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Tobisawa Y, Nakane K, Koie T, Taniguchi T, Tomioka M, Tomioka-Inagawa R, Kawase K, Kawase M, Iinuma K. Low GCNT2/I-Branching Glycan Expression Is Associated with Bladder Cancer Aggressiveness. Biomedicines 2025; 13:682. [PMID: 40149658 DOI: 10.3390/biomedicines13030682] [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: 02/20/2025] [Revised: 03/04/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Abnormal glycan formation on the cancer cell surface plays a crucial role in regulating tumor functions in bladder cancer. In this study, we investigated the roles of glucosaminyl (N-acetyl) transferase 2 (GCNT2) in bladder cancer progression and immune evasion. GCNT2 synthesizes I-branched polylactosamine chains on cell surface glycoproteins. Understanding its functions will provide insights into tumor-immune interactions, facilitating the development of effective immunotherapeutic strategies. Methods: GCNT2 expression levels in bladder cancer cell lines and patient tumor samples were analyzed via quantitative polymerase chain reaction and immunohistochemistry. GCNT2 functions were assessed via overexpression and knockdown experiments. Its effect on natural killer (NK) cell-mediated cytotoxicity was evaluated via in vitro assay. Cytotoxic granule release from NK cells was measured via enzyme-linked immunosorbent assay. Results: GCNT2 expression was inversely correlated with bladder cancer aggressiveness in both cell lines and patient samples. Low GCNT2 levels were associated with advanced tumor stage and grade, suggesting the tumor-suppressive roles of GCNT2. Notably, GCNT2 overexpression enhanced the susceptibility of bladder cancer cells to NK cell-mediated killing, whereas its knockdown promoted immune evasion. GCNT2-overexpressing cells strongly induced the release of cytotoxic granules from NK cells, indicating enhanced immune recognition. Conclusions: Our findings suggest that aggressive bladder tumors evade NK cell immunity by decreasing the GCNT2 levels and that I-antigen glycans synthesized by GCNT2 are crucial for NK cell recognition by tumor cells. Our findings provide insights into the tumor-immune interactions in bladder cancer and GCNT2 and its associated pathways as potential targets for novel immunotherapeutic strategies.
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Affiliation(s)
- Yuki Tobisawa
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
- Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University, Gifu 5011194, Japan
| | - Keita Nakane
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Takuya Koie
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Tomoki Taniguchi
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Masayuki Tomioka
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Risa Tomioka-Inagawa
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Kota Kawase
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Makoto Kawase
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
| | - Koji Iinuma
- Department of Urology, Graduate School of Medicine, Gifu University, Gifu 5011194, Japan
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Wu DH, Qiu HC, Xu J, Lin J, Qian J. Hypomethylation of GCNT2 isoform A correlates with transcriptional expression and is associated with poor survival in acute myeloid leukemia. Front Immunol 2025; 16:1490330. [PMID: 40034691 PMCID: PMC11873079 DOI: 10.3389/fimmu.2025.1490330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Background The function of GCNT2 has been documented to act as an oncogenic driver or tumor suppressor in different types of tumor, but the role of GCNT2 and the epigenetic regulation mechanism in AML, however, has not yet been clarified. This study aimed to assay the expression and methylation profile of GCNT2 in AML, and further elucidate the clinical significance. Methods Multiple datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas projects (TCGA) were used to explore the expression and methylation profile of GCNT2 in normal hematopoiesis and AML. A pan-cancer analysis was performed to define the survival implications of GCNT2 across multiple cancers including AML. The relationships between GCNT2 expression/methylation and clinicopathologic features were investigated using a TCGA-AML dataset. Correlation analysis was performed to explore the relationship between transcriptional expression and DNA methylation. Differentially expressed genes (DEGs) on the KEGG pathway and GO terms were visualized using DAVID. Gene Set Enrichment Analysis (GESA) was carried out to assess the underlying mechanism. The relationship between methylation and immune cell infiltration was also examined. Results GCNT2 expression was highest in hematopoietic stem cells (HSC) but gradually decreased during the hematopoiesis differentiation, the monocytes, however, remained a high level of GCNT2 as an exception. In AML, GCNT2 was down-regulated as compared to normal hematopoiesis but was much higher in contrast to normal peripheral blood samples. Data from a pan-cancer analysis revealed that high-expressed GCNT2 contributed to a worse OS for AML. DNA methylation of GCNT2 showed a distinctive co-methylation pattern in AML and significantly negatively correlated with transcriptional expression. Methylation in the transcriptional start site of isoform A plays a critical role in the epigenetic regulation of GCNT2 expression. The silence of GCNT2 in AML was attributed to DNA methylation. Hypomethylation of isoform A significantly predicted poor survival in AML, linking to several cytogenetic and molecular abnormalities, such as t (8:21), inv (16), t (15;17), and genes mutations of DNMT3A, CEBPA, RUNX1, and WT1. Enrichment analysis disclosed that hypomethylation of isoform A was involved in the immune system, and it was further revealed that hypomethylation of isoform A was tightly associated with immune cell infiltration and could be served as a promising indicator for immunotherapy. Conclusions Our comprehensive research demonstrated that GCNT2 acted as an oncogene in AML, and was epigenetically regulated by DNA methylation in isoform A. Hypomethylation of isoform A could be served as a promising indicator to identify the high-risk AML patients who might be responsive to immunotherapy.
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Affiliation(s)
- De-hong Wu
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Hong-chun Qiu
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Jing Xu
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Jiang Lin
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun Qian
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Wang J, Liu B, Chen J. Validity of the Global Leadership Initiative on Malnutrition criteria in East Asian patients with gastric cancer: a comprehensive narrative review. Front Nutr 2024; 11:1462487. [PMID: 39634550 PMCID: PMC11614637 DOI: 10.3389/fnut.2024.1462487] [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: 07/10/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Background Malnutrition is a significant public health issue for patients with gastric cancer, particularly in East Asia, the region most affected globally. In response to the absence of adequate tools for assessing nutritional status, the Global Leadership Initiative on Malnutrition (GLIM) criteria were established in 2018, aiming to standardize the diagnosis of malnutrition. However, there is no consensus on the value of GLIM criteria for evaluating the nutritional status of patients with gastric cancer in East Asia. Given these facts, our study aimed to assess the validity of the GLIM criteria in East Asian patients with gastric cancer. Methods We conducted a rapid critical review of available literature, summarizing the existing problems in GLIM applications and possible improvement directions. After systematically summarizing the literature published in PubMed, Web of Science, and Cochrane Library, a total of 13 articles involving 7,679 cases were included in this study. Results The results indicated a lack of sufficient data on sensitivity and specificity to fully validate the GLIM criteria for diagnosing malnutrition in East Asian patients with gastric cancer. Additionally, some studies have reported moderate agreement between the GLIM and the PG-SGA. Furthermore, malnutrition defined by GLIM is a risk factor for short and long-term outcomes in East Asian patients with gastric cancer. However, the prognostic effect of moderate malnutrition on these patients remains controversial. Conclusion Despite being in the early application stages, GLIM has shown promising potential in diagnosing and predicting the prognosis of malnutrition. However, future research should incorporate more comprehensive validity parameters, including sensitivity, specificity, and PPV/NPV, to achieve a more thorough understanding of GLIM's diagnostic efficacy. Furthermore, further optimization of GLIM is necessary to address the needs of more diverse populations and situations.
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Affiliation(s)
- Jian Wang
- The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Bingyue Liu
- Hangzhou Zhanshi Traditional Chinese Hospital of Orthopaedics, Hangzhou, Zhejiang, China
| | - Jianxin Chen
- Department of Medical Oncology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, China
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Albano F, Russi S, Laurino S, Mazzone P, Di Paola G, Zoppoli P, Amendola E, Balzamo C, Bartolo O, Ciuffi M, Ignomirelli O, Sgambato A, Galasso R, De Felice M, Falco G, Calice G. Representing ECM composition and EMT pathways in gastric cancer using a new metastatic gene signature. Front Cell Dev Biol 2024; 12:1481818. [PMID: 39563861 PMCID: PMC11573575 DOI: 10.3389/fcell.2024.1481818] [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: 08/16/2024] [Accepted: 10/15/2024] [Indexed: 11/21/2024] Open
Abstract
Introduction Gastric cancer (GC) is an aggressive and heterogeneous malignancy marked by cellular and molecular diversity. In GC, cancer cells invade locally in the stomach at stage I and can progress to metastasis in distant organs by stage IV, where it often becomes fatal. Methods We analyzed gene expression profiles from 719 stage I and stage IV GC patients across seven public datasets, conducting functional enrichment analysis to identify a gene signature linked to disease progression. Additionally, we developed an in vitro model of a simplified extracellular matrix (ECM) for cell-based assays. Results Our analysis identified a progression-associated gene signature (APOD, COL1A2, FSTL1, GEM, LUM, and SPARC) that characterizes stage IV GC. This signature is associated with ECM organization and epithelial-to-mesenchymal transition (EMT), both of which influence the tumor microenvironment by promoting cell invasion and triggering EMT. Discussion This gene signature may help identify stage I GC patients at higher risk, offering potential utility in early-stage patient management. Furthermore, our experimental ECM model may serve as a platform for investigating molecular mechanisms underlying metastatic spread in gastric cancer.
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Affiliation(s)
- Francesco Albano
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Sabino Russi
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Pellegrino Mazzone
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Giuseppina Di Paola
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Pietro Zoppoli
- Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Napoli, Italy
| | - Elena Amendola
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Chiara Balzamo
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
| | - Ottavia Bartolo
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Mario Ciuffi
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Orazio Ignomirelli
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Alessandro Sgambato
- Department of Translational Medicine and Surgery, Catholic University of Sacro Cuore, Roma, Italy
- Scientific Direction, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB) Via Padre Pio 1, Rionero inVulture, Italy
| | - Rocco Galasso
- Scientific Direction, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB) Via Padre Pio 1, Rionero inVulture, Italy
| | - Mario De Felice
- Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Napoli, Italy
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Geppino Falco
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
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Johnston J, Jeon H, Choi YY, Kim G, Shi T, Khong C, Chang HC, Myung NV, Wang Y. Stimulative piezoelectric nanofibrous scaffolds for enhanced small extracellular vesicle production in 3D cultures. Biomater Sci 2024; 12:5728-5741. [PMID: 39403853 PMCID: PMC11474809 DOI: 10.1039/d4bm00504j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024]
Abstract
Small extracellular vesicles (sEVs) have great promise as effective carriers for drug delivery. However, the challenges associated with the efficient production of sEVs hinder their clinical applications. Herein, we report a stimulative 3D culture platform for enhanced sEV production. The proposed platform consists of a piezoelectric nanofibrous scaffold (PES) coupled with acoustic stimulation to enhance sEV production of cells in a 3D biomimetic microenvironment. Combining cell stimulation with a 3D culture platform in this stimulative PES enables a 15.7-fold increase in the production rate per cell with minimal deviations in particle size and protein composition compared with standard 2D cultures. We find that the enhanced sEV production is attributable to the activation and upregulation of crucial sEV production steps through the synergistic effect of stimulation and the 3D microenvironment. Moreover, changes in cell morphology lead to cytoskeleton redistribution through cell-matrix interactions in the 3D cultures. This in turn facilitates intracellular EV trafficking, which impacts the production rate. Overall, our work provides a promising 3D cell culture platform based on piezoelectric biomaterials for enhanced sEV production. This platform is expected to accelerate the potential use of sEVs for drug delivery and broad biomedical applications.
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Affiliation(s)
- James Johnston
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Hyunsu Jeon
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Yun Young Choi
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Gaeun Kim
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Tiger Shi
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Courtney Khong
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Hsueh-Chia Chang
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Nosang Vincent Myung
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Yichun Wang
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
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Yang X, Li D, Sun Y, Yi L, Chen Q, Lai Y. CircFLNA facilitates gastric cancer cell proliferation and glycolysis via regulating SOX5 by sponging miR-1200. Arab J Gastroenterol 2024; 25:369-377. [PMID: 39278782 DOI: 10.1016/j.ajg.2024.07.012] [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: 12/26/2023] [Revised: 06/17/2024] [Accepted: 07/20/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND AND STUDY AIMS Circular RNAs (circRNAs) are important regulators for gastric cancer (GC) progression. Our study aims to investigate the role and mechanism of circFLNA in GC progression. PATIENTS AND METHODS The levels of circFLNA, microRNA (miR)-1200 and SRY-box transcription factor 5 (SOX5) were examined using qRT-PCR. Flow cytometry, cell counting kit 8 assay and EdU assay were performed to measure cell proliferation and apoptosis. Cell glycolysis ability was assessed by examining glucose uptake and lactate produce. RNA interaction was determined using RNA pull-down assay and dual-luciferase reporter assay. Mice xenograft models were constructed to evaluate the regulation of circFLNA knockdown on GC tumor growth. RESULTS CircFLNA was upregulated in GC tissues. Functional experiments showed that circFLNA knockdown suppressed GC cell proliferation, inhibited glycolysis, and promoted apoptosis in vitro, as well as reduced GC tumor growth in vivo. CircFLNA sponged miR-1200, and miR-1200 targeted SOX5. MiR-1200 mimic reversed the promotion effect of circFLNA overexpression on GC cell growth and glycolysis, and SOX5 upregulation also abolished the inhibiting effect of miR-1200 mimic on GC cell growth and glycolysis. CONCLUSION Our data suggest that circFLNA might exert oncogenic role in GC development, which promoted GC proliferation and glycolysis through regulating miR-1200/SOX5 axis.
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Affiliation(s)
- Xinxing Yang
- Department of Gastroenterology, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China
| | - Dongsheng Li
- Department of Neurology, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China
| | - Yuqin Sun
- Department of Gastrointestinal Surgery, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China
| | - Lisha Yi
- Department of Gastroenterology, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China
| | - Qiuxian Chen
- Department of Gastrointestinal Surgery, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China
| | - Yadong Lai
- Department of Gastroenterology, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou 363000, Fujian, China.
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Zheng L, Lu J, Kong D, Zhan Y. Single-cell sequencing analysis revealed that WDR72 was a novel cancer stem cells related gene in gastric cancer. Heliyon 2024; 10:e35549. [PMID: 39170171 PMCID: PMC11336769 DOI: 10.1016/j.heliyon.2024.e35549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
Background Cancer stem cells (CSCs) are pivotal in tumor resistance to chemotherapy and gastric cancer's rapid proliferation and metastasis. We aimed to explore the CSCs-related genes in gastric cancer epithelial cells. Methods The mRNA expression profile and single-cell sequencing data of gastric cancer were downloaded from the public database. Results We identified WDR72 as a CSCs-related gene in gastric cancer epithelial cells. WDR72 was highly expressed in gastric cancer tissues, and high expression of WDR72 was associated with inferior prognosis of patients. WDR72 expression had a significant negative correlation with the infiltration of CD8 + T cells and activated memory CD4 + T cells. PD-L1 expression was significantly reduced in gastric cancer patients with high WDR72 expression. WDR72 was correlated with IC50 of multiple small-molecule drugs. Conclusion We identified a novel CSCs-related gene in gastric cancer epithelial cells, WDR72, which was highly expressed in patients with high stemness scores.
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Affiliation(s)
- Lei Zheng
- Department of Colorectal Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, China
| | - Jia Lu
- Department of Infection Management, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, China
| | - Dalu Kong
- Department of Colorectal Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, China
| | - Yang Zhan
- Department of Colorectal Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, China
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Wu P, Zhang Y, Lyu Y, Chen J, Jiang Y, Xiang J, Liu B, Wu C. MiRNA polymorphisms affect the prognosis of gastric cancer: insights from Xianyou, Fujian. Front Oncol 2024; 14:1355270. [PMID: 38817897 PMCID: PMC11138161 DOI: 10.3389/fonc.2024.1355270] [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: 12/13/2023] [Accepted: 04/22/2024] [Indexed: 06/01/2024] Open
Abstract
Introduction Gastric cancer, characterized by high incidence and substantial disease burden, has drawn continuous attention regarding its occurrence and prognosis. Genetics plays a crucial role in influencing the prognosis of gastric cancer, and single nucleotide polymorphisms are closely associated with the occurrence, development, and prognosis of this malignant tumor. Our study aims to conduct survival analysis on patients carrying different single nucleotide polymorphisms, exploring the relationship between miRNA single nucleotide polymorphisms and the prognosis of gastric cancer. Methods Genetic data from 344 patients in Xianyou, Fujian, formed the basis of our study. We delineated the survival rate and median survival time, utilizing the log-rank test and COX regression analysis as statistical tools. Results Upon stratifying the data by sex or operation, it was discerned that the GG genotype at MSH2 rs17502941 independently posed a heightened risk for gastric cancer. Other stratification analyses suggested that the subsequent single nucleotide polymorphisms were correlated with patient prognosis: rs17502941, rs884225, rs1468063, rs7143252, and rs2271738. Discussion The outcomes of this study strongly suggest that miRNA polymorphisms significantly influence the survival time of gastric cancer patients and can serve as effective predictors for the prognosis of gastric cancer.
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Affiliation(s)
- Ping Wu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yuling Zhang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yanping Lyu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Jingwen Chen
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yu Jiang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Jianjun Xiang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Baoying Liu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Chuancheng Wu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
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Kim HJ, Cho YB, Heo K, Kim JW, Shin HG, Lee EB, Park SM, Park JB, Lee S. Targeting cell surface glucose-regulated protein 94 in gastric cancer with an anti-GRP94 human monoclonal antibody. BMB Rep 2024; 57:188-193. [PMID: 38449302 PMCID: PMC11058359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/22/2023] [Accepted: 02/14/2024] [Indexed: 03/08/2024] Open
Abstract
Gastric cancer (GC), a leading cause of cancer-related mortality, remains a significant challenge despite recent therapeutic advancements. In this study, we explore the potential of targeting cell surface glucose-regulated protein 94 (GRP94) with antibodies as a novel therapeutic approach for GC. Our comprehensive analysis of GRP94 expression across various cancer types, with a specific focus on GC, revealed a substantial overexpression of GRP94, highlighting its potential as a promising target. Through in vitro and in vivo efficacy assessments, as well as toxicological analyses, we found that K101.1, a fully human monoclonal antibody designed to specifically target cell surface GRP94, effectively inhibits GC growth and angiogenesis without causing in vivo toxicity. Furthermore, our findings indicate that K101.1 promotes the internalization and concurrent downregulation of cell surface GRP94 on GC cells. In conclusion, our study suggests that cell surface GRP94 may be a potential therapeutic target in GC, and that antibody-based targeting of cell surface GRP94 may be an effective strategy for inhibiting GRP94-mediated GC growth and angiogenesis. [BMB Reports 2024; 57(4): 188-193].
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Affiliation(s)
- Hyun Jung Kim
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
| | - Yea Bin Cho
- Department of Chemistry, Kookmin University, Seoul 02707, Korea
| | - Kyun Heo
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
- Department of Chemistry, Kookmin University, Seoul 02707, Korea
- Antibody Research Institute, Kookmin University, Seoul 02707, Korea
| | - Ji Woong Kim
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
| | - Ha Gyeong Shin
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
| | - Eun-bi Lee
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
| | - Seong-Min Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea
| | - Jong Bae Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea
| | - Sukmook Lee
- Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Korea
- Department of Chemistry, Kookmin University, Seoul 02707, Korea
- Antibody Research Institute, Kookmin University, Seoul 02707, Korea
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Montecino RMB, Sukhorosl M, Francis MA, Kancherla N, Akuma O, Nwangene NL, Nandyal S, Raj R, Akuma CM, Zahdeh T, Kaushik S, Khan AM. A Rare Case of Primary Gastric Signet Ring Cell Carcinoma: a Review of Guidelines for the Management of Gastric Cancer. Indian J Surg Oncol 2024; 15:153-159. [PMID: 38511028 PMCID: PMC10948689 DOI: 10.1007/s13193-023-01852-3] [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: 08/03/2023] [Accepted: 11/18/2023] [Indexed: 03/22/2024] Open
Abstract
Gastric carcinoma is the fifth most common and the third leading cause of cancer deaths worldwide. The incidence of diffuse-type gastric cancer, of which signet ring cell carcinoma is a subtype, is rising in the world. Due to non-specific gastritis-like symptoms, difficulty in assessing true tumor characteristics owing to its horizontal spread, and non-distinguishable endoscopic appearance from other gastric pathologies, the diagnosis of this subtype is challenging. We present a case of a 67-year-old woman with progressively worsening abdominal pain who came for an endoscopic ultrasound evaluation of an incidentally noted pancreatic cyst on a previous MRI. During endoscopy, a 1-cm gastric ulcer was noted along the lesser curvature of the gastric body. Biopsy confirmed a diagnosis of gastric signet ring cell carcinoma (SRCC) with CDX-2 and keratin positivity. The patient underwent total gastrectomy with Roux-en-Y reconstruction. Gross specimen revealed a diffuse SRCC invading the muscularis propria, along with lymphovascular and perineural invasion. In the context of our case, we discuss the morphological features of SRCC and the effectiveness of treatment options based on existing literature. Early accurate diagnosis and staging play an important role in determining treatment options as well as the clinical course of gastric SRCC.
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Affiliation(s)
| | - Mikhail Sukhorosl
- S M Kirov Military Medical Academy: Voenno-Medicinskaa Akademia Imeni S M Kirova Ministerstva Oborony Rossijskoj Federacii, Saint Petersburg, Russia
| | - Mayi Ann Francis
- Windsor University School of Medicine, Cayon, Saint Kitts and Nevis
| | | | | | | | - Shreyas Nandyal
- Gandhi Medical College, 8-2-601/B/3 G2, Ashoka Silent Valley, Road Number 10, Banjara Hills, Hyderabad, TS 500034 India
| | - Rohan Raj
- Nalanda Medical College and Hospital, Patna, India
| | | | | | - Sharanya Kaushik
- Bangalore Medical College and Research Institute: Bangalore Medical College, Bengaluru, India
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11
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Xiang T, Wei Z, Ye C, Liu G. Prognostic impact and immunotherapeutic implications of NETosis-related gene signature in gastric cancer patients. J Cell Mol Med 2024; 28:e18087. [PMID: 38146607 PMCID: PMC10902305 DOI: 10.1111/jcmm.18087] [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: 10/04/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 12/27/2023] Open
Abstract
The role of NETosis and its related molecules remains unclear in gastric cancer. The data used in this study was directly downloaded from the Cancer Genome Atlas (TCGA) database. All analysis and plots are completed in R software using diverse R packages. In our study, we collected the list of NETosis-related genes from previous publications. Based on the list and expression profile of gastric cancer patients from the TCGA database, we identified the NETosis-related genes significantly correlated with patients survival. Then, CLEC6A, BST1 and TLR7 were identified through LASSO regression and multivariate Cox regression analysis for prognosis model construction. This prognosis model showed great predictive efficiency in both training and validation cohorts. We noticed that the high-risk patients might have a worse survival performance. Next, we explored the biological enrichment difference between high- and low-risk patients and found that many carcinogenic pathways were upregulated in the high-risk patients. Meanwhile, we investigated the genomic instability, mutation burden and immune microenvironment difference between high- and low-risk patients. Moreover, we noticed that low-risk patients were more sensitive to immunotherapy (85.95% vs. 56.22%). High-risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin-3a (-)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis-related genes in gastric cancer, which can provide direction for relevant studies.
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Affiliation(s)
- Tian Xiang
- Department of Clinical Laboratory CenterCentral Hospital of Enshi Tujia and Miao Autonomous PrefectureEnshiChina
| | | | - Chen Ye
- Hubei University of MedicineShiyanChina
| | - Gao Liu
- Department of Gastrointestinal SurgeryCentral Hospital of Enshi Tujia and Miao Autonomous PrefectureEnshiChina
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12
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Xiang YH, Mou H, Qu B, Sun HR. Machine learning-based radiomics score improves prognostic prediction accuracy of stage II/III gastric cancer: A multi-cohort study. World J Gastrointest Surg 2024; 16:345-356. [PMID: 38463348 PMCID: PMC10921214 DOI: 10.4240/wjgs.v16.i2.345] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/01/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Although accurately evaluating the overall survival (OS) of gastric cancer patients remains difficult, radiomics is considered an important option for studying prognosis. AIM To develop a robust and unbiased biomarker for predicting OS using machine learning and computed tomography (CT) image radiomics. METHODS This study included 181 stage II/III gastric cancer patients, 141 from Lichuan People's Hospital, and 40 from the Cancer Imaging Archive (TCIA). Primary tumors in the preoperative unenhanced CT images were outlined as regions of interest (ROI), and approximately 1700 radiomics features were extracted from each ROI. The skeletal muscle index (SMI) and skeletal muscle density (SMD) were measured using CT images from the lower margin of the third lumbar vertebra. Using the least absolute shrinkage and selection operator regression with 5-fold cross-validation, 36 radiomics features were identified as important predictors, and the OS-associated CT image radiomics score (OACRS) was calculated for each patient using these important predictors. RESULTS Patients with a high OACRS had a poorer prognosis than those with a low OACRS score (P < 0.05) and those in the TCIA cohort. Univariate and multivariate analyses revealed that OACRS was a risk factor [RR = 3.023 (1.896-4.365), P < 0.001] independent of SMI, SMD, and pathological features. Moreover, OACRS outperformed SMI and SMD and could improve OS prediction (P < 0.05). CONCLUSION A novel biomarker based on machine learning and radiomics was developed that exhibited exceptional OS discrimination potential.
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Affiliation(s)
- Ying-Hao Xiang
- Department of General Surgery, Lichuan People's Hospital, Enshi 445400, Hubei Province, China
| | - Huan Mou
- Department of General Surgery, Lichuan People's Hospital, Enshi 445400, Hubei Province, China
| | - Bo Qu
- Department of General Surgery, Lichuan People's Hospital, Enshi 445400, Hubei Province, China
| | - Hui-Rong Sun
- Department of General Surgery, Lichuan People's Hospital, Enshi 445400, Hubei Province, China
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13
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Díaz Del Arco C, Fernández Aceñero MJ, Ortega Medina L. Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration. Int J Mol Sci 2024; 25:2649. [PMID: 38473896 DOI: 10.3390/ijms25052649] [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: 01/11/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Gastric cancer (GC) is a heterogeneous disease, often diagnosed at advanced stages, with a 5-year survival rate of approximately 20%. Despite notable technological advancements in cancer research over the past decades, their impact on GC management and outcomes has been limited. Numerous molecular alterations have been identified in GC, leading to various molecular classifications, such as those developed by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG). Other authors have proposed alternative perspectives, including immune, proteomic, or epigenetic-based classifications. However, molecular stratification has not yet transitioned into clinical practice for GC, and little attention has been paid to alternative molecular classifications. In this review, we explore diverse molecular classifications in GC from a practical point of view, emphasizing their relationships with clinicopathological factors, prognosis, and therapeutic approaches. We have focused on classifications beyond those of TCGA and the ACRG, which have been less extensively reviewed previously. Additionally, we discuss the challenges that must be overcome to ensure their impact on patient treatment and prognosis. This review aims to serve as a practical framework to understand the molecular landscape of GC, facilitate the development of consensus molecular categories, and guide the design of innovative molecular studies in the field.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Luis Ortega Medina
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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14
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Yin SY, Liu YJ, Li JP, Liu J. Overexpression of FERM Domain Containing Kindlin 2 (FERMT2) in Fibroblasts Correlates with EMT and Immunosuppression in Gastric Cancer. Int J Genomics 2024; 2024:4123737. [PMID: 38352691 PMCID: PMC10864055 DOI: 10.1155/2024/4123737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/26/2023] [Accepted: 01/16/2024] [Indexed: 02/16/2024] Open
Abstract
The mesenchymal feature, dominated by epithelial mesenchymal transition (EMT) and stromal cell activation, is one of the main reasons for the aggressive nature of tumors, yet it remains poorly understood. In gastric cancer (GC), the fermitin family homolog-2 (FERMT2) is involved in macrophage signaling, promoting migration and invasion. However, the function of FERMT2 in fibroblasts remains unclear. Here, we demonstrated that downregulation of FERMT2 expression can block EMT in GC cells by inhibiting fibroblast activation in vitro. Furthermore, we found that, in addition to the known pathways, fibroblast-derived FERMT2 promotes M2-like macrophage growth and that in human GC samples, there is a strong positive correlation between FERMT2 and CD163 and CD206 levels. Notably, high FERMT2 expression was significantly associated with poor clinical outcomes and was upregulated in patients with advanced disease. Taken together, our results provide evidence that the fibroblast-FERMT2-EMT-M2 macrophage axis plays a critical role in the GC mesenchymal phenotype and may be a promising target for the treatment of advanced GC.
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Affiliation(s)
- Sheng-yan Yin
- The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Second Chinese Medicine Hospital, Nanjing, Jiangsu 210029, China
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Yuan-jie Liu
- The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Second Chinese Medicine Hospital, Nanjing, Jiangsu 210029, China
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Jie-pin Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Jian Liu
- The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Second Chinese Medicine Hospital, Nanjing, Jiangsu 210029, China
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15
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Su Y, Zhang X, Liang Y, Sun J, Lu C, Huang Z. Integrated analysis of single-cell RNA-seq and bulk RNA-seq to unravel the molecular mechanisms underlying the immune microenvironment in the development of intestinal-type gastric cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166849. [PMID: 37591405 DOI: 10.1016/j.bbadis.2023.166849] [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: 05/26/2023] [Revised: 08/02/2023] [Accepted: 08/12/2023] [Indexed: 08/19/2023]
Abstract
Intestinal-type gastric cancer (IGC) is the most frequent type of gastric cancer in high-incidence populations. The early stages of IGC growth successively include nonatrophic gastritis (NAG), chronic atrophic gastritis (CAG) and intestinal metaplasia (IM). However, the mechanisms of IGC development through these stages remain unclear. For this study, single-cell RNA-seq data related to IGC were downloaded from the GEO database, and immune cells of the tumor microenvironment (TME) were annotated using R software. Changes in the proportion of immune cells and altered cell-to-cell interactions were explored at different disease stages using R software, with a focus on plasma cells. Additionally, IGC samples from the TCGA database were used for immune cell infiltration analysis, and a Cox proportional risk regression model was constructed to identify possible prognostic genes. The results indicated that for precancerous lesions, interactions between immune cells were mainly dominated by chemokines to stimulate the infiltration and activation of immune cells. In tumors, intercellular movement of upregulated molecules and amplified signals were associated with the tumor necrosis factor family and immunosuppression to escape immune surveillance and promote tumor growth. Regarding prognostic analysis, IGLC3, IGLV1-44, IGKV1-16, IGHV3-21, IGLV1-51, and IGLV3-19 were found to be novel biomarkers for IGC. Our analysis of the IGC single-cell atlas together with bulk transcriptome data contributes to understanding TME heterogeneity at the molecular level during IGC development and provides insights for elucidating the mechanism of IGC and discovering novel targets for precise therapy.
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Affiliation(s)
- Yongjian Su
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xiaoqing Zhang
- School of Basic Medicine, Guangdong Medical University, Dongguan, China
| | - Youcheng Liang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Jianbo Sun
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Chengyu Lu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.
| | - Zunnan Huang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.
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16
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Jiang W, Zhang T, Zhang H, Han T, Ji P, Ou Z. Metabolic Patterns of High-Invasive and Low-Invasive Oral Squamous Cell Carcinoma Cells Using Quantitative Metabolomics and 13C-Glucose Tracing. Biomolecules 2023; 13:1806. [PMID: 38136676 PMCID: PMC10742159 DOI: 10.3390/biom13121806] [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] [Received: 11/01/2023] [Revised: 11/24/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Most current metabolomics studies of oral squamous cell carcinoma (OSCC) are mainly focused on identifying potential biomarkers for early screening and diagnosis, while few studies have investigated the metabolic profiles promoting metastasis. In this study, we aimed to explore the altered metabolic pathways associated with metastasis of OSCC. Here, we identified four OSCC cell models (CAL27, HN6, HSC-3, SAS) that possess different invasive heterogeneity via the transwell invasion assay and divided them into high-invasive (HN6, SAS) and low-invasive (CAL27, HSC-3) cells. Quantitative analysis and stable isotope tracing using [U-13C6] glucose were performed to detect the altered metabolites in high-invasive OSCC cells, low-invasive OSCC cells and normal human oral keratinocytes (HOK). The metabolic changes in the high-invasive and low-invasive cells included elevated glycolysis, increased fatty acid metabolism and an impaired TCA cycle compared with HOK. Moreover, pathway analysis demonstrated significant differences in fatty acid biosynthesis; arachidonic acid (AA) metabolism; and glycine, serine and threonine metabolism between the high-invasive and low-invasive cells. Furthermore, the high-invasive cells displayed a significant increase in the percentages of 13C-glycine, 13C-palmitate, 13C-stearic acid, 13C-oleic acid, 13C-AA and estimated FADS1/2 activities compared with the low-invasive cells. Overall, this exploratory study suggested that the metabolic differences related to the metastatic phenotypes of OSCC cells were concentrated in glycine metabolism, de novo fatty acid synthesis and polyunsaturated fatty acid (PUFA) metabolism, providing a comprehensive understanding of the metabolic alterations and a basis for studying related molecular mechanisms in metastatic OSCC cells.
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Affiliation(s)
- Wenrong Jiang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Ting Zhang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Hua Zhang
- Ministry of Education of China International Collaborative Joint Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing 400016, China; (H.Z.); (T.H.)
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing 400016, China
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Tingli Han
- Ministry of Education of China International Collaborative Joint Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing 400016, China; (H.Z.); (T.H.)
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Ping Ji
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Zhanpeng Ou
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
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17
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Zhu M, Zhang N, Ma J. Hierarchical clustering identifies oxidative stress-related subgroups for the prediction of prognosis and immune microenvironment in gastric cancer. Heliyon 2023; 9:e20804. [PMID: 37928388 PMCID: PMC10622623 DOI: 10.1016/j.heliyon.2023.e20804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 09/12/2023] [Accepted: 10/06/2023] [Indexed: 11/07/2023] Open
Abstract
Background Gastric cancer (GC) is a prevalent malignancy of the digestive tract globally, demonstrating a substantial occurrence of relapse and metastasis, alongside the absence of efficacious treatment. Tumor progression and the development of cancer are linked to oxidative stress. Our objective was twofold: first, to determine distinct subcategories based on oxidative stress in GC patients, and second, to establish oxidative stress-related genes that would aid in stratifying the risk for GC patients. Methods TCGA-STAD and GSE84437 datasets were utilized to obtain the mRNA expression profiles and corresponding clinical information of GC patients. Through consensus clustering analysis, distinct subgroups related to oxidative stress were identified. To uncover the underlying mechanisms, GSEA and GSVA were performed. xCell, CIBERSORT, MCPCounter, and TIMER algorithms were employed to evaluate the immune microenvironment and immune status of the different GC subtypes. A prognostic risk model was developed using the TCGA-STAD dataset and substantiated using the GSE84437 dataset. Furthermore, qRT-PCR was employed to validate the expression of genes associated with prognosis. Results Two distinct subtypes of oxidative stress were discovered, with markedly different survival rates. The C1 subtype demonstrated an activated immune signal pathway, a significant presence of immune cell infiltration, high immune score, and a high microenvironment score, indicating a poor prognosis. Moreover, a prognostic signature related to oxidative stress (IMPACT and PXDN) was able to accurately estimate the likelihood of survival for patients with gastric cancer. A nomogram incorporating the patients' gender, age, and risk score was able to predict survival in gastric cancer patients. Additionally, the expression of IMPACT and PXDN showed a strong correlation with overall survival and the infiltration of immune cells. Conclusion Based on signatures related to oxidative stress, we developed an innovative system for categorizing patients with GC. This stratification enables accurate prognostication of individuals with GC.
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Affiliation(s)
- Meng Zhu
- College of Basic Medicine, Ningxia Medical University, Ningxia, Yinchuan, 750004, China
| | - Ning Zhang
- Department of pathology, General Hospital of Ningxia Medical University, Ningxia, Yinchuan, 750004, China
| | - Jingwei Ma
- The second department of tumor surgery, General Hospital of Ningxia Medical University, Ningxia, Yinchuan, 750004, China
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18
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Zhang M, Yang H, Fu T, Meng M, Feng Y, Qu C, Li Z, Xing X, Li W, Ye M, Li S, Bu Z, Jia S. Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer. Mol Oncol 2023; 17:1930-1942. [PMID: 37356061 PMCID: PMC10483607 DOI: 10.1002/1878-0261.13481] [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: 10/06/2022] [Revised: 03/09/2023] [Accepted: 06/23/2023] [Indexed: 06/27/2023] Open
Abstract
A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer (GC). We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II-III GC. Seventy-nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2-lymphadenectomy. Plasma at baseline, post-NACT, and after surgery, and tissue at pretreatment and surgery were collected. We used a 425-gene panel to detect genomic alterations (GAs). Results show that the mean cell-free DNA concentration of patients with clinical stage III was significantly higher than patients with stage II (15.43 ng·mL-1 vs 14.40 ng·mL-1 ). After receiving NACT and surgery, the overall detection rate of ctDNA gradually reduced (59.5%, 50.8%, and 47.4% for baseline, post-NACT, and postsurgery). The maximum variant allele frequency (max-VAF) and the number of GAs decreased from 0.50% to 0.08% and from 2.9 to 1.7 after NACT. For patients with a partial response after NACT, the max-VAF and the number of GAs declined significantly, but they increased for patients with progressive disease. Patients with detectable ctDNA at baseline, after NACT, or after surgery have a worse overall survival (OS) than patients with undetectable ctDNA. The estimated 3-year OS was 73% for the post-NACT ctDNA-negative patients and 34% for ctDNA-positive. Patients with perpetual negative ctDNA before and after NACT have the best prognosis. In conclusion, ctDNA was proposed as a potential biomarker to predict prognosis and monitor the NACT response for stage II-III GC patients.
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Affiliation(s)
- Meng Zhang
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Heli Yang
- Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Tao Fu
- Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Meizhu Meng
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Yi Feng
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Changda Qu
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Xiaofang Xing
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Wenmei Li
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Meiying Ye
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Sisi Li
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zhaode Bu
- Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Shuqin Jia
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
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19
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Ottaiano A, Ianniello M, Santorsola M, Ruggiero R, Sirica R, Sabbatino F, Perri F, Cascella M, Di Marzo M, Berretta M, Caraglia M, Nasti G, Savarese G. From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies. BIOLOGY 2023; 12:1183. [PMID: 37759584 PMCID: PMC10525472 DOI: 10.3390/biology12091183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023]
Abstract
Cancer manifests as a multifaceted disease, characterized by aberrant cellular proliferation, survival, migration, and invasion. Tumors exhibit variances across diverse dimensions, encompassing genetic, epigenetic, and transcriptional realms. This heterogeneity poses significant challenges in prognosis and treatment, affording tumors advantages through an increased propensity to accumulate mutations linked to immune system evasion and drug resistance. In this review, we offer insights into tumor heterogeneity as a crucial characteristic of cancer, exploring the difficulties associated with measuring and quantifying such heterogeneity from clinical and biological perspectives. By emphasizing the critical nature of understanding tumor heterogeneity, this work contributes to raising awareness about the importance of developing effective cancer therapies that target this distinct and elusive trait of cancer.
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Affiliation(s)
- Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Monica Ianniello
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Raffaella Ruggiero
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Roberto Sirica
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy;
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Massimiliano Di Marzo
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, Italy;
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Giovanni Savarese
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
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Zhang D, Zou T, Liu Q, Chen J, Xiao M, Zheng A, Zhang Z, Du F, Dai Y, Xiang S, Wu X, Li M, Chen Y, Zhao Y, Shen J, Chen G, Xiao Z. Transcriptomic characterization revealed that METTL7A inhibits melanoma progression via the p53 signaling pathway and immunomodulatory pathway. PeerJ 2023; 11:e15799. [PMID: 37547717 PMCID: PMC10404031 DOI: 10.7717/peerj.15799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 07/05/2023] [Indexed: 08/08/2023] Open
Abstract
METTL7A is a protein-coding gene expected to be associated with methylation, and its expression disorder is associated with a range of diseases. However, few research have been carried out to explore the relationship between METTL7A and tumor malignant phenotype as well as the involvement potential mechanism. We conducted our research via a combination of silico analysis and molecular biology techniques to investigate the biological function of METTL7A in the progression of cancer. Gene expression and clinical information were extracted from the TCGA database to explore expression variation and prognostic value of METTL7A. In vitro, CCK8, transwell, wound healing and colony formation assays were conducted to explore the biological functions of METT7A in cancer cell. GSEA was performed to explore the signaling pathway involved in METTL7A and validated via western blotting. In conclusion, METTL7A was downregulated in most cancer tissues and its low expression was associated with shorter overall survival. In melanoma, METTL7A downregulation was associated with poorer clinical staging, lower levels of TIL infiltration, higher IC50 levels of chemotherapeutic agents, and poorer immunotherapy outcomes. QPCR results confirm that METTL7A is down-regulated in melanoma cells. Cell function assays showed that METTL7A knockdown promoted proliferation, invasion, migration and clone formation of melanoma cells. Mechanistic studies showed that METTL7A inhibits tumorigenicity through the p53 signaling pathway. Meanwhile, METTL7A is also a potential immune regulatory factor.
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Affiliation(s)
- Duoli Zhang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Tao Zou
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Qingsong Liu
- Department of Pathology, The First People’s Hospital of Neijiang, Neijiang, China
| | - Jie Chen
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Mintao Xiao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Anfu Zheng
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Zhuo Zhang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
| | - Fukuan Du
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yalan Dai
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Shixin Xiang
- Department of Pharmacy, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Xu Wu
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Guiquan Chen
- Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Zhangang Xiao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Laboratory of Molecular Pharmacology, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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Liu YH, Meng R, Zhu B, Zhan QQ, Yang X, Ding GY, Jia CL, Liu QY, Xu WG. Integrated oxidative stress score for predicting prognosis in stage III gastric cancer undergoing surgery. Pathol Oncol Res 2023; 29:1610897. [PMID: 37334172 PMCID: PMC10272382 DOI: 10.3389/pore.2023.1610897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 05/16/2023] [Indexed: 06/20/2023]
Abstract
Objective: This study aimed to develop a novel scoring system, named the integrated oxidative stress score (IOSS), based on oxidative stress indices to predict the prognosis in stage III gastric cancer. Methods: Retrospective analysis of stage III gastric cancer patients who were operated on between January 2014 and December 2016 were enrolled into this research. IOSS is a comprehensive index based on an achievable oxidative stress index, comprising albumin, blood urea nitrogen, and direct bilirubin. The patients were divided according to receiver operating characteristic curve into two groups of low IOSS (IOSS ≤ 2.00) and high IOSS (IOSS > 2.00). The grouping variable was performed by Chi-square test or Fisher's precision probability test. The continuous variables were evaluated by t-test. The disease free survival (DFS) and overall survival (OS) were performed by Kaplan-Meier and Log-Rank tests. Univariate Cox proportional hazards regression models and stepwise multivariate Cox proportional hazards regression analysis were determined to appraise the potential prognostic factors for DFS and OS. A nomogram of the potential prognostic factors by the multivariate analysis for DFS and OS was established with R software. In order to assess the accuracy of the nomogram in forecasting prognosis, the calibration curve and decision curve analysis were produced, contrasting the observed outcomes with the predicted outcomes. Results: The IOSS was significantly correlated with the DFS and OS, and was a potential prognostic factor in patients with stage III gastric cancer. Patients with low IOSS had longer survival (DFS: χ2 = 6.632, p = 0.010; OS: χ2 = 6.519, p = 0.011), and higher survival rates. According to the univariate and multivariate analyses, the IOSS was a potential prognostic factor. The nomograms were conducted on the potential prognostic factors to improve the correctness of survival prediction and evaluate the prognosis in stage III gastric cancer patients. The calibration curve indicated a good agreement in 1-, 3-, 5-year lifetime rates. The decision curve analysis indicated that the nomogram's predictive clinical utility for clinical decision was better than IOSS. Conclusion: IOSS is a nonspecific tumor predictor based on available oxidative stress index, and low IOSS is found to be a vigorous factor of better prognosis in stage III gastric cancer.
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Affiliation(s)
- Yu-hang Liu
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, China
| | - Rui Meng
- Department of Emergency Intensive Care Unit, Yangpu Hospital, Tongji University, Shanghai, China
| | - Bing Zhu
- Tangshan Gongren Hospital, Tangshan, China
| | - Qi-qi Zhan
- North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Xin Yang
- North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | | | | | - Qian-yu Liu
- North China University of Science and Technology Affiliated Hospital, Tangshan, China
| | - Wei-guo Xu
- North China University of Science and Technology Affiliated Hospital, Tangshan, China
- Department of Gastrointestinal Surgery, China Hospital Medical Sciences, Shenzhen, China
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Wu LH, Wang XX, Wang Y, Wei J, Liang ZR, Yan X, Wang J. Construction and validation of a prognosis signature based on the immune microenvironment in gastric cancer. Front Surg 2023; 10:1088292. [PMID: 37066015 PMCID: PMC10102374 DOI: 10.3389/fsurg.2023.1088292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/02/2023] [Indexed: 04/03/2023] Open
Abstract
BackgroundGastric cancer (GC) is an aggressive malignant tumor with a high degree of heterogeneity, and its immune microenvironment is closely associated with tumor growth, development and drug resistance. Therefore, a classification system of gastric cancer based explicitly on the immune microenvironment context might enrich the strategy for gastric cancer prognosis and therapy.MethodsA total of 668 GC patients were collected from TCGA-STAD (n = 350), GSE15459 (n = 192), GSE57303 (n = 70) and GSE34942 (n = 56) datasets. Three immune-related subtypes (immunity-H, -M, and -L) were identified by hierarchical cluster analysis based on the ssGSEA score of 29 immune microenvironment-related gene sets. The immune microenvironment-related prognosis signature (IMPS) was constructed via univariate Cox regression, Lasso-Cox regression and multivariate Cox regression, and nomogram model combining IMPS and clinical variables was further constructed by the “rms” package. RT-PCR was applied to validate the expression of 7 IMPS genes between two human GC cell lines (AGS and MKN45) and one normal gastric epithelial cell line (GES-1).ResultsThe patients classified as immunity-H subtype exhibited highly expressed immune checkpoint and HLA-related genes, with enriched naïve B cells, M1 macrophages and CD8 T cells. We further constructed and validated a 7-gene (CTLA4, CLDN6, EMB, GPR15, ENTPD2, VWF and AKR1B1) prognosis signature, termed as IMPS. The patients with higher IMPS expression were more likely to be associated with higher pathology grade, more advanced TNM stages, higher T and N stage, and higher ratio of death. In addition, the prediction values of the combined nomogram in predicting 1-year (AUC = 0.750), 3-year (AUC = 0.764) and 5-year (AUC = 0.802) OS was higher than IMPS and individual clinical characteristics.ConclusionsThe IMPS is a novel prognosis signature associated with the immune microenvironment and clinical characteristics. The IMPS and the combined nomogram model provide a relatively reliable predictive index for predicting the survival outcomes of gastric cancer.
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Affiliation(s)
- Li-Hong Wu
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Xiang-Xu Wang
- Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yan Wang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Jing Wei
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Zi-Rong Liang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Xi Yan
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
- Correspondence: Jun Wang Xi Yan
| | - Jun Wang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
- Correspondence: Jun Wang Xi Yan
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Ji D, Feng H, Hou L, Xu Y, Wang X, Zhao W, Pei H, Zhao Q, Chen Q, Tan G. LINC00511, a future star for the diagnosis and therapy of digestive system malignant tumors. Pathol Res Pract 2023; 244:154382. [PMID: 36868095 DOI: 10.1016/j.prp.2023.154382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 02/17/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023]
Abstract
The digestive system malignant tumors (DSMTs), mainly consist of digestive tract and digestive gland tumors, become an inescapable culprit to hazard human health worldwide. Due to the huge hysteresis in the cognitive theories of DSMTs occurrence and progression, advances in medical technology have not improved the prognosis. Therefore, more studies on a variety of tumor-associated molecular biomarkers and more detailed disclosure on potential regulatory networks are urgently needed to facilitate the diagnostic and therapeutic strategies of DSMTs. With the development of cancer bioinformatics, a special type of endogenous RNA involved in multi-level cellular function regulation rather than encoding protein, is categorized as non-coding RNAs (ncRNAs) and becomes a hotspot issue in oncology. Among them, long non-coding RNAs (lncRNAs), transcription length > 200 nt, show obvious superiority in both research quantity and dimension compared to microRNAs (miRNAs) and circular RNAs (circRNAs). As a recently discovered lncRNA, LINC00511 has been confirmed to be closely associated with DSMTs and might be exploited as a novel biomarker. In the present review, the comprehensive studies of LINC00511 in DSMTs are summarized, as well as the underlying molecular regulatory networks. In addition, deficiencies in researches are point out and discussed. The Cumulative oncology studies provide a fully credible theoretical basis for identifying the regulatory role of LINC00511 in human DSMTs. LINC00511, proved to be an oncogene in DSMTs, might be defined as a potential biomarker for diagnosis and prognosis evaluation, as well as a rare therapeutic target.
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Affiliation(s)
- Daolin Ji
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Haonan Feng
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Li Hou
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Xiuhong Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Weili Zhao
- Department of Postgraduate Management, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Hongyu Pei
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Qi Zhao
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Qian Chen
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Gang Tan
- Department of Hepatopancreatobiliary Surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
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Chen T, zhao L, Chen J, Jin G, Huang Q, Zhu M, Dai R, Yuan Z, Chen J, Tang M, Chen T, Lin X, Ai W, Wu L, Chen X, Qin L. Identification of three metabolic subtypes in gastric cancer and the construction of a metabolic pathway-based risk model that predicts the overall survival of GC patients. Front Genet 2023; 14:1094838. [PMID: 36845398 PMCID: PMC9950121 DOI: 10.3389/fgene.2023.1094838] [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: 11/10/2022] [Accepted: 01/31/2023] [Indexed: 02/12/2023] Open
Abstract
Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1-3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.
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Affiliation(s)
- Tongzuan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liqian zhao
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Junbo Chen
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gaowei Jin
- Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qianying Huang
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruixia Dai
- Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhengxi Yuan
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junshuo Chen
- College of International Education, Henan University, Kaifeng, Henan, China
| | - Mosheng Tang
- Scientific Research Laboratory, Lishui City People’s Hospital, Lishui, Zhejiang, China
| | - Tongke Chen
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaokun Lin
- The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weiming Ai
- Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Liang Wu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Xiangjian Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
| | - Le Qin
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Le Qin, ; Xiangjian Chen, ; Liang Wu, ; Weiming Ai,
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Al-Ani A, Amarin JZ, Al-Huneidy L, Al-Hussaini M. Sex differences in cancer incidence and mortality among patients managed at King Hussein Cancer Center. Int J Cancer 2022; 151:1960-1968. [PMID: 35830208 DOI: 10.1002/ijc.34213] [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: 02/17/2022] [Revised: 06/16/2022] [Accepted: 07/05/2022] [Indexed: 11/08/2022]
Abstract
We investigated if female survival advantage trends in cancer are consistent within Jordanian patients with cancer across different age groups and non-sex specific cancer types. We explored the King Hussein Cancer Center registry for primary malignant tumors from 2006 to 2019. The registry (n = 16,454) was stratified into three groups based on age: children (<15 years), adolescents and young adults (AYA) (modified; 15 - 49 years), and older adults (≥50 years). Kaplan-Meier analysis was used to estimate the 5-year all-site cancer-specific survival probabilities, which were compared using the log-rank test by sex and age group. Out of 16,454 eligible records, 2286 (13.9%) were children, 5975 (36.3%) were AYAs, and 8193 (49.8%) were older adults. Males outnumbered females 10,339 (62.8%) to 6115 (37.2%). The 5-year OS rates were 74.0% (71.6%-76.4%) and 72.7% (69.9%-75.5%) for pediatric males and females, respectively, 57.3% (55.6%-59.0%) and 64.5% (62.6%-66.4%) for male and female AYAs, respectively, and 37.5% (36.2%-38.9%) and 44.2% (42.3%-46.2%) for older adult males and females, respectively. Females demonstrated significantly better overall survival in the AYA and older adults' groups. In conclusion, females exhibit a survival advantage in terms of non-sex specific cancers. This advantage peaks at the AYA age stratum and mitigates thereafter. Further studies are warranted to examine the etiological factors behind such discrepancy on a site-by-site basis so that sex-specific interventions can be designed and validated. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Abdallah Al-Ani
- Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan
| | - Justin Z Amarin
- Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan
| | | | - Maysa Al-Hussaini
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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Zhu Y, Zhao Y, Cao Z, Chen Z, Pan W. Identification of three immune subtypes characterized by distinct tumor immune microenvironment and therapeutic response in stomach adenocarcinoma. Gene X 2022; 818:146177. [PMID: 35065254 DOI: 10.1016/j.gene.2021.146177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/05/2021] [Accepted: 12/06/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND In primary stomach adenocarcinoma (STAD), the tumor immune microenvironment (TIME) is important for cancer occurrence and progression; however, its clinical significance remains unclear. This study investigated the association between patient survival, TIME, and therapeutic response to STAD. METHODS Gene expression profiles of STAD cases were collected from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus. Molecular subtypes were explored with consistent clustering methods according to 119 immune signatures and the infiltrating scores of 22 immune cells using the Multi-Omics Immuno-Oncology Biological Research algorithm. We determined IFNγ scores and immune cytolytic activity (CYT) scores on the basis of corresponding gene signatures via single-sample Gene Set Enrichment Analysis. Comparisons of survival, TIME, 10 immunity-related oncogenic pathways, immune checkpoint expression, and therapeutic response were conducted among the three subtypes. We further applied linear discriminant analysis to construct a characteristic index to classify the subtypes, and the Pearson correlation coefficient for the relationship between the index and immune checkpoint genes. Weighted Correlation Network Analysis (WGCNA) was used to mine the associated modules and specific genes. RESULTS We collected gene expression profiles from 352 STAD cases in the TCGA database, 300 in GSE62254, and 344 in GSE84437. Three STAD subtypes (IS1-IS3) were established according to the TIME signatures. The IS3 subtype had the highest immune score and the best prognosis, as well as markedly increased immune T-cell CYT, Th1/IFNγ scores, and immune checkpoint gene expression, compared to the other two subtypes. It was highly similar to the PD-1 response group in the previous study samples of GSE91061. The established TIME classification index performed well in classifying subtypes and was directly proportional to immune checkpoint-related gene expression levels. WGCNA explored 6 modules and 14 genes, namely DYSF, MAN1C1, HTRA3, EMCN, RFLNB, KANK3, MAGEH1, CD93, PCAT19, FUT11, BMP1, FOSB, DCHS1, and TCF3, which were associated with the established TIME classification index and STAD patient prognosis. CONCLUSION TIME phenotypes of STAD patients could be divided into three different molecular subtypes, which displayed different prognoses, immune features, and therapeutic responses. Our results shed new light on predicting patient outcomes and the discovery of new anti-STAD therapeutic strategies according to the TIME.
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Affiliation(s)
- Yimiao Zhu
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou 215006, People's Republic of China; Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China
| | - Yu Zhao
- Department of Endocrinology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China
| | - Zhongsheng Cao
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China
| | - Zhihao Chen
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China
| | - Wensheng Pan
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou 215006, People's Republic of China; Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China.
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Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K. Diagnostics (Basel) 2022; 12:diagnostics12010198. [PMID: 35054365 PMCID: PMC8775085 DOI: 10.3390/diagnostics12010198] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 01/20/2023] Open
Abstract
The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.
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Sremac M, Paic F, Grubelic Ravic K, Serman L, Pavicic Dujmovic A, Brcic I, Krznaric Z, Nikuseva Martic T. Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma. Oncol Lett 2021; 22:822. [PMID: 34691249 PMCID: PMC8527567 DOI: 10.3892/ol.2021.13083] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Diffuse gastric carcinoma (DGC) is characterized by poorly cohesive cells, highly invasive growth patterns, poor prognosis and resistance to the majority of available systemic therapeutic strategies. It has been previously reported that the Wnt/β-catenin signaling pathway serves a prominent role in the tumorigenesis of gastric carcinoma. However, the mechanism underlying the dysregulation of this pathway in DGC has not been fully elucidated. Therefore, the present study aimed to investigate the expression profiles of Wnt antagonists, secreted frizzled-related protein 1 (SFRP1) and secreted frizzled-related protein 3 (SFRP3), and dishevelled protein family members, dishevelled segment polarity protein 2 (DVL2) and dishevelled segment polarity protein 3 (DVL3), in DGC tissues. The association between the expression levels of these factors and the clinicopathological parameters of the patients was determined. Protein and mRNA expression levels in 62 DGC tumor tissues and 62 normal gastric mucosal tissues obtained from patients with non-malignant disease were measured using immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) analysis. Significantly lower protein expression levels of SFRP1 (P<0.001) and SFRP3 (P<0.001), but significantly higher protein expression levels of DVL2 (P<0.001) and DVL3 (P<0.001) were observed in DGC tissues compared with in control tissues by immunohistochemistry. In addition, significantly lower expression levels of SFRP1 (P<0.05) and higher expression levels of DVL3 (P<0.05) were found in in DGC tissues compared with those in normal gastric mucosal tissues using RT-qPCR. According to correlation analysis between the SFRP1, SFRP3, DVL2 and DVL3 protein expression levels and the clinicopathological characteristics of patients with DGC, a statistically significant correlation was found between the SFRP3 volume density and T stage (r=0.304; P=0.017) and between the SFRP3 volume density and clinical stage (r=0.336; P=0.008). In conclusion, the findings of the present study suggested that the Wnt signaling pathway components SFRP1, SFRP3, DVL2 and DVL3 may be aberrantly expressed in DGC tissues, implicating their possible role in the development of this malignant disease. The present data also revealed a positive relationship between SFRP3 protein expression and the clinical and T stage of DGC.
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Affiliation(s)
- Maja Sremac
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Frane Paic
- Laboratory for Epigenetics and Molecular Medicine, Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Katja Grubelic Ravic
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Ljiljana Serman
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Aja Pavicic Dujmovic
- Department of Radiology, General Hospital 'Dr. Ivo Pedisic', 44000 Sisak, Croatia
| | - Iva Brcic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, A-8010 Graz, Austria
| | - Zeljko Krznaric
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Tamara Nikuseva Martic
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Hempel L, de Oliveira JV, Gaumann A, Milani V, Schweneker K, Schenck K, Fleischmann B, Philipp P, Mederle S, Garg A, Piehler A, Gandorfer B, Schick C, Kleespies A, Sellmann L, Bartels M, Goetze TO, Stein A, Goekkurt E, Pfitzner L, Robert S, Hempel D. Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach-A Real World Data Analysis. Cancers (Basel) 2021; 13:cancers13174453. [PMID: 34503263 PMCID: PMC8431038 DOI: 10.3390/cancers13174453] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/24/2021] [Accepted: 08/31/2021] [Indexed: 11/16/2022] Open
Abstract
After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.
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Affiliation(s)
- Louisa Hempel
- Medical School, Sigmund Freud University, 1090 Vienna, Austria;
| | - Julia Veloso de Oliveira
- Fraunhofer Institute of Optronics System Technologies, and Image Exploitation IOSB, 76131 Karlsruhe, Germany; (J.V.d.O.); (P.P.)
| | - Andreas Gaumann
- Molekularpathologie Suedbayern, 87600 Kaufbeuren, Germany; (A.G.); (L.P.)
| | - Valeria Milani
- Facharztzentrum Fuerstenfeldbruck, 82256 Fürstenfeldbruck, Germany;
| | | | - Kristina Schenck
- Oncological Center Dachau, 85221 Dachau, Germany; (K.S.); (K.S.)
| | | | - Patrick Philipp
- Fraunhofer Institute of Optronics System Technologies, and Image Exploitation IOSB, 76131 Karlsruhe, Germany; (J.V.d.O.); (P.P.)
| | - Stefanie Mederle
- Oncological Center Donauwörth, 86609 Donawörth, Germany; (S.M.); (A.G.)
| | - Arun Garg
- Oncological Center Donauwörth, 86609 Donawörth, Germany; (S.M.); (A.G.)
| | - Armin Piehler
- MVZ Laboratory Freising, 85354 Freising, Germany; (A.P.); (B.G.); (C.S.)
| | - Beate Gandorfer
- MVZ Laboratory Freising, 85354 Freising, Germany; (A.P.); (B.G.); (C.S.)
| | - Cordula Schick
- MVZ Laboratory Freising, 85354 Freising, Germany; (A.P.); (B.G.); (C.S.)
| | | | - Ludger Sellmann
- Praxis für Onkologie Moenchengladbach, 41066 Mönchengladbach, Germany; (L.S.); (M.B.)
| | - Marius Bartels
- Praxis für Onkologie Moenchengladbach, 41066 Mönchengladbach, Germany; (L.S.); (M.B.)
| | | | - Alexander Stein
- Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), 20144 Hamburg, Germany; (A.S.); (E.G.)
| | - Eray Goekkurt
- Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), 20144 Hamburg, Germany; (A.S.); (E.G.)
| | - Lucia Pfitzner
- Molekularpathologie Suedbayern, 87600 Kaufbeuren, Germany; (A.G.); (L.P.)
| | - Sebastian Robert
- Faculty of Applied Health and Social Sciences, Technical University of Applied Sciences Rosenheim, 83024 Rosenheim, Germany;
| | - Dirk Hempel
- Institute of Translational Molecular Tumor Research, 85354 Freising, Germany
- Correspondence:
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30
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NF-κB in Gastric Cancer Development and Therapy. Biomedicines 2021; 9:biomedicines9080870. [PMID: 34440074 PMCID: PMC8389569 DOI: 10.3390/biomedicines9080870] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/09/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy.
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31
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Perez M, Chakraborty A, Lau LS, Mohammed NBB, Dimitroff CJ. Melanoma-associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target. Br J Dermatol 2021; 185:294-301. [PMID: 33660254 DOI: 10.1111/bjd.19891] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2021] [Indexed: 12/17/2022]
Abstract
In metastatic melanoma, with a dismal survival rate and propensity for treatment resistance and recurrence, it is critical to establish biomarkers that better predict treatment response and disease severity. The melanoma glycome, composed of complex carbohydrates termed glycans, is an under-investigated area of research, although it is gaining momentum in the cancer biomarker and therapeutics field. Novel findings suggest that glycans play a major role in influencing melanoma progression and could be exploited for prognosticating metastatic activity and/or as therapeutic targets. In this review, we discuss the role of aberrant glycosylation, particularly the specialized function of β1,6 N-acetylglucosaminyltransferase 2 (GCNT2), in melanoma pathogenesis and summarize mechanisms of GCNT2 regulation to illuminate its potential as a predictive marker and therapeutic target.
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Affiliation(s)
- M Perez
- Department of Translational Medicine, Translational Glycobiology Institute at FIU, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - A Chakraborty
- Department of Translational Medicine, Translational Glycobiology Institute at FIU, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - L S Lau
- Department of Translational Medicine, Translational Glycobiology Institute at FIU, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - N B B Mohammed
- Department of Translational Medicine, Translational Glycobiology Institute at FIU, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - C J Dimitroff
- Department of Translational Medicine, Translational Glycobiology Institute at FIU, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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32
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Chen X, Chen Y, Li T, Jun L, Lin T, Hu Y, Huang H, Chen H, Liu H, Li T, Li G, Yu J. Impact of diabetes on prognosis of gastric cancer patients performed with gastrectomy. Chin J Cancer Res 2020; 32:631-644. [PMID: 33223758 PMCID: PMC7666786 DOI: 10.21147/j.issn.1000-9604.2020.05.08] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective This study aimed to determine the impact of type 2 diabetes mellitus (T2DM) on clinical outcomes of gastric cancer (GC) patients and explore whether metformin use and good glycemic control could reverse it. Methods Clinicopathologic data of consecutive GC patients who underwent gastrectomy at Nanfang Hospital between October 2004 and December 2015 were included. Propensity score matching (PSM) was performed to balance the important factors of the disease status between non-T2DM and T2DM group. The last follow-up time was January 2019. Results A total of 1,692 eligible patients (1,621 non-T2DM vs. 71 T2DM) were included. After PSM, non-T2DM group (n=139) and T2DM group (n=71) were more balanced in baseline variables. The 5-year cancer-specific survival (CSS) rate in T2DM group (47.0%) was inferior to that in non-T2DM group (58.0%), but did not reach statistical significance [hazard ratio (HR)=1.319, 95% confidence interval (95% CI): 0.868−2.005, P=0.192]. While the 5-year progress-free survival (PFS) rate of T2DM group (40.6%) is significantly worse than that in non-T2DM group (56.3%) (HR=1.516, 95% CI: 1.004−2.290, P=0.045). Univariate and multivariate analyses showed that T2DM was an independent risk factor for PFS but not for CSS. In T2DM group, metformin use subgroup was associated with superior 5-year CSS and PFS in compared with non-metformin use subgroup, although the difference was not statistically significant (5-year CSS: 48.0%vs. 45.4%, HR=0.680, 95% CI: 0.352−1.313, P=0.246; 5-year PFS: 43.5%vs. 35.7%, HR=0.763, 95% CI: 0.400−1.454, P=0.406). The 5-year CSS rate was 47.5% in good glycemic control subgroup and 44.1% in poor glycemic control subgroup (HR=0.826, 95% CI: 0.398−1.713, P=0.605). And both two subgroups yielded a similar 5-year PFS rate (42.2%vs. 36.3%, HR=0.908, 95% CI: 0.441−1.871, P=0.792).
Conclusions DM promoted disease progress of GC after gastrectomy but had not yet led to the significant discrepancy of CSS. For GC patients with T2DM, metformin use was associated with superior survival but without statistical significance, while better glycemic control could not improve the prognosis.
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Affiliation(s)
- Xinhua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuehong Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Tao Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Luo Jun
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Tian Lin
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Huilin Huang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Tuanjie Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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