFs, and 209 mRNAs were involved in Hp-GA while 16 lncRNAs, 11 TFs, and 92 mRNAs were contained in the Hp-GC network. In terms of the ceRNA network, 120 mRNAs, 18 miRNAs, and 27 lncRNAs were shown in Hp-GA while 72 mRNAs, 8 miRNAs, and 1 lncRNA were included in the Hp-GC network. In the cross-network, we found that immune regulation and differentiation regulation were important in the process of NO-GA. Neuroendocrine regulation was mainly related to the process of GA-GC. In the end, we verified that CDX2 plays an important role in the pathological process of NO to Hp-GA. Comparing Hp-GA with Hp-GC, DEGs (FPR1, TFF2, GAST, SST, FUT9, and SHH), TF, and GATA5 were of great significance. Conclusions We identified the DEGs, and their lncRNA regulatory network of Hp-associated diseases might provide insights into the mechanism between Hp infection and GC. Furthermore, in-depth studies of the molecules might be useful to explore the multistep process of gastric diseases.
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A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis. Gastric Cancer 2020; 23:811-823. [PMID: 32215766 DOI: 10.1007/s10120-020-01064-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin). METHODS This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results. RESULTS Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level. CONCLUSIONS Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.
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Pádua D, Barros R, Luísa Amaral A, Mesquita P, Filipa Freire A, Sousa M, Filipe Maia A, Caiado I, Fernandes H, Pombinho A, Filipe Pereira C, Almeida R. A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin. Cancers (Basel) 2020; 12:E495. [PMID: 32093282 PMCID: PMC7072720 DOI: 10.3390/cancers12020495] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/12/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.
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Affiliation(s)
- Diana Pádua
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Rita Barros
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Ana Luísa Amaral
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Patrícia Mesquita
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Ana Filipa Freire
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Mafalda Sousa
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - André Filipe Maia
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Inês Caiado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Hugo Fernandes
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
| | - António Pombinho
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Carlos Filipe Pereira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Raquel Almeida
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Biology Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
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Investigation of the thermodynamic drivers of the interaction between the high mobility group box domain of Sox2 and bacterial lipopolysaccharide. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183106. [DOI: 10.1016/j.bbamem.2019.183106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/05/2019] [Accepted: 10/08/2019] [Indexed: 01/02/2023]
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Lopes N, Bergsland CH, Bjørnslett M, Pellinen T, Svindland A, Nesbakken A, Almeida R, Lothe RA, David L, Bruun J. Digital image analysis of multiplex fluorescence IHC in colorectal cancer recognizes the prognostic value of CDX2 and its negative correlation with SOX2. J Transl Med 2020; 100:120-134. [PMID: 31641225 PMCID: PMC6917572 DOI: 10.1038/s41374-019-0336-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/18/2019] [Accepted: 09/18/2019] [Indexed: 01/10/2023] Open
Abstract
Flourescence-based multiplex immunohistochemistry (mIHC) combined with multispectral imaging and digital image analysis (DIA) is a quantitative high-resolution method for determination of protein expression in tissue. We applied this method for five biomarkers (CDX2, SOX2, SOX9, E-cadherin, and β-catenin) using tissue microarrays of a Norwegian unselected series of primary colorectal cancer. The data were compared with previously obtained chromogenic IHC data of the same tissue cores, visually assessed by the Allred method. We found comparable results between the methods, although confirmed that DIA offered improved resolution to differentiate cases with high and low protein expression. However, we experienced inherent challenges with digital image analysis of membrane staining, which was better assessed visually. DIA and mIHC enabled quantitative analysis of biomarker coexpression on the same tissue section at the single-cell level, revealing a strong negative correlation between the differentiation markers CDX2 and SOX2. Both methods confirmed known prognostic associations for CDX2, but DIA improved data visualization and detection of clinicopathological and biological associations. In summary, mIHC combined with DIA is an efficient and reliable method to evaluate protein expression in tissue, here shown to recapitulate and improve detection of known clinicopathological and survival associations for the emerging biomarker CDX2, and is therefore a candidate approach to standardize CDX2 detection in pathology laboratories.
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Affiliation(s)
- Nair Lopes
- 0000 0004 0389 8485grid.55325.34Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ,0000 0001 1503 7226grid.5808.5i3S—Institute for Research and Innovation in Health, University of Porto, Porto, Portugal ,0000 0001 1503 7226grid.5808.5IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal ,0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Christian Holst Bergsland
- 0000 0004 0389 8485grid.55325.34Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ,0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Merete Bjørnslett
- 0000 0004 0389 8485grid.55325.34Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ,0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Teijo Pellinen
- 0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 0410 2071grid.7737.4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Aud Svindland
- 0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Arild Nesbakken
- 0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway ,0000 0004 0389 8485grid.55325.34Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Raquel Almeida
- 0000 0001 1503 7226grid.5808.5i3S—Institute for Research and Innovation in Health, University of Porto, Porto, Portugal ,0000 0001 1503 7226grid.5808.5Faculty of Medicine, University of Porto, Porto, Portugal ,0000 0001 1503 7226grid.5808.5Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Ragnhild A. Lothe
- 0000 0004 0389 8485grid.55325.34Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ,0000 0004 0389 8485grid.55325.34K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Leonor David
- 0000 0001 1503 7226grid.5808.5i3S—Institute for Research and Innovation in Health, University of Porto, Porto, Portugal ,0000 0001 1503 7226grid.5808.5IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal ,0000 0001 1503 7226grid.5808.5Faculty of Medicine, University of Porto, Porto, Portugal
| | - Jarle Bruun
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. .,K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
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Koulis A, Buckle A, Boussioutas A. Premalignant lesions and gastric cancer: Current understanding. World J Gastrointest Oncol 2019; 11:665-678. [PMID: 31558972 PMCID: PMC6755108 DOI: 10.4251/wjgo.v11.i9.665] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/29/2019] [Accepted: 08/21/2019] [Indexed: 02/05/2023] Open
Abstract
Over the last two decades there has been a broad paradigm shift in our understanding of gastric cancer (GC) and its premalignant states from gross histological models to increasingly precise molecular descriptions. In this review we reflect upon the historic approaches to describing premalignant lesions and GC, highlight the current molecular landscape and how this could inform future risk assessment prevention strategies.
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Affiliation(s)
- Athanasios Koulis
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
| | - Andrew Buckle
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
| | - Alex Boussioutas
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, 3050, Australia
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Abstract
An organ-specific chronic inflammation–remodeling–carcinoma sequence has been proposed, mainly for the alimentary tract. As representative diseases, gastroesophageal reflux disease, chronic gastritis and inflammatory bowel disease (ulcerative colitis and Crohn’s disease of the colitis type) were adopted for this discussion. Tissue remodeling is such an important part of tumorigenesis in this sequence that an organ-specific chronic inflammation–remodeling–carcinoma sequence has been proposed in detail. Chronic inflammation accelerates the cycle of tissue injury and regeneration; in other words, cell necrosis (or apoptosis) and proliferation result in tissue remodeling in long-standing cases of inflammation. Remodeling encompasses epithelial cell metaplasia and stromal fibrosis, and modifies epithelial–stromal cell interactions. Further, the accumulation of genetic, epigenetic and molecular changes—as well as morphologic disorganization—also occurs during tissue remodeling. The expression of mucosal tissue adapted to chronic inflammatory injury is thought to occur at an early stage. Subsequently, dysplasia and carcinoma develop on a background of remodeling due to continuous, active inflammation. Accordingly, organ-specific chronic inflammation should be ameliorated or well controlled with appropriate monitoring if complete healing is unachievable.
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Zhao Y, Zhou X, He Y, Liao C. SLC6A1-miR133a-CDX2 loop regulates SK-OV-3 ovarian cancer cell proliferation, migration and invasion. Oncol Lett 2018; 16:4977-4983. [PMID: 30250563 PMCID: PMC6144910 DOI: 10.3892/ol.2018.9273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 01/05/2018] [Indexed: 02/07/2023] Open
Abstract
The present study assessed the expression of solute carrier 6 member 1 (SLC6A1) in ovarian cancer (OC) tissues and evaluated the effect of silencing SLC6A1 or caudal type homeobox 2 (CDX2) on the proliferation, migration, and invasion of SK-OV-3 OC cells. The levels of caudal type homeobox 2 (CDX2) and SLC6A1 mRNA were also examined in OC SK-OV-3, OVCAR3 and A2780 cell lines. The mRNA levels of CDX2 and SLC6A1 in SK-OV-3 OC cells were assessed following transection with microRNA (miR) 133a mimics; the mRNA and protein levels of SLC6A1 were determined following the silencing of CDX2, and the mRNA expression of CDX2 was gauged following the silencing of SLC6A1. A luciferase reporter assay was performed to assess the effect of miR133a on the CDX2 and SLC6A1 3′-untranslated regions (3′UTRs). The proliferation, migration and invasion rate of SK-OV-3 cells were then examined following the silencing of CDX2 or SLC6A1. The expression of SLC6A1 was increased in OC compared with adjacent tissue. The expression of CDX2 and SLC6A1 in SK-OV-3 and OVCAR3 cells was increased compared with A2780 cells (P<0.05). The level of CDX2 and SLC6A1 mRNA in SK-OV-3 cells decreased when the cells were transected with the miR133a mimics, compared with a negative control (P<0.05). Transfection with the miR133a mimics significantly reduced the luciferase activity of reporter plasmids with the SLC6A1 or CDX2 3′UTRs (P<0.05). The mRNA level of CDX2 was decreased subsequent to the silencing of SLC6A1; the mRNA and protein level of SLC6A1 were decreased when CDX2 was silenced (P<0.05). The proliferation, migration, and invasion of SK-OV-3 cells were significantly reduced following the silencing of CDX2 or SLC6A1 (P<0.05). CDX2 may therefore be inferred to promote the proliferation, migration and invasion in SK-OV-3 OC cells, acting as a competing endogenous RNA.
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Affiliation(s)
- Yuan Zhao
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, Yunnan 650118, P.R. China
| | - Xiaokui Zhou
- Department of Gynecology and Obstetrics, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yangyan He
- Department of Gynecology and Obstetrics, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Changjun Liao
- College of Medicine, Chengdu Medical College, Chengdu, Sichuan 610000, P.R. China
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Chen BJ, Zeng S, Xie R, Hu CJ, Wang SM, Wu YY, Xiao YF, Yang SM. hTERT promotes gastric intestinal metaplasia by upregulating CDX2 via NF-κB signaling pathway. Oncotarget 2018; 8:26969-26978. [PMID: 28460480 PMCID: PMC5432311 DOI: 10.18632/oncotarget.15926] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 02/20/2017] [Indexed: 12/17/2022] Open
Abstract
Background hTERT has been reported involved in the proliferation and metastasis of gastric cancer, but the role of hTERT in gastric intestinal metaplasia, a premalignant lesion of the gastric mucosa was unknown. The aim of the present study was to investigate the role of hTERT in GIM and the effect of hTERT on CDX2 expression in gastric cells. Results Experiments showed that expression of hTERT was significantly higher in GIM than in normal gastric mucosa. Moreover, hTERT increased the KLF4 level via NF-κB during GIM. Furthermore, KLF4 is involved in the up-regulation of CDX2 induced by hTERT, and hTERT can interact with p50, thereby increasing the level of CDX2. Materials and Methods Immunohistochemistry was used to detect the expression of hTERT in gastric intestinal metaplasia tissue. Then, effect of hTERT on the expression of CDX2 was detected by qRT-PCR, WB and dual luciferase experiment. The role of p65 and p50 in the regulation of CDX2 were further detected by WB, CO-IP and ChIP. Conclusions We may conclude that hTERT promotes GIM by up-regulating CDX2 via NF-κB signaling pathway.
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Affiliation(s)
- Bai-Jun Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China.,Department of Gastroenterology, The First Affiliated Hospital, Chengdu Medical College, Chengdu, PR China
| | - Shuo Zeng
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Rui Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Chang-Jiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Su-Ming Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Yu-Yun Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Yu-Feng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
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22
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Niu H, Jia Y, Li T, Su B. SOX2 Inhibition Promotes Promoter Demethylation of CDX2 to Facilitate Gastric Intestinal Metaplasia. Dig Dis Sci 2017; 62:124-132. [PMID: 27913994 DOI: 10.1007/s10620-016-4361-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 10/19/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Gastric intestinal metaplasia (IM) is regarded as a premalignant lesion, conferring risks for gastric cancer development. An intestinal transcription factor, CDX2, plays a vital role in establishing and maintaining IM. SOX2, an HMG-box transcription factor, is expressed in normal gastric mucosa and downregulated in IM. Therefore, it is important to elucidate the mutual interaction of SOX2 and CDX2 in gastric IM. AIMS This study aims to evaluate the negative correlation between SOX2 and CDX2 in mRNA expression and promoter methylation and to illuminate the effect of SOX2 on the promoter methylation of CDX2. METHODS Immunohistochemistry, real-time PCR and methylation-specific polymerase chain reaction assays were performed to evaluate the expression and promoter methylation of SOX2 and CDX2 in IM tissues from patients. SOX2 knockdown and CDX2 overexpression were performed in GES-1 cells to further clarify the relationship between SOX2 and CDX2. RESULTS A negative correlation between SOX2 and CDX2 was found in 120 gastric IM specimens. Additionally, significant DNA demethylation of CDX2 promoter in clinical IM specimens was observed concomitantly with partial methylation of the SOX2 promoter. Furthermore, SOX2 knockdown in GES-1 cells triggered promoter demethylation of CDX2. Finally, the phenotype shift of gastric intestinal metaplasia in GES-1 cells, marked by MUC2 expression, was effectively induced by the combination of SOX2 RNAi and CDX2 overexpression. CONCLUSIONS Aberrant DNA methylation of SOX2 and CDX2 genes contributes to the development of IM. Notably, SOX2 may play a role in establishing and maintaining the methylation status of the CDX2 gene in gastric tissues and cells.
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Affiliation(s)
- Haijing Niu
- Department of Gastroenterology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Yuchen Jia
- School of Life Sciences, Inner Mongolia University, Hohhot, 010021, China.,Research Center of Molecular Biology, Inner Mongolia Medical University, Hohhot, 010058, China
| | - Tao Li
- College of Medicine, Hunan Normal University, Changsha, 410081, China.,Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, 321004, Zhejiang, China
| | - Bingzhong Su
- Department of Gastroenterology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China.
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23
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Rolim I, Rodrigues RV, Bettencourt A, Barros R, Camilo V, Dias Pereira A, Almeida R, Chaves P. Mid-Esophagus Columnar Metaplasia: What Is the Biopathogenic Pathway? Int J Surg Pathol 2016; 25:262-265. [DOI: 10.1177/1066896916672332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Inês Rolim
- Portuguese Oncology Institute Francisco
Gentil, E.P.E., Lisbon, Portugal
| | | | | | - Rita Barros
- Institute of Molecular Pathology and
Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Instituto de Investigação e Inovação em Saúde
(i3S), Porto, Portugal
- Faculty of Dental Medicine of the University
of Porto, Porto, Portugal
- Faculty of Medicine of the University of
Porto, Porto, Portugal
| | - Vânia Camilo
- Institute of Molecular Pathology and
Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Instituto de Investigação e Inovação em Saúde
(i3S), Porto, Portugal
| | - António Dias Pereira
- Portuguese Oncology Institute Francisco
Gentil, E.P.E., Lisbon, Portugal
- Beira Interior University, Covilhã,
Portugal
| | - Raquel Almeida
- Institute of Molecular Pathology and
Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Instituto de Investigação e Inovação em Saúde
(i3S), Porto, Portugal
- Faculty of Medicine of the University of
Porto, Porto, Portugal
- Biology Department, Faculty of Sciences of the
University of Porto, Porto, Portugal
| | - Paula Chaves
- Portuguese Oncology Institute Francisco
Gentil, E.P.E., Lisbon, Portugal
- Beira Interior University, Covilhã,
Portugal
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24
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Dynamics of SOX2 and CDX2 Expression in Barrett's Mucosa. DISEASE MARKERS 2016; 2016:1532791. [PMID: 27766003 PMCID: PMC5059566 DOI: 10.1155/2016/1532791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 08/31/2016] [Accepted: 09/01/2016] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus (BE) is the replacement of the normal esophageal squamous epithelium by a columnar lining epithelium. It is a premalignant condition for the development of adenocarcinoma of the esophagus and esophagogastric junction. BE is associated with gastroesophageal reflux which might change the expression profile of key transcription factors involved in the establishment of tissue differentiation, namely, SOX2 (associated with esophageal and gastric differentiation) and CDX2 (associated with intestinal differentiation). Here, we sought to characterize the expression profile of SOX2 and CDX2 in the sequential alterations of the esophageal mucosa towards adenocarcinoma and compare it with the well-established gastric and intestinal mucin profiles (MUC5AC, MUC6, and MUC2). We observed that SOX2 and CDX2 expression correlates with gastric and intestinal differentiation in BE, defined by morphological parameters and mucin expression. We show the presence of a complete intestinal profile in BE, without gastric mucins and without SOX2, and we observed an evolutionary modulation of the metaplastic phenotype by SOX2 and CDX2. We observed that adenocarcinomas harbor more frequently a mixed gastric and intestinal phenotype. In conclusion, our study establishes a role for transcription factors SOX2 and CDX2 in the progression from gastric to gastrointestinal differentiation in Barrett's metaplasia.
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25
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Sarkar A, Huebner AJ, Sulahian R, Anselmo A, Xu X, Flattery K, Desai N, Sebastian C, Yram MA, Arnold K, Rivera M, Mostoslavsky R, Bronson R, Bass AJ, Sadreyev R, Shivdasani RA, Hochedlinger K. Sox2 Suppresses Gastric Tumorigenesis in Mice. Cell Rep 2016; 16:1929-41. [PMID: 27498859 DOI: 10.1016/j.celrep.2016.07.034] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 03/22/2016] [Accepted: 07/14/2016] [Indexed: 01/10/2023] Open
Abstract
Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2(+) cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.
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Affiliation(s)
- Abby Sarkar
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA
| | - Aaron J Huebner
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA
| | - Rita Sulahian
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Anthony Anselmo
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Xinsen Xu
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Kyle Flattery
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA
| | - Niyati Desai
- Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Carlos Sebastian
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mary Anna Yram
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA
| | - Katrin Arnold
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA
| | - Miguel Rivera
- Division of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Raul Mostoslavsky
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Roderick Bronson
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| | - Adam J Bass
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Ruslan Sadreyev
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ramesh A Shivdasani
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Konrad Hochedlinger
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
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26
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Chen Y, Huang Y, Zhu L, Chen M, Huang Y, Zhang J, He S, Li A, Chen R, Zhou J. SOX2 inhibits metastasis in gastric cancer. J Cancer Res Clin Oncol 2016; 142:1221-30. [PMID: 26960758 DOI: 10.1007/s00432-016-2125-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 01/25/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate the potential role of SOX2 in gastric cancer (GC) metastasis. METHODS The SOX2 expression was detected using immunohistochemistry on a GC tissue microarray. The correlations of SOX2 expression with clinicopathological factors and 5-year survival were evaluated. To test the role of SOX2 in inhibiting GC metastasis, the cell transwell assay was performed. Real-time PCR and Western blot were used to explore the possible mechanism that SOX2 inhibits GC metastasis. RESULTS In the present study, SOX2 expression was downregulated in GC tissues when compared to matching normal tissues. Moreover, patients with high SOX2 expression in cancerous tissues had less lymph node metastasis and better treatment outcome. At the subcellular level, SOX2 inhibited the GC cell migration and invasion by upregulating p21 expression. Moreover, SOX2 was determined to associate with the nuclear p21 expression. GC patients with high SOX2 and nuclear p21 expression had synergistically less lymph node metastasis and the better overall survival. CONCLUSION Our results suggest that SOX2 is a promising and favorable metastatic biomarker for GC.
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Affiliation(s)
- Yansu Chen
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
- School of Public Health, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, People's Republic of China
| | - Yefei Huang
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
- School of Public Health, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, People's Republic of China
| | - Liwen Zhu
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Minjuan Chen
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Yulin Huang
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Jianbing Zhang
- Department of Pathology, Nantong Cancer Hospital, 30 North Tongyang Road, Pingchao, Nantong, 226361, Jiangsu Province, People's Republic of China
| | - Song He
- Department of Pathology, Nantong Cancer Hospital, 30 North Tongyang Road, Pingchao, Nantong, 226361, Jiangsu Province, People's Republic of China
| | - Aiping Li
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Rui Chen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China.
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China.
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27
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Jiang Y, Zhang Y, Li F, Du X, Zhang J. CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p. Tumour Biol 2016; 37:1041-9. [PMID: 26269116 DOI: 10.1007/s13277-015-3900-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/05/2015] [Indexed: 12/16/2022] Open
Abstract
CDX2 has recently been identified as a prognostic marker for pancreatic adenocarcinoma. However, the role and mechanism of CDX2 in progression of pancreatic adenocarcinoma are still elusive. In this study, we observed that CDX2 expression was much lower in mouse pancreatic adenocarcinoma tissues and pancreatic cancer cells. A network integrated by ChIPBase platform hinted that miR-615-5p, a most newly discovered tumor suppressor, was probably bound by CDX2 in the promoter region. Chromatin immunoprecipitation (ChIP)-qPCR assay showed that CDX2 exhibited a high capacity of binding to miR-615-5p promoter region compared to the negative control. Real-time PCR and western blotting analyses revealed that CDX2 overexpression caused inflation of miR-615-5p and depression of insulin-like growth factor 2 (IGF2), a direct target of miR-615-5p. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and EdU approaches showed that CDX2 overexpression markedly suppressed pancreatic adenocarcinoma cell proliferation. CDX2 small interfering RNA (siRNA) transfection showed an opposite effect on gene expression and cell proliferation to that of CDX2 overexpression. Collectively, CDX2 inhibited pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p. Our findings suggested a potential molecular target for pancreatic adenocarcinoma therapy.
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Affiliation(s)
- Yuanyuan Jiang
- Department of Gastroenterology, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yan Zhang
- Department of Gastroenterology, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China
| | - Fuqing Li
- Department of Gastroenterology, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China
| | - Xiaolin Du
- Department of Gastroenterology, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jinping Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Eastern Road, Erqi District, Zhengzhou, 450052, People's Republic of China.
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28
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Koos B, Kamali-Moghaddam M, David L, Sobrinho-Simões M, Dimberg A, Nilsson M, Wählby C, Söderberg O. Next-Generation Pathology—Surveillance of Tumor Microecology. J Mol Biol 2015; 427:2013-22. [DOI: 10.1016/j.jmb.2015.02.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 02/18/2015] [Accepted: 02/18/2015] [Indexed: 11/30/2022]
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29
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Guo C, Wang W, Shi Q, Chen P, Zhou C. An abnormally high expression of ISL-1 represents a potential prognostic factor in gastric cancer. Hum Pathol 2015; 46:1282-9. [PMID: 26142548 DOI: 10.1016/j.humpath.2015.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 05/06/2015] [Accepted: 05/08/2015] [Indexed: 12/15/2022]
Abstract
Insulin gene enhancer binding protein-1 (ISL-1) is a transcription factor involved in development of the heart, motor neurons, and pancreas. Our previous study indicated that ISL-1 was overexpressed in gastric cancer but not in other gastrointestinal tumors. However, no immunohistochemical or clinicopathological studies of ISL-1 in gastric carcinoma have been performed. The aim of this study was to determine the expression and prognostic value of ISL-1 in gastric carcinoma. A nude mouse xenograft model was established to study the role of ISL-1 on cancer genesis and development in vivo. Overexpression of ISL-1 significantly enhanced the tumorigenicity of NIH3T3 cells in vivo. ISL-1 expression was evaluated using immunohistochemistry in 456 human gastric carcinoma and normal tissues. ISL-1 was significantly overexpressed in gastric adenocarcinoma compared with normal gastric tissues. ISL-1 expression was significantly associated with depth of invasion, lymph node metastasis, TNM stage, and histological grade (P < .05, χ(2) test). Positive ISL-1 expression was associated with poorer 5-year overall survival in gastric cancer (P = .001, log-rank test). Multivariate Cox regression analysis demonstrated that ISL-1 expression (P = .047) could be an independent prognostic factor for overall survival in gastric carcinoma. This study suggests that ISL-1 may be a useful prognostic biomarker and may represent a novel therapeutic target for gastric adenocarcinoma.
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Affiliation(s)
- Chen Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences (Ministry of Education), Key Laboratory of Protein Posttranslational Modifications and Cell Function (Beijing), Peking University,38 Xue Yuan Rd, Beijing 100191, China.
| | - Weiping Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences (Ministry of Education), Key Laboratory of Protein Posttranslational Modifications and Cell Function (Beijing), Peking University,38 Xue Yuan Rd, Beijing 100191, China.
| | - Qiong Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences (Ministry of Education), Key Laboratory of Protein Posttranslational Modifications and Cell Function (Beijing), Peking University,38 Xue Yuan Rd, Beijing 100191, China.
| | - Ping Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences (Ministry of Education), Key Laboratory of Protein Posttranslational Modifications and Cell Function (Beijing), Peking University,38 Xue Yuan Rd, Beijing 100191, China.
| | - Chunyan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences (Ministry of Education), Key Laboratory of Protein Posttranslational Modifications and Cell Function (Beijing), Peking University,38 Xue Yuan Rd, Beijing 100191, China.
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