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Deng H, Xiao Q, Xu X, Zhang L, Zhang Y. Quercetin Inhibits Gastric Cancer Progression via FAM198B/MAPK Pathway Modulation. Pharmgenomics Pers Med 2025; 18:115-141. [PMID: 40390771 PMCID: PMC12087595 DOI: 10.2147/pgpm.s511324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025] Open
Abstract
Background The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC. Methods FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays. Results FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05). Conclusion Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.
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Affiliation(s)
- Hongyang Deng
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Qi Xiao
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Xiaodong Xu
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Lingyi Zhang
- Department of Liver Disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
| | - Youcheng Zhang
- Department of General Surgery, Hepatic-Biliary-Pancreatic Institute, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China
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Meng K, Song J, Qi F, Li J, Fang Z, Song L, Shi S. The mutualistic relationship between M2c macrophages of TGFβ1 induction and gastric cancer cells: the correlation between protective mechanisms in the tumor microenvironment and polarization of subtypes of cells. J Cancer 2025; 16:1598-1617. [PMID: 39991579 PMCID: PMC11843238 DOI: 10.7150/jca.97784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 01/08/2025] [Indexed: 02/25/2025] Open
Abstract
Background: Gastric cancer (GC) is one of the most common malignant tumors worldwide, with fast metastasis and high mortality rate. GC cells and tumor immune microenvironment exhibit high heterogeneity. Multiple pieces of evidence suggest that TGFβ1 intervenes in the tumor microenvironment, immune cells and GC prognosis. The aim of this study is to comprehensively investigate the functional intervention of macrophage polarization subtypes on gastric cancer cell lines in the GC tumor microenvironment, providing valuable insights into tumor microenvironment research and potential targets for treatment strategies. Methods: TCGA database and multiple GEO datasets were used to validate the role of TGFβ1 in cancer prognosis, immune infiltration and subtype macrophage polarization. Construct different subtypes of macrophages and establish cell co culture systems using Transwell chambers. Enzyme linked immunosorbent assay (ELISA), western blotting (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to verify the changes in the metastatic function and defense mechanism of gastric cancer cells (Hgc27 and MKN45) in different co culture systems. Further analyze the effect of gastric cancer cell metabolites on macrophage subtype polarization. Results: TGFβ1 was highly expressed in GC tissues, highly expressed TGFβ1 could reduce the survival time of GC patients. The GC immune infiltration results confirmed the correlation between TGFβ1 and M2 macrophages. The GEO dataset results of gastric cancer at different stages showed that some M2 macrophage markers showed consistent changes with TGFβ1. The WB, ELISA and RT-qPCR have identified TGFβ1-induced polarization of M2c macrophages, most biomarkers are associated with M2c. M2c macrophages can enhance cell migration and function, can inhibit ferroptosis in gastric cancer cells, endowing them with stronger special environmental resistance. Gastric cancer cells tend to polarize towards M2 macrophages, with M2c being the main M2 subtype of macrophages. Conclusion: In conclusion, our study reveals a mutually beneficial symbiotic relationship between M2c macrophages and cancer cells in the microenvironment of gastric cancer tumors. TGFβ1 promotes the production of M2c macrophages, which enhance the function and ferroptosis resistance of gastric cancer cells. Gastric cancer cells provide the material basis for M2c macrophage polarization. This new evidence may provide new insights into developing more effective targeted therapies for gastric cancer to combat the formation of immune escape and metastasis in gastric cancer.
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Affiliation(s)
- Kaiqiang Meng
- College of Traditional Chinese Medicine, Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Jian Song
- College of Traditional Chinese Medicine, Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Fan Qi
- College of Integrated Traditional Chinese and Western Medicine, Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Jiamin Li
- Basic Medical College,Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Zhichao Fang
- Basic Medical College,Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Liang Song
- Basic Medical College,Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
| | - Shaonan Shi
- College of Traditional Chinese Medicine, Shaanxi University of Chinese Medicine, 712046, Shaanxi, China
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3
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Mo Y, Huang E, Deng C, Huang H, Zhu Y, Wei X, Zhong J, Wang Y, Huang Z, Zhang J. NAT10 functions as a pivotal regulator in gastric cancer metastasis and tumor immunity. J Cell Physiol 2025; 240:e31474. [PMID: 39467076 DOI: 10.1002/jcp.31474] [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: 06/28/2024] [Revised: 10/08/2024] [Accepted: 10/16/2024] [Indexed: 10/30/2024]
Abstract
Gastric cancer (GC) presents a significant global health burden, with metastasis being the leading cause of treatment failure and mortality. NAT10, a regulatory protein involved in mRNA acetylation, has been implicated in various cancers. However, its role in GC, especially concerning metastasis and immune interactions, remains unclear. Utilizing multi-omics data from gastric cancer samples, we conducted comprehensive analyses to investigate NAT10 expression, its correlation with clinical parameters and immune relevance. Bioinformatics analysis and digital image processing were employed for this purpose. Furthermore, in vitro and in vivo experiments were conducted to elucidate the functional role of NAT10 in gastric cancer progression, aiming to provide deeper biological insights. Our findings reveal a significant association between NAT10 expression and various aspects of transcriptional, protein, as well as tumor immunity in GC patients. Additionally, we demonstrated that NAT10 promotes gastric cancer cell proliferation and migration, both in cellular models and in animal studies, suggesting its involvement in early tumor microvascular metastasis. NAT10 emerges as a promising molecular target, offering potential avenues for further research into molecular mechanisms and therapeutic strategies for GC.
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Affiliation(s)
- Yuqian Mo
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
- Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Guangdong Medical University, Zhanjiang, China
| | - Enyu Huang
- Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Guangdong Medical University, Zhanjiang, China
| | - Chao Deng
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Haofeng Huang
- Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Guangdong Medical University, Zhanjiang, China
| | - Ying Zhu
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Xinlong Wei
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Jinlin Zhong
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Yuzhi Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Zhigang Huang
- Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
- Key Laboratory of Noncommunicable Diseases Control and Health Data Statistics of Guangdong Medical University, Dongguan, China
| | - Jingjing Zhang
- Affiliated Hospital of Guangdong Medical University & Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Guangdong Medical University, Zhanjiang, China
- School of Medical Technology, Guangdong Medical University, Dongguan, China
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4
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Pino MTL, Rocca MV, Acosta LH, Cabilla JP. Challenging the Norm: The Unrecognized Impact of Soluble Guanylyl Cyclase Subunits in Cancer. Int J Mol Sci 2024; 25:10053. [PMID: 39337539 PMCID: PMC11432225 DOI: 10.3390/ijms251810053] [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: 06/19/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/30/2024] Open
Abstract
Since the discovery of nitric oxide (NO), a long journey has led us to the present, during which much knowledge has been gained about its pathway members and their roles in physiological and various pathophysiological conditions. Soluble guanylyl cyclase (sGC), the main NO receptor composed of the sGCα1 and sGCβ1 subunits, has been one of the central figures in this narrative. However, the sGCα1 and sGCβ1 subunits remained obscured by the focus on sGC's enzymatic activity for many years. In this review, we restore the significance of the sGCα1 and sGCβ1 subunits by compiling and analyzing available but previously overlooked information regarding their roles beyond enzymatic activity. We delve into the basics of sGC expression regulation, from its transcriptional regulation to its interaction with proteins, placing particular emphasis on evidence thus far demonstrating the actions of each sGC subunit in different tumor models. Exploring the roles of sGC subunits in cancer offers a valuable opportunity to enhance our understanding of tumor biology and discover new therapeutic avenues.
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Affiliation(s)
- María Teresa L Pino
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - María Victoria Rocca
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - Lucas H Acosta
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
| | - Jimena P Cabilla
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET-Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina
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5
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Aqil A, Li Y, Wang Z, Islam S, Russell M, Kallak TK, Saitou M, Gokcumen O, Masuda N. Switch-like Gene Expression Modulates Disease Susceptibility. RESEARCH SQUARE 2024:rs.3.rs-4974188. [PMID: 39315271 PMCID: PMC11419265 DOI: 10.21203/rs.3.rs-4974188/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five (~18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p<10-4) and vaginal atrophy (44-fold, p<10-4), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12. We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.
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Affiliation(s)
- Alber Aqil
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Yanyan Li
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | - Zhiliang Wang
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | - Saiful Islam
- Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA
| | - Madison Russell
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | | | - Marie Saitou
- Faculty of Biosciences, Norwegian University of Life Sciences, Aas, Norway
| | - Omer Gokcumen
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Naoki Masuda
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
- Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA
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6
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Aliyari M, Hashemy SI, Hashemi SF, Reihani A, Kesharwani P, Hosseini H, Sahebkar A. Targeting the Akt signaling pathway: Exploiting curcumin's anticancer potential. Pathol Res Pract 2024; 261:155479. [PMID: 39068859 DOI: 10.1016/j.prp.2024.155479] [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: 04/28/2024] [Revised: 07/13/2024] [Accepted: 07/19/2024] [Indexed: 07/30/2024]
Abstract
Cancer is recognized as one of the leading causes of death worldwide. In recent years, advancements in early detection and expanding treatment options have contributed to a decrease in mortality rates. However, the emergence of drug-resistant cancers necessitates the exploration of innovative and more effective drugs. The Akt kinases play a central role in various signaling pathways that regulate crucial cellular processes, including cell growth, proliferation, survival, angiogenesis, and glucose metabolism. Due to frequent disruptions of the Akt signaling pathway in numerous human cancers and its broad biological implications, targeting this pathway has become a key focus in combating tumor aggressiveness and a promising avenue for therapeutic intervention. Curcumin, a compound found in turmeric, has been extensively studied for its potential as an anti-cancer agent. It demonstrates inhibitory effects on cancer initiation, progression, and metastasis by influencing various processes involved in tumor growth and development. These effects are achieved through negative regulation of transcription factors, growth factors, cytokines, protein kinases, and other oncogenic molecules. This review aims to explore curcumin's anticancer activity against different types of cancer mediated via the PI3K/Akt signaling pathway, as well as its practical applications in treatment.
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Affiliation(s)
- Mahdieh Aliyari
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Fatemeh Hashemi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirali Reihani
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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7
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Aqil A, Li Y, Wang Z, Islam S, Russell M, Kallak TK, Saitou M, Gokcumen O, Masuda N. Switch-like Gene Expression Modulates Disease Susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.24.609537. [PMID: 39229158 PMCID: PMC11370615 DOI: 10.1101/2024.08.24.609537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five (~18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p<10-4) and vaginal atrophy (44-fold, p<10-4), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12. We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.
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Affiliation(s)
- Alber Aqil
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Yanyan Li
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | - Zhiliang Wang
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | - Saiful Islam
- Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA
| | - Madison Russell
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
| | | | - Marie Saitou
- Faculty of Biosciences, Norwegian University of Life Sciences, Aas, Norway
| | - Omer Gokcumen
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Naoki Masuda
- Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA
- Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA
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8
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Keykhosravi M, Asgarian-Omran H, Valadan R, Tehrani M, Javadzadeh SM, Taghiloo S, Najafi A, Fatehi Q, Majd I, Ajami A. Clinical Significance of TNFSF14/LIGHT and CD160 in Gastric Cancer and Peptic Ulcer Dyspepsia. Asian Pac J Cancer Prev 2024; 25:2669-2677. [PMID: 39205564 PMCID: PMC11495460 DOI: 10.31557/apjcp.2024.25.8.2669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Previous studies have reported the role of the Herpes Virus Entry Mediator (HVEM) in various cancer including gastric cancer. However, the expression level and clinical significance of CD160 and Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14) pathways in gastric cancer and gastric dyspepsia patients have remained unexplored. METHODS The study involved the collection of gastric tissue biopsies from 42 patients with non-ulcerative dyspepsia (NUD) as the control group, 43 gastric cancer (GC) patients, and 48 patients with peptic-ulcerative dyspepsia (PUD). All the patients were endoscopically examined at Imam Khomeini Hospital in Sari, Mazandaran, Iran. The expression levels of TNFSF14 and CD160 mRNA were assessed using quantitative real-time PCR (qPCR) with the SYBR Green method. Statistical analysis was performed to investigate the potential association between the clinical and experimental data. RESULTS Among the 133 gastric endoscopic biopsies examined, LIGHT exhibited a significant overexpression in GC patients (p-value < 0.01). Moreover, the expression of TNFSF14 was higher in GC patients with stages I and II (p-value<0.05). Furthermore, GC patients with TNM stages III+IV were accompanied by high expression levels of LIGHT (p-value < 0.01) as well as CD160 (p-value<0.05). The expression of CD160 was also higher in younger adults with PUD (p-value<0.05). Whereas TNFSF14 exhibited higher expression in older adults with GC (p-value<0.05). Furthermore, this research provided insights into the potential biological pathways and significant gene enrichment of TNFSF14 and CD160, suggesting the potential role of CD160 and TNFSF14 in the regulation of immune system in GC and PUD. CONCLUSION These findings suggest the possible role of LIGHT and CD160 expression in gastric cancer patients in immune dysregulation toward gastric cancer. Targeted immunotherapy that harnessing co-stimulatory molecules like LIGHT and CD160 could be a promising approach in the treatment of GC as well as potential GC tumor markers.
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Affiliation(s)
- Mohsen Keykhosravi
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Hossein Asgarian-Omran
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Reza Valadan
- Department of Immunology, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mohsen Tehrani
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Seyed Mohammad Javadzadeh
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Saeid Taghiloo
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Ahmad Najafi
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Qasem Fatehi
- Babol University of Medical Science, Mazandaran, Babol, Iran.
| | - Islam Majd
- Ardebil University of Medical science, Ardebil, Iran.
| | - Abolghasem Ajami
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
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9
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Yang Y, Zhang J. Ascites-derived hsa-miR-181a-5p serves as a prognostic marker for gastric cancer-associated malignant ascites. BMC Genomics 2024; 25:628. [PMID: 38914980 PMCID: PMC11194912 DOI: 10.1186/s12864-024-10359-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/29/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related immune regulation activities in GC-associated malignant ascites. METHODS GSE126399 were downloaded from GEO database. Differentially expressed miRNAs in GC ascites samples was firstly screened, and critical miRNAs were further investigated by LASSO (least absolute shrinkage and selection operator) logistic regression and random forest (RF) algorithm. Receiver operating characteristic of critical miRNAs was also constructed. Moreover, functional analysis, immune cell infiltration associated with differentially expressed mRNAs were further analyzed. After selecting key modules by weighted gene co-expression network analysis, mRNAs related with survival performance and transcription factor (TF)-miRNA-mRNA network were constructed. RESULTS Hsa-miR-181b-5p was confirmed as critical differentially expressed miRNAs in GC ascites. Then, the tumor samples were divided into high- and low- expression groups divided by mean expression levels of hsa-miR-181b-5p, and subjects with high hsa-miR-181b-5p levels had better survival outcomes. In total, 197 differentially expressed mRNAs associated with hsa-miR-181b-5p levels were obtained, and these mRNAs were mainly enriched in muscle activity and vascular smooth muscle contraction. Hsa-miR-181b-5 was positively related with activated CD4 T cells and negatively related with eosinophil. 17 mRNAs were selected as mRNAs significantly related with prognosis of GC, such as PDK4 and RAMP1. Finally, 75 TF-miRNA-mRNA relationships were obtained, including 15 TFs, hsa-miR-181b-5p, and five mRNAs. CONCLUSION Our data suggest that the differentially expressed hsa-miR-181b-5p in ascites samples of GC patients may be a valuable prognostic marker and a potential target for therapeutic intervention, which should be validated in the near future.
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Affiliation(s)
- Yongchao Yang
- Department of General Surgery 1, Sunshine Union Hospital, Weifang City, 261072, Shandong Province, China
| | - Junliang Zhang
- Department of Emergency Medicine, Sunshine Union Hospital, No. 9000, Yingqian Street, High-tech Zone, Weifang City, 261072, Shandong Province, China.
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10
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Feng Z, Gao L, Lu Y, He X, Xie J. The potential contribution of aberrant cathepsin K expression to gastric cancer pathogenesis. Discov Oncol 2024; 15:218. [PMID: 38856944 PMCID: PMC11164852 DOI: 10.1007/s12672-023-00814-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/26/2023] [Indexed: 06/11/2024] Open
Abstract
The role of cathepsin K (CTSK) expression in the pathogenesis and progression of gastric cancer (GC) remains unclear. Hence, the primary objective of this study is to elucidate the precise expression and biological role of CTSK in GC by employing a combination of bioinformatics analysis and in vitro experiments. Our findings indicated a significant upregulation of CTSK in GC. The bioinformatics analysis revealed that GC patients with a high level of CTSK expression exhibited enrichment of hallmark gene sets associated with angiogenesis, epithelial-mesenchymal transition (EMT), inflammatory response, KRAS signaling up, TNFα signaling via KFκB, IL2-STAT5 signaling, and IL6-JAK-STAT3 signaling. Additionally, these patients demonstrated elevated levels of M2-macrophage infiltration, which was also correlated with a poorer prognosis. The results of in vitro experiments provided confirmation that the over-expression of CTSK leads to an increase in the proliferative and invasive abilities of GC cells. However, further evaluation was necessary to determine the impact of CTSK on the migration capability of these cells. Our findings suggested that CTSK has the potential to facilitate the initiation and progression of GC by augmenting the invasive capacity of GC cells, engaging in tumor-associated EMT, and fostering the establishment of an immunosuppressive tumor microenvironment (TME).
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Affiliation(s)
- Zhijun Feng
- Jiangmen Central Hospital, No. 23, Haibang Street, Pengjiang District, Jiangmen, Guangdong, China
- The Second Clinical Medical College, Lanzhou University, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China
| | - Lina Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China
| | - Yapeng Lu
- Department of Anesthesiology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China
| | - Xiaodong He
- The Second Clinical Medical College, Lanzhou University, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China.
| | - Jianqin Xie
- Department of Anesthesiology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China.
- The Second Clinical Medical College, Lanzhou University, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, China.
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11
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Wang BS, Zhang CL, Cui X, Li Q, Yang L, He ZY, Yang Z, Zeng MM, Cao N. Curcumin inhibits the growth and invasion of gastric cancer by regulating long noncoding RNA AC022424.2. World J Gastrointest Oncol 2024; 16:1437-1452. [PMID: 38660661 PMCID: PMC11037052 DOI: 10.4251/wjgo.v16.i4.1437] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/19/2023] [Accepted: 01/17/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Gastric cancer, characterized by a multifactorial etiology and high heterogeneity, continues to confound researchers in terms of its pathogenesis. Curcumin, a natural anticancer agent, exhibits therapeutic promise in gastric cancer. Its effects include promoting cell apoptosis, curtailing tumor angiogenesis, and enhancing sensitivity to radiation and chemotherapy. Long noncoding RNAs (lncRNAs) have garnered significant attention as biomarkers for early screening, diagnosis, treatment, and drug response because of their remarkable specificity and sensitivity. Recent investigations have revealed an association between aberrant lncRNA expression and early diagnosis, clinical staging, metastasis, drug sensitivity, and prognosis in gastric cancer. A profound understanding of the intricate mechanisms through which lncRNAs influence gastric cancer development can provide novel insights for precision treatment and tailored management of patients with gastric cancer. This study aimed to unravel the potential of curcumin in suppressing the malignant behavior of gastric cancer cells by upregulating specific lncRNAs and modulating gastric cancer onset and progression. AIM To identify lncRNAs associated with curcumin treatment and investigate the role of lncRNA AC022424.2 in the effects of curcumin on gastric cancer cell apoptosis, proliferation, and invasion. Furthermore, these findings were validated in clinical samples. METHODS The study employed CCK-8 assays to assess the impact of curcumin on gastric cancer cell proliferation, flow cytometry to investigate its effects on apoptosis, and scratch and Transwell assays to evaluate its influence on the migration and invasion of BGC-823 and MGC-803 cells. Western blotting was used to gauge changes in the protein expression levels of CDK6, CDK4, Bax, Bcl-2, caspase-3, P65, and the PI3K/Akt/mTOR pathway in gastric cancer cell lines after curcumin treatment. Differential expression of lncRNAs before and after curcumin treatment was assessed using lncRNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in BGC-823 and MGC-803 cells. AC022424.2-1 knockdown BGC-823 and MGC-803 cells were generated to scrutinize the impact of lncRNA AC022424.2 on apoptosis, proliferation, migration, and invasion of gastric cancer cells. Western blotting was performed to ascertain changes in the expression of proteins implicated in the PI3K/Akt/mTOR and NF-κB signaling pathways. RT-PCR was employed to measure lncRNA AC022424.2 expression in clinical gastric cancer tissues and to correlate its expression with clinical pathological characteristics. RESULTS Curcumin induced apoptosis and hindered proliferation, migration, and invasion of gastric cancer cells in a dose- and time-dependent manner. LncRNA AC022424.2 was upregulated after curcumin treatment, and its knockdown enhanced cancer cell aggressiveness. LncRNA AC022424.2 may have affected cancer cells via the PI3K/Akt/mTOR and NF-κB signaling pathways. LncRNA AC022424.2 downregulation was correlated with lymph node metastasis, making it a potential diagnostic and prognostic marker. CONCLUSION Curcumin has potential anticancer effects on gastric cancer cells by regulating lncRNA AC022424.2. This lncRNA plays a significant role in cancer cell behavior and may have clinical implications in diagnosis and prognosis evaluation. The results of this study enhance our understanding of gastric cancer development and precision treatment.
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Affiliation(s)
- Bin-Sheng Wang
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Chen-Li Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiang Cui
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Qiang Li
- Third Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Lei Yang
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhi-Yun He
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ze Yang
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Miao-Miao Zeng
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Nong Cao
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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12
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Gan L, Yang C, Zhao L, Wang S, Ye Y, Gao Z. L3MBTL3 Is a Potential Prognostic Biomarker and Correlates with Immune Infiltrations in Gastric Cancer. Cancers (Basel) 2023; 16:128. [PMID: 38201555 PMCID: PMC10778146 DOI: 10.3390/cancers16010128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/23/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
Recent research has linked lethal (3) malignant brain tumor-like 3 (L3MBTL3) to cancer aggressiveness and a dismal prognosis, but its function in gastric cancer (GC) is unclear. This research investigated the association between L3MBTL3 expression and clinicopathological characteristics of GC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that L3MBTL3 expression was upregulated in malignant GC tissues, which was associated with a shortened survival time and poor clinicopathological characteristics, including TNM staging. A functional enrichment analysis including GO/KEGG and GSEA illustrated the enrichment of different L3MBTL3-associated pathways involved in carcinogenesis and immune response. In addition, the correlations between L3MBTL3 and tumor-infiltrating immune cells were determined based on the TIMER database; the results showed that L3MBTL3 was associated with the immune infiltration of macrophages and their polarization from M1 to M2. Furthermore, our findings suggested a possible function for L3MBTL3 in the regulation of the tumor immune microenvironment of GC. In summary, L3MBTL3 has diagnostic potential, and it also offers new insights into the development of aggressiveness and prognosis in GC.
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Affiliation(s)
- Lin Gan
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
| | - Changjiang Yang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (C.Y.); (L.Z.); (S.W.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Long Zhao
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (C.Y.); (L.Z.); (S.W.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Shan Wang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (C.Y.); (L.Z.); (S.W.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (C.Y.); (L.Z.); (S.W.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
| | - Zhidong Gao
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China; (C.Y.); (L.Z.); (S.W.)
- Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing 100044, China
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13
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Xiao L, Zhang Y, Luo Q, Guo C, Chen Z, Lai C. DHRS4-AS1 regulate gastric cancer apoptosis and cell proliferation by destabilizing DHX9 and inhibited the association between DHX9 and ILF3. Cancer Cell Int 2023; 23:304. [PMID: 38041141 PMCID: PMC10693172 DOI: 10.1186/s12935-023-03151-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/18/2023] [Indexed: 12/03/2023] Open
Abstract
Gastric cancer (GC) causes millions of cancer-related deaths due to anti-apoptosis and rapid proliferation. However, the molecular mechanisms underlying GC cell proliferation and anti-apoptosis remain unclear. The expression levels of DHRS4-AS1 in GC were analyzed based on GEO database and recruited GC patients in our institution. We found that DHRS4-AS1 was significantly downregulated in GC. The expression of DHRS4-AS1 in GC tissues showed a significant correlation with tumor size, advanced pathological stage, and vascular invasion. Moreover, DHRS4-AS1 levels in GC tissues were significantly associated with prognosis. DHRS4-AS1 markedly inhibited GC cell proliferation and promotes apoptosis in vitro and in vivo assays. Mechanically, We found that DHRS4-AS1 bound to pro-oncogenic DHX9 (DExH-box helicase 9) and recruit the E3 ligase MDM2 that contributed to DHX9 degradation. We also confirmed that DHRS4-AS1 inhibited DHX9-mediated cell proliferation and promotes apoptosis. Furthermore, we found DHX9 interact with ILF3 (Interleukin enhancer Binding Factor 3) and activate NF-kB Signaling in a ILF3-dependent Manner. Moreover, DHRS4-AS1 can also inhibit the association between DHX9 and ILF3 thereby interfered the activation of the signaling pathway. Our results reveal new insights into mechanisms underlying GC progression and indicate that LncRNA DHRS4-AS1 could be a future therapeutic target and a biomarker for GC diagnosis.
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Affiliation(s)
- Lei Xiao
- Department of General Surgery, Xiangya Hospital of Central South University, Xiangya Road No. 87, Kaifu District, Changsha, 410000, Hunan Province, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumors, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yang Zhang
- Department of General Surgery, Xiangya Hospital of Central South University, Xiangya Road No. 87, Kaifu District, Changsha, 410000, Hunan Province, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumors, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Qingqing Luo
- Department of Oncology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, Hunan Province, China
| | - Cao Guo
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital of Central South University, Xiangya Road No. 87, Kaifu District, Changsha, 410000, Hunan Province, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumors, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Chen Lai
- Department of General Surgery, Xiangya Hospital of Central South University, Xiangya Road No. 87, Kaifu District, Changsha, 410000, Hunan Province, China.
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumors, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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14
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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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15
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Rezaee A, Ahmadpour S, Jafari A, Aghili S, Zadeh SST, Rajabi A, Raisi A, Hamblin MR, Mahjoubin-Tehran M, Derakhshan M. MicroRNAs, long non-coding RNAs, and circular RNAs and gynecological cancers: focus on metastasis. Front Oncol 2023; 13:1215194. [PMID: 37854681 PMCID: PMC10580988 DOI: 10.3389/fonc.2023.1215194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/28/2023] [Indexed: 10/20/2023] Open
Abstract
Gynecologic cancer is a significant cause of death in women worldwide, with cervical cancer, ovarian cancer, and endometrial cancer being among the most well-known types. The initiation and progression of gynecologic cancers involve a variety of biological functions, including angiogenesis and metastasis-given that death mostly occurs from metastatic tumors that have invaded the surrounding tissues. Therefore, understanding the molecular pathways underlying gynecologic cancer metastasis is critical for enhancing patient survival and outcomes. Recent research has revealed the contribution of numerous non-coding RNAs (ncRNAs) to metastasis and invasion of gynecologic cancer by affecting specific cellular pathways. This review focuses on three types of gynecologic cancer (ovarian, endometrial, and cervical) and three kinds of ncRNAs (long non-coding RNAs, microRNAs, and circular RNAs). We summarize the detailed role of non-coding RNAs in the different pathways and molecular interactions involved in the invasion and metastasis of these cancers.
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Affiliation(s)
- Aryan Rezaee
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Ahmadpour
- Biotechnology Department, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sarehnaz Aghili
- Department of Gynecology and Obstetrics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Arash Raisi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Maryam Mahjoubin-Tehran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Marzieh Derakhshan
- Shahid Beheshti Fertility Clinic, Department of Gynecology and Obsteterics, Isfahan University of Medical Sciences, Isfahan, Iran
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16
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González-Castrillón LM, Wurmser M, Öhlund D, Wilson SI. Dysregulation of core neurodevelopmental pathways-a common feature of cancers with perineural invasion. Front Genet 2023; 14:1181775. [PMID: 37719704 PMCID: PMC10501147 DOI: 10.3389/fgene.2023.1181775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 07/31/2023] [Indexed: 09/19/2023] Open
Abstract
Background: High nerve density in tumors and metastasis via nerves (perineural invasion-PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve-tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve-tumor crosstalk and to determine common molecular features between PNI-associated cancers. Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%-16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin-Eph, semaphorin-neuropilin/plexin, and slit-robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival. Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.
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Affiliation(s)
| | - Maud Wurmser
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Daniel Öhlund
- Wallenberg Centre for Molecular Medicine, Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Sara Ivy Wilson
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
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17
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Zhou YQ, Bao TS, Xie JX, Yao LL, Yu ST, Li Q, Huang PQ, Zhou WZ, Wang YY, Chen SY, Wang XQ, Zhang XL, Jiang SH, Yi SQ, Zhang ZG, Ma MZ, Hu LP, Xu J, Li J. The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells. Cell Oncol (Dordr) 2023; 46:1049-1067. [PMID: 37012514 DOI: 10.1007/s13402-023-00795-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2023] [Indexed: 04/05/2023] Open
Abstract
PURPOSE Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. METHODS The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. RESULTS By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. CONCLUSION In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.
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Affiliation(s)
- Yao-Qi Zhou
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Tian-Shang Bao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Jia-Xuan Xie
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Lin-Li Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Si-Te Yu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Qing Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Pei-Qi Huang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Wan-Zhen Zhou
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yang-Yang Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Su-Yuan Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Xiao-Qi Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Xue-Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Shuang-Qin Yi
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Hachioji, Japan
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China
| | - Ming-Ze Ma
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Li-Peng Hu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China.
| | - Jia Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| | - Jun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China.
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18
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Li M, Zhang HY, Zhang RG. MFAP2 enhances cisplatin resistance in gastric cancer cells by regulating autophagy. PeerJ 2023; 11:e15441. [PMID: 37304872 PMCID: PMC10257393 DOI: 10.7717/peerj.15441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/28/2023] [Indexed: 06/13/2023] Open
Abstract
Background Cisplatin (CDDP) is of importance in cancer treatment and widely used in advanced gastric cancer (GC). However, its clinical usage is limited due to its resistance, and the regulatory mechanism of CDDP resistance in GC has not yet been fully elucidated. In this study, we first conducted a comprehensive study to investigate the role of MFAP2 through bioinformatics analysis. Methods The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were applied to downloadgene expression data and clinicopathologic data, and the differentially expressed genes (DEGs) were further analyzed. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and survival analysis were conducted. Furthermore, according to the clinicopathological characteristics of TCGA, clinical correlation analysis was conducted, and a receiver operating characteristic curve (ROC) was plotted. Results We revealed that FAP, INHBA and MFAP2 were good diagnostic factors of GC. However, the mechanism of MFAP2 in GC remains elusive, especially in the aspect of chemotherapy resistance. We developed the CDDP-resistant cell line, and found that MFAP2 was upregulated in CDDP-resistant cells, and MFAP2-knockdown improved CDDP sensitivity. Finally, we found that MFAP2 enhanced CDDP resistance by inducing autophagy in drug-resistant cell lines. Conclusions The above results suggested that MFAP2 could affect the chemotherapy resistance by altering the level of autophagy in GC patients as a potential therapeutic target.
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Affiliation(s)
- Meng Li
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Hong-Yi Zhang
- Department of Stomatology, Beijing Electric Power Hospital, Capital Medical University, Beijing, China
| | - Rong-Gui Zhang
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
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19
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Vo D, Ghosh P, Sahoo D. Artificial intelligence-guided discovery of gastric cancer continuum. Gastric Cancer 2023; 26:286-297. [PMID: 36692601 PMCID: PMC9871434 DOI: 10.1007/s10120-022-01360-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 12/19/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Detailed understanding of pre-, early and late neoplastic states in gastric cancer helps develop better models of risk of progression to gastric cancers (GCs) and medical treatment to intercept such progression. METHODS We built a Boolean implication network of gastric cancer and deployed machine learning algorithms to develop predictive models of known pre-neoplastic states, e.g., atrophic gastritis, intestinal metaplasia (IM) and low- to high-grade intestinal neoplasia (L/HGIN), and GC. Our approach exploits the presence of asymmetric Boolean implication relationships that are likely to be invariant across almost all gastric cancer datasets. Invariant asymmetric Boolean implication relationships can decipher fundamental time-series underlying the biological data. Pursuing this method, we developed a healthy mucosa → GC continuum model based on this approach. RESULTS Our model performed better against publicly available models for distinguishing healthy versus GC samples. Although not trained on IM and L/HGIN datasets, the model could identify the risk of progression to GC via the metaplasia → dysplasia → neoplasia cascade in patient samples. The model could rank all publicly available mouse models for their ability to best recapitulate the gene expression patterns during human GC initiation and progression. CONCLUSIONS A Boolean implication network enabled the identification of hitherto undefined continuum states during GC initiation. The developed model could now serve as a starting point for rationalizing candidate therapeutic targets to intercept GC progression.
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Affiliation(s)
- Daniella Vo
- Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0703, Leichtag Building 132, La Jolla, CA, 92093-0703, USA
| | - Pradipta Ghosh
- Moores Cancer Center, University of California San Diego, La Jolla, USA
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, USA
- Department of Medicine, University of California San Diego, La Jolla, USA
| | - Debashis Sahoo
- Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0703, Leichtag Building 132, La Jolla, CA, 92093-0703, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, USA.
- Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, La Jolla, USA.
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20
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The Comprehensive Analysis of N6-Methyadenosine Writer METTL3 and METTL14 in Gastric Cancer. JOURNAL OF ONCOLOGY 2023; 2023:9822995. [PMID: 36866236 PMCID: PMC9974280 DOI: 10.1155/2023/9822995] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/13/2022] [Accepted: 11/24/2022] [Indexed: 02/23/2023]
Abstract
Methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) were two core components of the N6-methyadenosine (m6A) methyltransferase complex (MTC) and played a basic role in maintaining an appropriate m6A level of target genes. In gastric cancer (GC), previous researches on the expression and role of METTL3 and METTL14 were not consistent, and their specific function and mechanism have remained elusive. In this study, the expression of METTL3 and METTL14 was evaluated based on the TCGA database, 9 paired GEO datasets, and our 33 GC patient samples, and METTL3 was highly expressed and acted as a poor prognostic factor, whereas METTL14 showed no significant difference. Moreover, GO and GSEA analyses were performed, and the results pointed out that METTL3 and METTL14 were jointly involved in multiple biological processes, while they could also take part in different oncogenic pathways independently. And BCLAF1 was predicted and identified as a novel shared target of METTL3 and METTL14 in GC. In total, we conducted a comprehensive analysis of METTL3 and METTL14 in GC including their expression, function, and role, which could provide a novel insight into the research of m6A modification in GC.
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21
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Screening and identification of CNIH4 gene associated with cell proliferation in gastric cancer based on a large-scale CRISPR-Cas9 screening database DepMap. Gene 2023; 850:146961. [DOI: 10.1016/j.gene.2022.146961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 02/05/2023]
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22
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Taghehchian N, Alemohammad R, Farshchian M, Asoodeh A, Abbaszadegan MR. Inhibitory role of LINC00332 in gastric cancer progression through regulating cell EMT and stemness. Life Sci 2022; 305:120759. [PMID: 35787995 DOI: 10.1016/j.lfs.2022.120759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/11/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Gastric cancer (GC) is one of the most common lethal malignancies worldwide. The molecular mechanisms underlying GC early detection are poorly understood. Identifying potential coding and non-coding markers and related pathways in the GC progression is essential. Some Long non-coding RNAs (lncRNAs) reportedly play vital roles during gastric GC development. However, the clinical significance and biological function of LINC00332 in GC remain largely unclear. METHODS The gene expression patterns of GC from an RNAseq dataset (GSE122401) were retrieved from the Gene Expression Omnibus (GEO) database to recognize differentially expressed genes (DEGs) and lncRNAs (DELs) between normal and GC samples through several bioinformatic analysis. The expression of LINC00332 and MMP-13 as a target gene was quantified in fresh frozen tissues obtained from GC patients. In addition, we investigated the potential function of LINC00332 in silico and in vitro. RESULTS The expressions of LINC00332 and MMP-13 were significantly downregulated and upregulated in GC tissues, respectively. A significant inverse correlation between LINC00332 and MMP-13 mRNA expression was observed in tumor samples. The mRNA expression level of mesenchymal markers, stem cell factors, and MMP genes were significantly decreased after the LINC00332 ectopic expression, while epithelial markers expression was significantly increased. The LINC00332 overexpression markedly repressed proliferation, migration, and invasion and did not induce apoptosis in AGS cells. In addition, LINC00332 overexpression notably promoted the E-cadherin protein expression. Moreover, LINC00332 significantly decreased the cisplatin resistance. CONCLUSION Our findings indicated that LINC00332 may be a critical anti-EMT factor and provided a new efficient therapeutic strategy for GC treatment.
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Affiliation(s)
- Negin Taghehchian
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Reza Alemohammad
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR), Khorasan Razavi, Mashhad, Iran
| | - Moein Farshchian
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture, and Research (ACECR), Khorasan Razavi, Mashhad, Iran.
| | - Ahmad Asoodeh
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
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23
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Liu S, Cao X, Wu S. High expression of SMARCC1 predicts poor prognosis in gastric cancer patients. Am J Cancer Res 2022; 12:4428-4438. [PMID: 36225646 PMCID: PMC9548000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/14/2022] [Indexed: 06/16/2023] Open
Abstract
The switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes use the energy of ATP hydrolysis to remodel nucleosomes and modulate transcription, which plays an important role in tumors by regulating epigenetics. SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily C, Member 1 (SMARCC1) has dual roles in tumors but its role in gastric cancer remains unclear. This study was aimed to find the role of SMARCC1 in gastric cancer. SMARCC1 expression across various tumors from The Cancer Genome Atlas was analyzed using TIMER 2.0 (http://timer.comp-genomics.org/). SMARCC1 mRNA expression profiles in gastric cell lines and gastric tissues were compared with normal tissues and analyzed in the Cancer Cell Line Encyclopedia, Oncomine, and Gene Expression Omnibus databases. SMARCC1 mRNA and protein were then examined in fresh gastric cancer tissues and compared with adjacent normal tissues using quantitative real-time PCR, western blotting, and immunohistochemistry. Associations between SMARCC1 expression and clinicopathological factors, overall survival, and disease-free survival were further evaluated using 130 gastric cancer samples harvested from patients after radical total gastrectomy or subtotal gastrectomy at the Xiangya Hospital of Central South University (Changsha, China). SMARCC1 was frequently upregulated in gastric cancer cells and tissues. SMARCC1 overexpression was significantly associated with tumor size (P=0.002), differentiation (P=0.006), depth of invasion (P=0.001), lymph node involvement (P=0.016), and TNM stage (P=0.007). Furthermore, univariate and multivariate Cox analysis revealed that high SMARCC1 expression, depth invasion, lymph node involvement, and TNM stage were independent risk factors for both overall and disease-free survival in gastric cancer patients (all P<0.05). Kaplan-Meier survival analysis revealed that high SMARCC1 expression predicted poor prognosis in gastric cancer patients (P<0.01). High SMARCC1 expression contributes to poor prognosis in gastric cancer patients. SMARCC1 may be a prognostic biomarker and therapeutic target in gastric cancer.
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Affiliation(s)
- Sheng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South UniversityChangsha, Hunan, PR China
| | - Xinghua Cao
- Department of General Surgery, People’s Hospital of NingxiangNingxiang, Hunan, PR China
| | - Shaobin Wu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South UniversityChangsha, Hunan, PR China
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24
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Hu S, Li P, Wang C, Liu X. Expression and the Prognostic Value of Biglycan in Gastric Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2656480. [PMID: 36110576 PMCID: PMC9470332 DOI: 10.1155/2022/2656480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022]
Abstract
Background Biglycan (BGN) is a family member of small leucine-rich repeat proteoglycans. High expression of BGN might enhance the invasion and metastasis in some types of tumors. Here, the prognostic significance of BGN was evaluated in gastric cancer. Material and Methods. Two independent Gene Expression Omnibus (GEO) gastric cancer microarray datasets (n = 64 and n = 432) were collected for this study. Kaplan-Meier analysis was applied to evaluate if BGN impacts the outcomes of gastric cancer. Protein-protein interaction (PPI) analysis was performed on gastric cancer-related genes and BGN targets, and those interactions with confidence interval (CI) ≥ 0.7 were chosen to construct a PPI network. The gene set enrichment analysis (GSEA) was used to explore BGN and cancer-related gene signatures. Gene Transcription Regulation Database (GTRD) and ALGGEN-PROMO predicted the transcription factor binding sites (TFBSs) of the BGN promoter. BGN protein level in gastric cancer tissue was determined by immunohistochemistry (IHC). Bioinformatic analysis predicted the putative TFs of BGN. Results For gastric cancer, the mRNA expression level of BGN in tumor tissue was significantly higher than that in normal tissue. Kaplan-Meier analysis showed that higher expression of BGN mRNA was significantly associated with more reduced recurrence-free survival (RFS). GSEA results suggested that BGN was significantly enriched in gene signatures related to metastasis and poor prognosis, revealing that BGN might be associated with cell proliferation, poor differentiation, and high invasiveness of gastric cancer. Meanwhile, the putative TFs, including AR, E2F1, and TCF4, were predicted by bioinformatic analysis and also significantly correlated with expression of BGN in mRNA levels. Conclusion High expression of BGN mRNA was significantly related to poor prognosis, which suggested that BGN was a potential prognostic biomarker and therapeutic target of gastric cancer.
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Affiliation(s)
- Sizhe Hu
- Department of Gastrointestinal Surgery, Affiliated Dongyang People's Hospital of Wenzhou Medical University, Dongyang, Zhejiang 322100, China
| | - Peipei Li
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, China
| | - Chenying Wang
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, China
| | - Xiyong Liu
- Sino-American Cancer Foundation, Covina, CA 91722, USA
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25
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Huang W, Zhong W, He Q, Xu Y, Lin J, Ding Y, Zhao H, Zheng X, Zheng Y. Time-series expression profiles of mRNAs and lncRNAs during mammalian palatogenesis. Oral Dis 2022. [PMID: 35506257 DOI: 10.1111/odi.14237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/12/2022] [Accepted: 04/17/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Mammalian palatogenesis is a highly regulated morphogenetic process to form the intact roof of the oral cavity. Long noncoding RNAs (lncRNAs) and mRNAs participate in numerous biological and pathological processes, but their roles in palatal development and causing orofacial clefts (OFC) remain to be clarified. METHODS Palatal tissues were separated from ICR mouse embryos at four stages (E10.5, E13.5, E15, and E17). Then, RNA sequencing (RNA-seq) was used. Various analyses were performed to explore the results. Finally, hub genes were validated via qPCR and in situ hybridization. RESULTS Starting from E10.5, the expression of cell adhesion genes escalated in the following stages. Cilium assembly and ossification genes were both upregulated at E15 compared with E13.5. Besides, the expression of cilium assembly genes was also increased at E17 compared with E15. Expression patterns of three lncRNAs (H19, Malat1, and Miat) and four mRNAs (Cdh1, Irf6, Grhl3, Efnb1) detected in RNA-seq were validated. CONCLUSIONS This study provides a time-series expression landscape of mRNAs and lncRNAs during palatogenesis, which highlights the importance of processes such as cell adhesion and ossification. Our results will facilitate a deeper understanding of the complexity of gene expression and regulation during palatogenesis.
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Affiliation(s)
- Wenbin Huang
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and- 3 -Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Wenjie Zhong
- The Affiliated Stomatology Hospital, Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
| | - Qing He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Yizhu Xu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jiuxiang Lin
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and- 3 -Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Yi Ding
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Huaxiang Zhao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaowen Zheng
- Department of Orthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Oral Disease, Shanghai, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yunfei Zheng
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and- 3 -Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, Beijing, China
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26
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Wang J, Ge J, Wang Y, Xiong F, Guo J, Jiang X, Zhang L, Deng X, Gong Z, Zhang S, Yan Q, He Y, Li X, Shi L, Guo C, Wang F, Li Z, Zhou M, Xiang B, Li Y, Xiong W, Zeng Z. EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1. Nat Commun 2022; 13:866. [PMID: 35165282 PMCID: PMC8844414 DOI: 10.1038/s41467-022-28479-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 01/26/2022] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy. Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.
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27
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Zheng T, Sun M, Liu L, Lan Y, Wang L, Lin F. GPR116 overexpression correlates with poor prognosis in gastric cancer. Medicine (Baltimore) 2021; 100:e28059. [PMID: 35049225 PMCID: PMC9191289 DOI: 10.1097/md.0000000000028059] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/18/2022] Open
Abstract
ABSTRACT The G protein-coupled receptor 116 (GPR116) is an adhesion subtype of the G protein-coupled receptor family and has been reported to be involved in tumorigenesis and cancer progression. Moreover, it has been shown to predict poor prognosis in breast and colorectal cancers. However, little is known about the role of GPR116 in gastric cancer (GC). In this study, we aimed to investigate the expression and clinical prognostic significance of GPR116 in GC.The mRNA expression levels of GPR116 in GC were analyzed using Gene Expression Omnibus and UALCAN databases, and GPR116 protein expression in GC tissues was detected using immunohistochemistry. The relationship between GPR116 expression and prognosis in patients with GC was analyzed and further validated using the Kaplan-Meier Plotter database. The correlation between GPR116 and the differentially expressed genes identified was analyzed using the LinkedOmics database. Gene set enrichment analysis was performed using WebGestalt. The results revealed that GPR116 expression was significantly upregulated in GC tissues, which was positively correlated with tumor node metastasis (TNM) staging and tumor invasion. Prognostic analysis suggested that high GPR116 expression contributed to poor overall survival in GC patients. Multivariate Cox analysis indicated that GPR116 overexpression was an independent prognostic indicator in patients with GC (HR = 1.855, 95% CI 1.021-3.370, P = .043). Enrichment analysis showed that GPR116 co-expression genes were mainly involved in extracellular matrix-receptor interaction, focal adhesion, cell adhesion, PI3K-Akt signaling, DNA replication, and cell cycle pathways. In conclusion, GPR116 was highly expressed in GC tissues and associated with poor prognosis in patients with GC, Thus GPR116 may be a novel prognostic marker and a potential therapeutic target for GC treatment.
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Affiliation(s)
- Tian Zheng
- Shengli Clinical Medical College of Fujian Medical University, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Geriatrics, Fuzhou, Fujian, China
| | - Mingyao Sun
- Department of Clinical nutrition, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Lanzai Liu
- Gastrointestinal Endoscopy Center, Fujian Provincial Hospital South Branch, Fuzhou, Fujian, China
| | - Yanfen Lan
- Department of Radiology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Lihua Wang
- Shengli Clinical Medical College of Fujian Medical University, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Geriatrics, Fuzhou, Fujian, China
| | - Fan Lin
- Shengli Clinical Medical College of Fujian Medical University, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Geriatrics, Fuzhou, Fujian, China
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28
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Zhao Y, Hu S, Zhang J, Cai Z, Wang S, Liu M, Dai J, Gao Y. Glucoside xylosyltransferase 2 as a diagnostic and prognostic marker in gastric cancer via comprehensive analysis. Bioengineered 2021; 12:5641-5654. [PMID: 34506251 PMCID: PMC8806449 DOI: 10.1080/21655979.2021.1967067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/07/2021] [Indexed: 02/08/2023] Open
Abstract
To investigate the potential role of GXYLT2 (glucoside xylosyltransferase 2) in gastric cancer (GC), the TCGA (The Cancer Genome Atlas) database and Gene Expression Omnibus (GEO) dataset were used to evaluate GXYLT2 mRNA expression, and the standardized mean difference and diagnostic value were comprehensively assessed. Survival analysis and univariate/multivariate cox regression analysis were performed to evaluate the prognostic value of GXYLT2 in GC patients. The correlation between GXYLT2 and tumor immune cells was identified by using the CIBERSORT algorithm. The results showed that GXYLT2 expression level was significantly increased in GC tissues. GXYLT2 expression was significantly correlated with the grade, stage, and invasion depth of gastric cancer. Overall survival was reduced in the high GXYLT2 expression group. Univariate and multivariate Cox regression analyses showed that GXYLT2 was a reliable prognostic factor. GSEA showed that GXYLT2 might participate in the development of GC through tumor-related pathways. The expression of GXYLT2 was positively correlated with 5 tumor-infiltrating immune cells (resting dendritic cells, m2 macrophages, monocytes, active NK cells and resting mast cells), and was negatively correlated with 6 tumor-infiltrating immune cells (plasma cells, activated memory CD4 T cells, resting NK cells, activated dendritic cells, and activated neutrophils and mast cells). Through cell experiment verification, GXYLT2 expression level in gastric cancer cells was found to be high, which verified the results from the bioinformatics analysis. Furthermore, immunohistochemical staining results also showed that GC tissues had positive GXYLT2 expression. In summary, GXYLT2 might be a potential diagnostic and prognostic biomarker for gastric cancer.
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Affiliation(s)
- Yunxia Zhao
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China
| | - Shangshang Hu
- Research Center of Clinical Laboratory Science, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
| | - Jinyan Zhang
- School of Life Science, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
| | - Zhaogen Cai
- Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu, China
| | - Shuanhu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Mulin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Jing Dai
- School of Life Science, Bengbu Medical College, Bengbu, China
| | - Yu Gao
- School of Life Science, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
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29
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Liu GX, Tan YZ, He GC, Zhang QL, Liu P. EMX2OS plays a prognosis-associated enhancer RNA role in gastric cancer. Medicine (Baltimore) 2021; 100:e27535. [PMID: 34731149 PMCID: PMC8519253 DOI: 10.1097/md.0000000000027535] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 09/27/2021] [Indexed: 01/05/2023] Open
Abstract
Enhancer RNAs (eRNAs), a subclass of lncRNAs, are derived from enhancer regions. The function of eRNAs has been reported by many previous studies. However, the role of eRNAs in gastric cancer, especially the prognosis-associated eRNAs, has not been studied yet.In this study, we have used a novel approach to screened key eRNAs in gastric cancer. Kaplan-Meier correlation analysis and Co-expression analysis were used to find the most significant survival-associated eRNAs. Enrichment analysis is applied to explore the key functions and pathways of screened eRNAs. The correlation and survival analysis are used to evaluate targeted genes in the pan-cancer analysisA total of 63 prognostic-associated eRNAs in gastric cancer were identified, the top 6 eRNAs were LINC01714, ZNF192P1, AC079760.2, LINC01645, EMX2OS, and AC114489.2. The correlation analysis demonstrated the top 10 screened eRNAs and their targeted genes. The results demonstrated that EMX2OS was ranked as the top eRNA according to the results of the Kaplan-Meier analysis. The correlation analysis demonstrated that eRNA EMX2OS is correlated with age, grade, stage, and cancer status. The pan-cancer analysis demonstrated that EMX2OS was associated with poor survival outcomes in adrenocortical carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney renal clear cell carcinoma, stomach adenocarcinoma, and uveal melanoma.In this study, survival-related eRNAs were screened and the correlation between survival-related eRNAs and their targeted genes was demonstrated. EMX2OS plays a prognosis-associated eRNA role in gastric cancer, which might be a novel therapeutic target in clinical practice.
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Affiliation(s)
- Ge-Xin Liu
- Department of Emergency, Zhuzhou Central Hospital, Zhuzhou, China
| | - Yu-Zhen Tan
- Department of Emergency, Zhuzhou Central Hospital, Zhuzhou, China
| | - Guo-Chao He
- Department of Emergency, Zhuzhou Central Hospital, Zhuzhou, China
| | - Qin-Lin Zhang
- Department of Neurology, Zhuzhou Central Hospital, Zhuzhou, China
| | - Pan Liu
- Department of Emergency, Zhuzhou Central Hospital, Zhuzhou, China
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30
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Xu J, Wang X, Ke Q, Liao K, Wan Y, Zhang K, Zhang G, Wang X. Combined bioinformatics technology to explore pivot genes and related clinical prognosis in the development of gastric cancer. Sci Rep 2021; 11:15412. [PMID: 34326374 PMCID: PMC8322082 DOI: 10.1038/s41598-021-94291-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/04/2021] [Indexed: 12/24/2022] Open
Abstract
To screen the key genes in the development of gastric cancer and their influence on prognosis. The GEO database was used to screen gastric cancer-related gene chips as a training set, and the R packages limma tool was used to analyze the differential genes expressed in gastric cancer tissues compared to normal tissues, and then the selected genes were verified in the validation set. The String database was used to calculate their Protein–protein interaction (PPI) network, using Cytoscape software's Centiscape and other plug-ins to analyze key genes in the PPI network. The DAVID database was used to enrich and annotate gene functions of differential genes and PPI key module genes, and further explore correlation between expression level and clinical stage and prognosis. Based on clinical data and patient samples, differential expression of key node genes was verified by immunohistochemistry. The 63 characteristic differential genes screened had good discrimination between gastric cancer and normal tissues, and are mainly involved in regulating extracellular matrix receptor interactions and the PI3k-AKT signaling pathway. Key nodes in the PPI network regulate tumor proliferation and metastasis. Analysis of the expression levels of key node genes found that relative to normal tissues, the expression of ITGB1 and COL1A2 was significantly increased in gastric cancer tissues, and patients with late clinical stages of tumors had higher expression of ITGB1 and COL1A2 in tumor tissues, and their survival time was longer (P < 0.05). This study found that ITGB1 and COL1A2 are key genes in the development of gastric cancer and can be used as prognostic markers and potential new targets for gastric cancer.
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Affiliation(s)
- Jiasheng Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Xinlu Wang
- Public Health College of Nanchang University, Nanchang, China
| | - Qiwen Ke
- Information Engineering School of Nanchang University, Nanchang, China
| | - Kaili Liao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China.,Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yanhua Wan
- Department of General Surgery, The Jiujiang Affiliated Hospital of Nanchang University, Jiujiang, China
| | - Kaihua Zhang
- Department of General Surgery, The Jiujiang Affiliated Hospital of Nanchang University, Jiujiang, China
| | - Guanyu Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China
| | - Xiaozhong Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China. .,Jiangxi Province Key Laboratory of Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China.
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31
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Bi Y, Zeng DX, Ye W, Xiao M, Yang QL, Ling Y. LncRNA PVT1 promotes cells proliferation via PI3K–AKT–mTOR Pathway in gastrointestinal stromal tumor. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1889685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Affiliation(s)
- YanZhi Bi
- Department of Medical Oncology, The Third Affiliated Hospital of Soochow University, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
| | - Dong Xiang Zeng
- Department of Medical Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
| | - Wei Ye
- Department of Medical Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
| | - Min Xiao
- Department of Medical Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
| | - Quan Liang Yang
- Department of Medical Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
| | - Yang Ling
- Department of Medical Oncology, Changzhou Tumor Hospital Affiliated to Soochow University, Changzhou, People’s Republic of China
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Badr MT, Omar M, Häcker G. Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease. Front Immunol 2021; 12:624117. [PMID: 33717131 PMCID: PMC7945594 DOI: 10.3389/fimmu.2021.624117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/04/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection.
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Affiliation(s)
- Mohamed Tarek Badr
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
- IMM-PACT-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mohamed Omar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center—University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
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33
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Jiang J, Ding Y, Wu M, Lyu X, Wang H, Chen Y, Wang H, Teng L. Identification of TYROBP and C1QB as Two Novel Key Genes With Prognostic Value in Gastric Cancer by Network Analysis. Front Oncol 2020; 10:1765. [PMID: 33014868 PMCID: PMC7516284 DOI: 10.3389/fonc.2020.01765] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 08/06/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Gastric cancer (GC) is the fifth most frequently diagnosed malignancy, and the third leading cause of tumor-related mortalities worldwide. Due to a high heterogeneity in GC, its treatment and prognosis are challenging, necessitating urgent identification of novel prognostic predictors for GC patients. Methods: We downloaded RNA sequence data, from the Cancer Genome Atlas and microarray data from Gene Expression Omnibus database, then identified common differentially-expressed genes (DEGs) between GC and normal gastric tissues across four datasets. We then used a combination of protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) to identify key genes with prognostic value in GC. Thereafter, we used quantitative real time polymerase chain reaction (qRT-PCR) to validate expression of the identified key genes in the Zhejiang University (ZJU) cohort. Finally, we evaluated the relationships between gene expression and immune factors, including immune cells and biomarkers of immunotherapy. Results: Among 426 common DEGs screened, 333 and 93 were upregulated and downregulated, respectively. PPI network and WGCNA successfully identified the top 30 hub genes, among which PTPRC, TYROBP, CCR1, CYBB, LCP2, and C1QB were common. Furthermore, TYROBP and C1QB were negatively associated with prognosis of GC patients, implying that they were key GC predictors. Interestingly, TYROBP and C1QB were positively correlated with predictive biomarkers for GC immunotherapy, including PD-L1 expression, CD8+ T cells infiltration, and EBV status. Conclusions: TYROBP and C1QB were identified as two novel key genes with prognostic value in GC by network analysis.
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Affiliation(s)
- Junjie Jiang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengjie Wu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiadong Lyu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haifeng Wang
- Department of Hematology & Oncology, The People's Hospital of Beilun District, Beilun Branch Hospital of the First Affiliated Hospital of Medical School of Zhejiang University, Ningbo, China
| | - Yanyan Chen
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyong Wang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Gong DY, Chen X, Yang TL, Wang Y, Guo Y, Zeng JH, Chen SZ. Upregulation of ECT2 is associated with transcriptional program of cancer stem cells and predicts poor clinical outcome in gastric cancer. Oncol Lett 2020; 20:54. [PMID: 32788941 PMCID: PMC7416382 DOI: 10.3892/ol.2020.11915] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer remains the third leading cause of cancer-associated mortality worldwide. The identification of prognostic indicators that are associated with clinical characteristics is urgently required. The aim of the present study was to determine the involvement of epithelial cell transforming 2 (ECT2) in gastric cancer. The results of the present study demonstrated that ECT2 expression was upregulated in human gastric cancer samples. Furthermore, high ECT2 expression was associated with advanced Tumor-Node-Metastasis stage and deeper tumor invasion. ECT2 upregulation was further confirmed in several independent publicly available clinical cohorts from the Gene Expression Omnibus database. In addition, patients with gastric cancer, with high ECT2 expression exhibited a significantly shorter overall survival time than those with low ECT2 expression, and Cox regression analysis demonstrated that ECT2 expression was an independent prognostic marker for overall survival time. Characterization of the transcriptome profiles of ECT2 upregulated gastric tumors indicated that ECT2 upregulation may be associated with transcriptional features of cancer stem cells (CSCs). Additionally, BUB1 mitotic checkpoint serine/threonine kinase and E2F transcription factor 7, two genes previously reported to account for the functionality of CSCs, were strongly enriched in ECT2High gastric cancer samples. Taken together, the results of the present study suggest that ECT2 may serve as a novel marker for CSCs and may be a potential prognostic indicator in gastric cancer.
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Affiliation(s)
- Dao-Yin Gong
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xian Chen
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Tian-Lin Yang
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Yi Wang
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Yu Guo
- Geriatric Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Jin-Hao Zeng
- Geriatric Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Shan-Ze Chen
- Department of Pathyphysiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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35
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Tan H, Zhang S, Zhang J, Zhu L, Chen Y, Yang H, Chen Y, An Y, Liu B. Long non-coding RNAs in gastric cancer: New emerging biological functions and therapeutic implications. Am J Cancer Res 2020; 10:8880-8902. [PMID: 32754285 PMCID: PMC7392009 DOI: 10.7150/thno.47548] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/28/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is currently the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs), transcriptional products with more than 200 nucleotides, are not as well-characterized as protein-coding RNAs. Accumulating evidence has recently revealed that maladjustments of diverse lncRNAs may play key roles in multiple genetic and epigenetic phenomena in GC, affecting all aspects of cellular homeostasis, such as proliferation, migration, and stemness. However, the full extent of their functionality remains to be clarified. Considering the lack of viable biomarkers and therapeutic targets, future research should be focused on unravelling the intricate relationships between lncRNAs and GC that can be translated from bench to clinic. Here, we summarized the state-of-the-art advances in lncRNAs and their biological functions in GC, and we further discuss their potential diagnostic and therapeutic roles. We aim to shed light on the interrelationships between lncRNAs and GC with respect to their potential therapeutic applications. With better understanding of these relationships, the biological functions of lncRNAs in GC development will be exploitable, and promising new strategies developed for the prevention and treatment of GC.
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36
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Xiao N, Hu Y, Juan L. Comprehensive Analysis of Differentially Expressed lncRNAs in Gastric Cancer. Front Cell Dev Biol 2020; 8:557. [PMID: 32695786 PMCID: PMC7338654 DOI: 10.3389/fcell.2020.00557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/11/2020] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common malignant tumor. The mechanism underlying GC occurrence and development remains unclear. Previous studies have indicated that long non-coding RNAs (lncRNAs) are significantly associated with gastric cancer, but a systematic understanding of the role of lncRNAs in gastric cancer is lacking. In recent years, with the development of next-generation sequencing technology, tens of thousands of lncRNAs have been discovered. However, a large number of unannotated lncRNAs remain unidentified in different tissues, including potential gastric cancer-related lncRNAs. In this study, RNA sequencing (RNA-seq) data from 16 samples of eight gastric cancer patients were obtained and analyzed. A total of 1,854 previously unannotated lncRNAs were identified by ab initio assembly, and 520 differentially expressed lncRNAs were validated in the TCGA expression dataset. Methylation and copy number variation (CNV) array data from the same sample were integrated in the analysis. Changes in DNA methylation levels and CNVs may be responsible for the differential expression of 91 lncRNAs. Differentially expressed lncRNAs were enriched in coexpressed clusters of genes related to functions such as cell signaling, cell cycle, immune response, metabolic processes, angiogenesis, and regulation of retinoic acid (RA) receptors. Finally, a differentially expressed lncRNA, AC004510.3, was identified as a potential biomarker for the prediction of the overall survival of gastric cancer patients.
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Affiliation(s)
- Nan Xiao
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China.,School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Yang Hu
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China
| | - Liran Juan
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China
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37
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Chen J, Chen JG, Sun B, Wu JH, Du CY. Integrative analysis of immune microenvironment-related CeRNA regulatory axis in gastric cancer. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2020; 17:3953-3971. [PMID: 32987562 DOI: 10.3934/mbe.2020219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
This study aimed to identify significant immune microenvironment-related competing endogenous RNA (CeRNA) regulatory axis in gastric cancer (GC). Analysis of differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was performed for the microarray datasets. After abundance analysis of immune cell's infiltration, immune-related mRNAs and lncRNAs were obtained. Meanwhile, according to the Pearson correlation coefficient between immune-related mRNAs and lncRNAs, the co-expression mRNA-lncRNA pairs were screened. Furthermore, the target genes of co-existance miRNAs were predicted, and miRNA-lncRNA pairs were identified. Finally, the lncRNA-miRNA and miRNA-mRNA relationship regulated by the same miRNA was screened. Combining with the co-expression relationship between lncRNA and mRNA, the CeRNA network was constructed. In abundance analysis of immune cell's infiltration, a total of eight immune cells were obtained, in addition, 83 immune-related DElncRNAs and 705 immune-related DEmRNAs were screened. KEGG pathway enrichment analysis showed that these mRNAs were mainly involved in PI3K-Akt signaling pathway and human papillomavirus infection, while lncRNA were relevant to gastric acid secretion. A total of 25 miRNAs were significantly associated with immune-related mRNAs, such as hsa-miR-148a-3p, hsa-miR-17-5p, and hsa-miR-25-3p. From the mRNA-miRNA-lncRNA CeRNA network, we observed that AC104389.28─miR-17-5─SMAD5 axis and LINC01133─miR-17-5p─PBLD axis played a crucial role in the development of GC. Furthermore, resting memory CD4 T cells and plasma cells were closely associated with the pathogenesis of GC, and these immune cells might be affected by the key genes. The present study identified key genes that associated with immune microenvironment in GC, providing potential molecular targets for immunotherapy of GC.
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Affiliation(s)
- Jie Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jing Gui Chen
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Bo Sun
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jiang Hong Wu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Chun Yan Du
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Sun D, Wang Y, Wang H, Xin Y. The novel long non-coding RNA LATS2-AS1-001 inhibits gastric cancer progression by regulating the LATS2/YAP1 signaling pathway via binding to EZH2. Cancer Cell Int 2020; 20:204. [PMID: 32514249 PMCID: PMC7260745 DOI: 10.1186/s12935-020-01285-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
Background To explore the expression pattern and role of the novel long non-coding RNA LATS2 antisense transcript 1 (LATS2-AS1-001) in gastric cancer (GC). Methods qRT-PCR was applied to evaluate LATS2-AS1-001 expression and correlation with LATS2 in GC. In vitro experiments were performed to investigate the role of LATS2-AS1-001 in GC cells. RNA immunoprecipitation (RIP) was performed to assess the interaction between EZH2 and LATS2-AS1-001. LATS2/YAP1 signaling pathway proteins were detected by immunoblot. Oncomine and KMPLOT data analysis was conducted to assess the prognostic value of YAP1 in GC. Results Decreased expression levels of LATS2-AS1-001 and LATS2 were confirmed in 357 GC tissues compared with the normal mucosa. A strong positive correlation between LATS2-AS1-001 and LATS mRNA expression was found in Pearson Correlation analysis (r = 0.719, P < 0.001). Furthermore, ROC curve analysis revealed areas under the curves for LATS2-AS1-001 and LATS2 of 0.7274 and 0.6865, respectively (P < 0.001), which indicated that LATS2-AS1-001 and LATS could be used as diagnostic indicators in GC. Moreover, ectopic expression of LATS2-AS1-001 decreased cell viability, induced G0/G1 phase arrest, and inhibited cell migration and invasion in GC cells. Mechanistically, overexpressing LATS2-AS1-001 upregulated LATS2 and induced YAP1 phosphorylation via binding to EZH2. Oncomine and KMPLOT database analysis demonstrated YAP1 was highly expressed in human GC samples, and high YAP1 expression predicted poor patient prognosis in GC. Conclusion This study revealed that lncRNA LATS2-AS1-001 might serve as a potential diagnostic index in GC and act as a suppressor of GC progression.
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Affiliation(s)
- Dan Sun
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
| | - Ying Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China.,Department of Oncology, Hanzhong Central Hospital, Hanzhong, 723000 China
| | - Huan Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
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Li Z, Liu Z, Shao Z, Li C, Li Y, Liu Q, Zhang Y, Tan B, Liu Y. Identifying multiple collagen gene family members as potential gastric cancer biomarkers using integrated bioinformatics analysis. PeerJ 2020; 8:e9123. [PMID: 32509452 PMCID: PMC7255341 DOI: 10.7717/peerj.9123] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer is one of the most common malignant cancers worldwide. Despite substantial developments in therapeutic strategies, the five-year survival rate remains low. Therefore, novel biomarkers and therapeutic targets involved in the progression of gastric tumors need to be identified. Methods We obtained the mRNA microarray datasets GSE65801, GSE54129 and GSE79973 from the Gene Expression Omnibus database to acquire differentially expressed genes (DEGs). We used the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to analyze DEG pathways and functions, and the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape to obtain the protein-protein interaction (PPI) network. Next, we validated the hub gene expression levels using the Oncomine database and Gene Expression Profiling Interactive Analysis (GEPIA), and conducted stage expression and survival analysis. Results From the three microarray datasets, we identified nine major hub genes: COL1A1, COL1A2, COL3A1, COL5A2, COL4A1, FN1, COL5A1, COL4A2, and COL6A3. Conclusion Our study identified COL1A1 and COL1A2 as potential gastric cancer prognostic biomarkers.
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Affiliation(s)
- Zhaoxing Li
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhiting Shao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
| | - Chuang Li
- The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qingwei Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Bibo Tan
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yu Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
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Feng Z, Qiao R, Ren Z, Hou X, Feng J, He X, Chen D. Could CTSK and COL4A2 be specific biomarkers of poor prognosis for patients with gastric cancer in Asia?-a microarray analysis based on regional population. J Gastrointest Oncol 2020; 11:386-401. [PMID: 32399279 DOI: 10.21037/jgo.2020.03.01] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background In the purpose of identifying reliable biomarkers for evaluating prognosis, monitoring recurrence and exploring new therapeutic targets, it is quite necessary to screen for the genetic changes and potential molecular mechanisms of the occurrence and development of gastric cancer (GC) from the aspects of race and region. Methods Target datasets were retrieved from Gene Expression Omnibus (GEO) database with "gastric cancer" as the key word, and corresponding data was downloaded. The differentially expressed genes (DEGs) were obtained by using limma R package, and the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for DEGs were analyzed in Enirchr database. Protein-protein interaction (PPI) network and molecular module were also constructed through STRING database and Cytoscape software. Survival analyses were completed for DEGs in GEO and Kaplan-Meier plotter database via cross validation. Finally, the correlation between gene expression and the infiltration cell levels in tumor microenvironment (TME) was explored based on the tumor immune estimation resource (TIMER) database. Results Five GC-related microarray datasets were selected and used for differential analysis, and 222 DEGs were identified. GO analyses of DEGs were mainly involved in cell metabolism and the formation of extracellular matrix (ECM). The top enriched pathways of DEGs were protein digestion and absorption, ECM-receptor interaction, focal adhesion (FA), PI3K-Akt signaling pathway. Survival analyses of DEGs revealed that the expression levels of CTSK and COL4A2 were significantly associated with poor prognosis of GC patients in Asian. Specifically, the high expression of CTSK had a closely related to the infiltration level of inflammatory cell in TME. Conclusions CTSK and COL4A2 could play a critical role in the pathogenesis of GC and act as the promising prognostic biomarkers. CTSK could induce the formation of immunosuppressive TME and promote the immune escape of GC cells.
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Affiliation(s)
- Zhijun Feng
- Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou 730030, China
| | - Ruili Qiao
- Department of VIP Internal Medicine, Lanzhou University First Hospital, Lanzhou 730000, China
| | - Zhijian Ren
- Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou 730030, China
| | - Xiaofeng Hou
- Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou 730030, China
| | - Jie Feng
- Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou 730030, China
| | - Xiaodong He
- Department of General Surgery, The Second Clinical Medical College, Lanzhou University, Lanzhou 730030, China
| | - Dongdong Chen
- Department of The First General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
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Zhang T, Wang BF, Wang XY, Xiang L, Zheng P, Li HY, Tao PX, Wang DF, Gu BH, Chen H. Key Genes Associated with Prognosis and Tumor Infiltrating Immune Cells in Gastric Cancer Patients Identified by Cross-Database Analysis. Cancer Biother Radiopharm 2020; 35:696-710. [PMID: 32401038 DOI: 10.1089/cbr.2019.3423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: The molecular mechanisms underlying gastric cancer (GC) progression are unclear. The authors examined key genes associated with the prognosis and tumor-infiltrating immune cells in patients with GC. Materials and Methods: Gene expression omnibus (GEO) was used to filter and obtain GC-related differentially expressed genes (DEGs). The molecular functions, biological processes, and cellular components of the DEGs were subjected to enrichment analysis. Protein-protein interaction networks of proteins encoded by the DEGs were analyzed using STRING. The authors also identified hub genes of GC, as well as their expression levels in GC and their relationship with patient prognosis. The relationship between hub genes and tumor-infiltrating immune cells was analyzed by Tumor IMmune Estimation Resource. Results: Six GEO datasets were included in this study, and 265 DEGs were identified. These DEGs were enriched in different signaling pathways and had different biological functions. Six hub genes were potentially significantly related to the molecular mechanisms of GC (TOP2A, FN1, SPARC, COL3A1, COL1A1, and TIMP1). These genes are potential markers of prognosis. Five hub genes were significantly positively correlated with the number of macrophages, neutrophils, and dendritic cells. Conclusions: The authors provide a theoretical basis for exploring the molecular regulation mechanism underlying GC and identifying therapeutic targets.
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Affiliation(s)
- Tao Zhang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China.,Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Bo-Fang Wang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xue-Yan Wang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Lin Xiang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Peng Zheng
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Hai-Yuan Li
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Peng-Xian Tao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Deng-Feng Wang
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Bao-Hong Gu
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Hao Chen
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China.,Cancer Center, Lanzhou University Second Hospital, Lanzhou, China.,Key Laboratory of Digestive System Tumors, Lanzhou University Second Hospital, Lanzhou, China
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Duan M, Fang M, Wang C, Wang H, Li M. LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis. Cancer Manag Res 2020; 12:2141-2154. [PMID: 32273754 PMCID: PMC7102881 DOI: 10.2147/cmar.s229013] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 02/09/2020] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Long noncoding RNA (lncRNA) deregulation is frequent in human ovarian cancers (OCs), but the role of specific miRNAs involved in this disease remains elusive. LncRNA EMX2OS was previously reported to act as an oncogene in human cancers. However, their accurate expression, function and underlying mechanisms in OC are largely unclear. MATERIALS AND METHODS The levels of EMX2OS in OC tissues and cell lines were determined by quantitative real-time PCR, and the function of EMX2OS was then analyzed both in vitro and in vivo. Luciferase assays and immunoprecipitation assays were performed to analyze the association between EMX2OS and miR-654 expression in OC cells. RESULTS EMX2OS is overexpressed in human ovarian cancer tissues. Knockdown of EMX2OS reduced, while overexpression of EMX2OS enhanced the proliferation, invasion and sphere formation of OC cells. In addition, EMX2OS enhanced tumor growth in an in vivo xenograft model of human OC. We discovered that EMX2OS directly binds to miR-654 and suppresses its expression, thus leading to the upregulation of AKT3, which served as a direct target of miR-654. Moreover, miR-654 inhibited cell proliferation, invasion and sphere formation, and restoration of AKT3 reversed the effects of EMX2OS silencing or miR-654 overexpression. Furthermore, PD-L1 was identified as the key oncogenic component acting downstream of AKT3 in OC cells. Ectopic expression of PD-L1 reversed the anti-cancer functions by EMX2OS knockdown, AKT3 silencing or miR-654 upregulation in OC cells. CONCLUSION These results demonstrated that the EMX2OS/miR-654/AKT3/PD-L1 axis confers aggressiveness in ovarian cancer and may represent a therapeutic target for OC metastasis.
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Affiliation(s)
- Meng Duan
- Department of Gynecology, Jining No. 1 People’s Hospital, Jining, Shandong272000, People’s Republic of China
| | - Meixia Fang
- Department of Gynecology, Jining No. 1 People’s Hospital, Jining, Shandong272000, People’s Republic of China
| | - Changhe Wang
- Department of Gynecology, Jining No. 1 People’s Hospital, Jining, Shandong272000, People’s Republic of China
| | - Hongyan Wang
- Department of Gynecology, Jining No. 1 People’s Hospital, Jining, Shandong272000, People’s Republic of China
| | - Meng Li
- Department of Gynecology, Jining No. 1 People’s Hospital, Jining, Shandong272000, People’s Republic of China
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Nie K, Shi L, Wen Y, Pan J, Li P, Zheng Z, Liu F. Identification of hub genes correlated with the pathogenesis and prognosis of gastric cancer via bioinformatics methods. Minerva Med 2019; 111:213-225. [PMID: 31638362 DOI: 10.23736/s0026-4806.19.06166-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world and 5-year overall survival (OS) rate is less than 10%. So, it is urgent to identified novel diagnostic and prognostic biomarkers. METHODS Twelve GEO (gene expression omnibus) datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between GC and normal tissues were screened and integrated using limma and RobustRankAggreg (RRA) packages in R software. Protein-protein interaction (PPI) network, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses for DEGs were conducted via STRING and DAVID, respectively. Moreover, Cox regression model was used to construct a gene prognosis signature. RESULTS Ten genes (COL1A1, CXCL8, COL3A1, SPP1, COL1A2, TIMP1, CXCL1, BGN, MMP3 and SERPINE1) were identified and might be highly related to GC. Further analysis showed high expression of CXCL8, COL3A1, CXCL1, MMP3 and SERPINE1, were significantly associated with late stage of GC. Lastly, we build a seven-gene prognosis signature (CYP19A1, SERPINE1, CGB5, CALCR, ASGR2, CYTL1 and ABCB5), which can give a good prediction of OS. CONCLUSIONS Our article screened out key genes highly associating with GC's developments and prognosis, and it is useful for researcher to further understand GC's molecular basis and direct the synthesis medicine of GC.
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Affiliation(s)
- Kechao Nie
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Laner Shi
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yi Wen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jinglin Pan
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Peiwu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhihua Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Fengbin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China -
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Xu B, Bai Z, Yin J, Zhang Z. Global transcriptomic analysis identifies SERPINE1 as a prognostic biomarker associated with epithelial-to-mesenchymal transition in gastric cancer. PeerJ 2019; 7:e7091. [PMID: 31218131 PMCID: PMC6563800 DOI: 10.7717/peerj.7091] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022] Open
Abstract
Background The plasminogen activation system plays a pivotal role in regulating tumorigenesis. In this work, we aim to identify key regulators of plasminogen activation associated with tumorigenesis and explore potential mechanisms in gastric cancer (GC). Methods Gene profiling datasets were extracted from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened for and obtained by the GEO2R tool. The Database for Annotation, Visualization and Integrated Discovery was used for GO and KEGG enrichment analysis. Gene set enrichment analysis (GSEA) was performed to verify molecular signatures and pathways among The Cancer Genome Atlas or GEO datasets. Correlations between SERPINE1 and markers of epithelial-to-mesenchymal transition (EMT) were analyzed using the GEPIA database and quantitative real-time PCR (qRT-PCR). Interactive networks of selected genes were built by STRING and Cytoscape software. Finally, selected genes were verified with the Kaplan–Meier (KM) plotter database. Results A total of 104 overlapped upregulated and 61 downregulated DEGs were obtained. Multiple GO and KEGG terms associated with the extracellular matrix were enriched among the DEGs. SERPINE1 was identified as the only regulator of angiogenesis and the plasminogen activator system among the DEGs. A high level of SERPINE1 was associated with a poor prognosis in GC. GSEA analysis showed a strong correlation between SERPINE1 and EMT, which was also confirmed with the GEPIA database and qRT-PCR validation. FN1, TIMP1, MMP2, and SPARC were correlated with SERPINE1.The KM plotter database showed that an overexpression of these genes correlated with a shorter survival time in GC patients. Conclusions In conclusion, SERPINE1 is a potent biomarker associated with EMT and a poor prognosis in GC. Furthermore, FN1, TIMP1, MMP2, and SPARC are correlated with SERPINE1 and may serve as therapeutic targets in reversing EMT in GC.
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Affiliation(s)
- Bodong Xu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jie Yin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing, China
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45
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Zhang JG, Xu C, Zhang L, Zhu W, Shen H, Deng HW. Identify gene expression pattern change at transcriptional and post-transcriptional levels. Transcription 2019; 10:137-146. [PMID: 30696368 PMCID: PMC6602563 DOI: 10.1080/21541264.2019.1575159] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/15/2022] Open
Abstract
Gene transcription is regulated with distinct sets of regulatory factors at multiple levels. Transcriptional and post-transcriptional regulation constitute two major regulation modes of gene expression to either activate or repress the initiation of transcription and thereby control the number of proteins synthesized during translation. Disruptions of the proper regulation patterns at transcriptional and post-transcriptional levels are increasingly recognized as causes of human diseases. Consequently, identifying the differential gene expression at transcriptional and post-transcriptional levels respectively is vital to identify potential disease-associated and/or causal genes and understand their roles in the disease development. Here, we proposed a novel method with a linear mixed model that can identify a set of differentially expressed genes at transcriptional and post-transcriptional levels. The simulation and real data analysis showed our method could provide an accurate way to identify genes subject to aberrant transcriptional and post-transcriptional regulation and reveal the potential causal genes that contributed to the diseases.
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Affiliation(s)
- Ji-Gang Zhang
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
- Computational Science, The Jackson Laboratory, Bar Harbor, ME, USA
| | - Chao Xu
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Lan Zhang
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
| | - Wei Zhu
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
| | - Hui Shen
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
| | - Hong-Wen Deng
- Center of Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, USA
- School of Basic Medical Science, Central South University, Changsha, China
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Hu Z, Yang D, Tang Y, Zhang X, Wei Z, Fu H, Xu J, Zhu Z, Cai Q. Five-long non-coding RNA risk score system for the effective prediction of gastric cancer patient survival. Oncol Lett 2019; 17:4474-4486. [PMID: 30988816 PMCID: PMC6447923 DOI: 10.3892/ol.2019.10124] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022] Open
Abstract
The prognosis for patients with gastric cancer (GC) is usually poor, as the majority of patients have reached the advanced stages of disease at the point of diagnosis. Therefore, revealing the mechanisms of GC is necessary for the identification of key biomarkers and the development of effective targeted therapies. The present study aimed to identify long non-coding RNAs (lncRNAs) prominently expressed in patients with GC. The GC dataset (including 384 GC samples) was downloaded from The Cancer Genome Atlas database as the training set. A number of other GC datasets were obtained from the Gene Expression Omnibus database as validation sets. Following data processing, lncRNAs were annotated, followed by co-expression module analysis to identify stable modules, using the weighted gene co-expression network analysis (WGCNA) package. Prognosis-associated lncRNAs were screened using the ‘survival’ package. Following the selection of the optimal lncRNA combinations using the ‘penalized’ package, risk score systems were constructed and assessed. Consensus differentially-expressed RNAs (DE-RNAs) were screened using the MetaDE package, and an lncRNA-mRNA network was constructed. Additionally, pathway enrichment analysis was conducted for the network nodes using gene set enrichment analysis (GSEA). A total of seven modules (blue, brown, green, grey, red, turquoise and yellow) were obtained following WGCNA analysis, among which the green and turquoise modules were stable and associated with the histological grade of GC. A total of 12 prognosis-associated lncRNAs were identified in the two modules. Combined with the optimal lncRNA combinations, risk score systems were constructed. The risk score system based on the green module [including ITPK1 antisense RNA 1 (ITPK1-AS1), KCNQ1 downstream neighbor (KCNQ1DN), long intergenic non-protein coding RNA 167 (LINC00167), LINC00173 and LINC00307] was the more efficient at predicting risk compared with those based on the turquoise, or the green + turquoise modules. A total of 1,105 consensus DE-RNAs were identified; GSEA revealed that LINC00167, LINC00173 and LINC00307 had the same association directions with 4 pathways and the 32 genes involved in those pathways. In conclusion, a risk score system based on the green module may be applied to predict the survival of patients with GC. Furthermore, ITPK1-AS1, KCNQ1DN, LINC00167, LINC00173 and LINC00307 may serve as biomarkers for GC pathogenesis.
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Affiliation(s)
- Zunqi Hu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Dejun Yang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Yuan Tang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Xin Zhang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ziran Wei
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hongbing Fu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jiapeng Xu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Zhenxin Zhu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Qingping Cai
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
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Wang J, Gao P, Song Y, Sun J, Chen X, Yu H, Wang Y, Wang Z. Prognostic value of gastric cancer-associated gene signatures: Evidence based on a meta-analysis using integrated bioinformatics methods. J Cell Mol Med 2018; 22:5743-5747. [PMID: 30133128 PMCID: PMC6201382 DOI: 10.1111/jcmm.13823] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/18/2018] [Accepted: 07/04/2018] [Indexed: 02/06/2023] Open
Abstract
Selecting differentially expressed genes (DEGs) based on integrated bioinformatics analyses has been used in previous studies to explore potential biomarkers in gastric cancer (GC) with microarray and RNA sequencing data. However, the genes obtained may be inaccurate because of noisy data and errors, as well as insufficient clinical sample sizes. Thus, we aimed to find robust and strong DEGs with prognostic value for GC, where the robust rank aggregation method was employed to select significant DEGs from eight Gene Expression Omnibus data sets with a total of 140 up‐regulated and 206 down‐regulated genes. Network data mining was then used to screen hub genes, and 11 genes were filtered using Fisher's exact test. Based on these results, we built a prognostic signature with seven genes (FBN1,MMP1,PLAU,SPARC,COL1A2,COL2A1 and ATP4A) using stepwise multivariate Cox proportional hazard regression. According to the risk score for each patient, we found that high‐risk group patients had significantly worse survival results compared with those in the low‐risk group (log‐rank test P‐value < 0.001). This seven‐gene signature was then validated with an external data set. Thus, we established a signature based on seven DEGs with prognostic value for GC patients using multi‐steps bioinformatics methods, which may provide novel insights and potential biomarkers for prognosis, as well as possibly serving as new therapeutic targets in clinical applications.
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Affiliation(s)
- Jun Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Jingxu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Xiaowan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Hong Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Yu Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China
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48
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Liu X, Wu J, Zhang D, Bing Z, Tian J, Ni M, Zhang X, Meng Z, Liu S. Identification of Potential Key Genes Associated With the Pathogenesis and Prognosis of Gastric Cancer Based on Integrated Bioinformatics Analysis. Front Genet 2018; 9:265. [PMID: 30065754 PMCID: PMC6056647 DOI: 10.3389/fgene.2018.00265] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 07/02/2018] [Indexed: 12/23/2022] Open
Abstract
Background and Objective: Despite striking advances in multimodality management, gastric cancer (GC) remains the third cause of cancer mortality globally and identifying novel diagnostic and prognostic biomarkers is urgently demanded. The study aimed to identify potential key genes associated with the pathogenesis and prognosis of GC. Methods: Differentially expressed genes between GC and normal gastric tissue samples were screened by an integrated analysis of multiple gene expression profile datasets. Key genes related to the pathogenesis and prognosis of GC were identified by employing protein–protein interaction network and Cox proportional hazards model analyses. Results: We identified nine hub genes (TOP2A, COL1A1, COL1A2, NDC80, COL3A1, CDKN3, CEP55, TPX2, and TIMP1) which might be tightly correlated with the pathogenesis of GC. A prognostic gene signature consisted of CST2, AADAC, SERPINE1, COL8A1, SMPD3, ASPN, ITGBL1, MAP7D2, and PLEKHS1 was constructed with a good performance in predicting overall survivals. Conclusion: The findings of this study would provide some directive significance for further investigating the diagnostic and prognostic biomarkers to facilitate the molecular targeting therapy of GC.
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Affiliation(s)
- Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhitong Bing
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jinhui Tian
- Evidence Based Medicine Center, School of Basic Medical Science, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Huang R, Gu W, Sun B, Gao L. Identification of COL4A1 as a potential gene conferring trastuzumab resistance in gastric cancer based on bioinformatics analysis. Mol Med Rep 2018; 17:6387-6396. [PMID: 29512712 PMCID: PMC5928613 DOI: 10.3892/mmr.2018.8664] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/27/2018] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab, the first targeted antibody against human epidermal growth factor receptor 2 (HER2), has been used to treat gastric cancer patients with HER2 overexpression. However, trastuzumab resistance often occurs following an initial period of benefits, and the underlying mechanisms remain largely unclear. The present study revealed that collagen type IV α1 chain (COL4A1), whose expression is upregulated in gastric cancer tissues and trastuzumab-resistant gastric cancer cells, may potentially confer trastuzumab resistance in gastric cancer. By performing bioinformatics analysis of 2 microarray datasets, the present study initially identified COL4A1, overexpressed in gastric cancer tissues and trastuzumab-resistant gastric cancer cells, as a potential candidate for inducing trastuzumab resistance. The drug resistance function of COL4A1 in gastric cancer was then validated by performing protein/gene interactions and biological process annotation analyses, and further validated by analyzing the functionality of microRNAs that target COL4A1 mRNA. Collectively, these data indicated that COL4A1 may confer trastuzumab resistance in gastric cancer.
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Affiliation(s)
- Ru Huang
- Department of Heart Failure, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Wenchao Gu
- Department of Heart Failure, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Bin Sun
- Department of Pharmacy, No. 210 Hospital of PLA, Dalian, Liaoning 116000, P.R. China
| | - Lei Gao
- Department of Heart Failure, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
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50
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Zhang Y, Xu J, Zhu X. A 63 signature genes prediction system is effective for glioblastoma prognosis. Int J Mol Med 2018; 41:2070-2078. [PMID: 29393370 PMCID: PMC5810221 DOI: 10.3892/ijmm.2018.3422] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 01/10/2018] [Indexed: 12/31/2022] Open
Abstract
The present study aimed to explore possible prognostic marker genes in glioblastoma (GBM). Differentially expressed genes (DEGs) were screened by comparing microarray data of tumor and normal tissue samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset GSE22866. Subsequently, the prognosis-associated DEGs were screened via Cox regression analysis, followed by construction of gene/protein/pathway interaction networks of these DEGs by calculating the correlation coefficient between the DEGs. Next, a prognostic prediction system was constructed using Bayes discriminant analysis, which was validated by the microarray data of samples from patients with good and bad prognosis from the TCGA and Chinese Glioma Genome Atlas (CGGA), as well as the GEO dataset. Finally, a co-expression network of the signature genes in the prediction system was constructed in combination with the significant pathways. A total of 288 overlapping DEGs (false discovery rate <0.5 and |log2 of fold change|>1) were screened, 123 of which were identified to be associated with the prognosis of GBM patients. The co-expression network of these prognosis-associated DEGs included 1405 interactions and 112 DEGs, and 6 functional modules were identified in the network. The prognostic prediction system was comprised of 63 signature genes with a specificity value of 0.929 and a sensitivity value of 0.948. GBM samples with good and bad prognosis in the TCGA, CGGA and GEO datasets were distinguishable by these signature genes (P=1.33×10−6, 1.63×10−4 and 0.00534, respectively). The co-expression network of signature genes with significant pathways was comprised of 56 genes and 361 interactions. Protein kinase Cγ (PRKCG), protein kinase Cβ (PRKCB) and calcium/calmodulin-dependent protein kinase IIα (CAMK2A) were important genes in the network, and based on the expression of these genes, it was possible to distinguish between samples with significantly different survival risks. In the present study, an effective prognostic prediction system for GBM patients was constructed and validated. PRKCG, PRKCB and CAMK2A may be potential prognostic factors for GBM.
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Affiliation(s)
- Yang Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jiaming Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Xiangdong Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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