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Zhang Z, Zhang W, Liu X, Yan Y, Fu W. T lymphocyte‑related immune response and immunotherapy in gastric cancer (Review). Oncol Lett 2024; 28:537. [PMID: 39319215 PMCID: PMC11421013 DOI: 10.3892/ol.2024.14670] [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: 05/29/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
Gastric cancer (GC) remains a global healthcare challenge because of its high incidence and poor prognosis. The efficacy of current chemotherapy regimens for advanced GC is limited. T cells, which have been implicated in the progression of GC, have a significant impact in the tumor microenvironment. With a more detailed understanding of the mechanisms underlying the cancer immunoediting process, immunotherapy may become a promising treatment option for patients with GC. Several clinical trials are currently investigating different mechanisms targeting the tumor immune response. The present review summarized T cell-involved immune responses and various immunotherapy strategies for GC.
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Affiliation(s)
- Zhaoxiong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Wenxin Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yongjia Yan
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Weihua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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He XX, Du B, Wu T, Shen H. Prognostic analysis of related factors of adverse reactions to immunotherapy in advanced gastric cancer and establishment of a nomogram model. World J Gastrointest Oncol 2024; 16:1268-1280. [PMID: 38660670 PMCID: PMC11037037 DOI: 10.4251/wjgo.v16.i4.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/10/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Immunotherapy for advanced gastric cancer has attracted widespread attention in recent years. However, the adverse reactions of immunotherapy and its relationship with patient prognosis still need further study. In order to determine the association between adverse reaction factors and prognosis, the aim of this study was to conduct a systematic prognostic analysis. By comprehensively evaluating the clinical data of patients with advanced gastric cancer treated by immunotherapy, a nomogram model will be established to predict the survival status of patients more accurately. AIM To explore the characteristics and predictors of immune-related adverse reactions (irAEs) in advanced gastric cancer patients receiving immunotherapy with programmed death protein-1 (PD-1) inhibitors and to analyze the correlation between irAEs and patient prognosis. METHODS A total of 140 patients with advanced gastric cancer who were treated with PD-1 inhibitors in our hospital from June 2021 to October 2023 were selected. Patients were divided into the irAEs group and the non-irAEs group according to whether or not irAEs occurred. Clinical features, manifestations, and prognosis of irAEs in the two groups were collected and analyzed. A multivariate logistic regression model was used to analyze the related factors affecting the occurrence of irAEs, and the prediction model of irAEs was established. The receiver operating characteristic (ROC) curve was used to evaluate the ability of different indicators to predict irAEs. A Kaplan-Meier survival curve was used to analyze the correlation between irAEs and prognosis. The Cox proportional risk model was used to analyze the related factors affecting the prognosis of patients. RESULTS A total of 132 patients were followed up, of whom 63 (47.7%) developed irAEs. We looked at the two groups' clinical features and found that the two groups were statistically different in age ≥ 65 years, Ki-67 index, white blood cell count, neutrophil count, and regulatory T cell (Treg) count (all P < 0.05). Multivariate logistic regression analysis showed that Treg count was a protective factor affecting irAEs occurrence (P = 0.030). The ROC curve indicated that Treg + Ki-67 + age (≥ 65 years) combined could predict irAEs well (area under the curve = 0.753, 95% confidence interval: 0.623-0.848, P = 0.001). Results of the Kaplan-Meier survival curve showed that progression-free survival (PFS) was longer in the irAEs group than in the non-irAEs group (P = 0.001). Cox proportional hazard regression analysis suggested that the occurrence of irAEs was an independent factor for PFS (P = 0.006). CONCLUSION The number of Treg cells is a separate factor that affects irAEs in advanced gastric cancer patients receiving PD-1 inhibitor immunotherapy. irAEs can affect the patients' PFS and result in longer PFS. Treg + Ki-67 + age (≥ 65 years old) combined can better predict the occurrence of adverse reactions.
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Affiliation(s)
- Xu-Xu He
- Department of Surgery, Fudan University Affiliated Zhongshan Hospital (Qingpu Branch), Shanghai 201700, China
| | - Bang Du
- Department of Surgery, Anhui Provincial Red Cross Society Hospital, Hefei 230031, Anhui Province, China
| | - Tao Wu
- Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Hao Shen
- Department of Surgery, Anhui Provincial Red Cross Society Hospital, Hefei 230031, Anhui Province, China
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Yang B, Wang Y, Liu T, Zhang M, Luo T. The necroptosis-related signature and tumor microenvironment immune characteristics associated with clinical prognosis and drug sensitivity analysis in stomach adenocarcinoma. Aging (Albany NY) 2024; 16:6098-6117. [PMID: 38546403 PMCID: PMC11042952 DOI: 10.18632/aging.205690] [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: 08/15/2023] [Accepted: 01/30/2024] [Indexed: 04/23/2024]
Abstract
PURPOSE Necroptosis plays an important role in the tumorigenesis, development, metastasis, and drug resistance of malignant tumors. This study explored the new model for assessing stomach adenocarcinoma (STAD) prognosis and immunotherapy by combining long noncoding RNAs associated with necroptosis. METHODS Patient clinical data and STAD gene expression profiles were curated from The Cancer Genome Atlas (TCGA). Immune-related genes were sourced from a specialized molecular database. Perl software and R software were used for data processing and analysis. Necroptosis-related lncRNAs in STAD were pinpointed via R's correlation algorithms. These lncRNAs, in conjunction with clinical data, informed the construction of a prognostic lncRNA-associated risk score model using univariate and multivariate Cox regression analyses. The model's prognostic capacity was evaluated by Kaplan-Meier survival curves and validated as an independent prognostic variable. Further, a nomogram incorporating this model with clinical parameters was developed, offering refined individual survival predictions. Subsequent analyses of immune infiltration and chemosensitivity within necroptosis-related lncRNA clusters utilized an arsenal of bioinformatic tools, culminating in RT-PCR validation of lncRNA expression. RESULTS Through rigorous Cox regression, 21 lncRNAs were implicated in the risk score model. Stratification by median risk scores delineated patients into high- and low-risk cohorts, with the latter demonstrating superior prognostic outcomes. The risk model was corroborated as an independent prognostic indicator for STAD. The integrative nomogram displayed high concordance between predicted and observed survival rates, as evidenced by calibration curves. Differential immune infiltration in risk-defined groups was illuminated by the single sample GSEA (ssGSEA), indicating pronounced immune presence in higher-risk patients. Tumor microenvironment (TME) analysis showed that cluster-C3 had the highest score in the analysis of the three TMEs. Through the differential analysis of immune checkpoints, it was found that almost all immune checkpoint-related genes were expressed differently in various tumor clusters. Among them, CD44 expression was the highest. By comparing all drug sensitivities, we screened out 29 drugs with differences in drug sensitivity across different clusters. Risk score gene expression identification results showed that these lncRNAs were abnormally expressed in gastric cancer cell lines. CONCLUSIONS This investigation provides a robust methodological advance in prognosticating and personalizing immunotherapy for STAD, leveraging quantitatively derived tumor cluster risk scores. It posits the use of necroptosis-related lncRNAs as pivotal molecular beacons for guiding therapeutic strategies and enhancing clinical outcomes in STAD.
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Affiliation(s)
- Biao Yang
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yingnan Wang
- Henan University of Science and Technology, Henan 471000, China
| | - Tao Liu
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Meijing Zhang
- Department of Oncology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Tianhang Luo
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
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4
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Shao J, Zhang W, Li Y, Tang Y, Fan L. Metabolic and immune-related gene signatures: Predictive stratification and prognostic implications in gastric cancer. J Gene Med 2024; 26:e3635. [PMID: 37984993 DOI: 10.1002/jgm.3635] [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: 09/05/2023] [Revised: 10/22/2023] [Accepted: 10/27/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Gastric cancer, marked by its heterogeneous nature, showcases various molecular subtypes and clinical trajectories. This research delves into the significance of metabolic and immune-driven pathways in gastric cancer, constructing a prognostic signature derived from differentially expressed metabolic and immune-correlated genes (DE-MIGs). METHODS Metabolic and immune-associated gene were sourced from the GeneCards database. Differential expression analysis on the TCGA-STAD dataset was executed using the limma package, unveiling 51 DE-MIGs that underwent functional enrichment scrutiny. The LASSO Cox regression methodology guided the creation of the prognostic signature, and individual patient risk scores were determined. Assessment tools like CIBERSORT, ESTIMATE and ssGSEA were deployed to study the immune microenvironment, while mutation profiles, genomic stability, resistance to chemotherapy and immunotherapy responsiveness were scrutinized across distinct signature categorizations. RESULTS Among the identified DE-MIGs, 26 were significantly tied to the overall survival of gastric cancer patients. The developed prognostic signature proficiently differentiated patients into high-risk and low-risk cohorts, with the latter showing markedly better outcomes. The study underscored the centrality of the immune microenvironment in influencing gastric cancer outcomes. Key pathways such as TGF-Beta, TP53 and NRF2 dominated the high-risk group, whereas the LRTK-RAS and WNT pathways characterized the low-risk group. Interestingly, the low-risk segment also manifested a heightened tumor mutation burden and enhanced susceptibility to immunotherapy. CONCLUSIONS Our findings introduce a pivotal prognostic signature, rooted in DE-MIGs, that effectively segregates gastric cancer patients into distinct risk-based segments. Insights into the influential role of the immune microenvironment in gastric cancer progression pave the way for more refined therapeutic interventions.
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Affiliation(s)
- Jian Shao
- Jiangzhong Pharmaceutical Co., Ltd., Nanchang, China
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Nanchang, China
| | - Wenjia Zhang
- Shanghai Clinical College, Anhui Medical University, Shanghai, China
- The Fifth Clinical Medical College, Anhui Medical University, Hefei, China
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yiguang Li
- National Key Laboratory for the Creation of Modern Traditional Chinese Medicine, Nanchang, China
| | - Yi Tang
- Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, China
| | - Lihong Fan
- Shanghai Clinical College, Anhui Medical University, Shanghai, China
- The Fifth Clinical Medical College, Anhui Medical University, Hefei, China
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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5
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Meng Y, Jin Z, Wang M, Chen D, Zhu M, Huang Y, Xia S, Xiong Z. Definition of a Novel Immunogenic Cell Death-Relevant Gene Signature Associated with Immune Landscape in Gastric Cancer. Biochem Genet 2023; 61:2092-2115. [PMID: 36943521 DOI: 10.1007/s10528-023-10361-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/03/2023] [Indexed: 03/23/2023]
Abstract
Immunogenic cell death (ICD) induces anti-tumor immunity and aids in dismantling the immunosuppressive immune microenvironment (TME), which belongs to a type of regulated cell death. The differentiation of gastric cancer (GC) subtypes and the discovery of prognostic biomarkers are crucial for its treatment because GC is a disease that is both highly heterogeneous and aggressive. However, although the induction of ICD in tumor cells is associated with a favorable prognosis, the exact mechanism of its role in GC remains unclear. Transcriptome profiling data and clinical data of GC patients were retrieved from The Cancer Genome Atlas (TCGA) database. Herein, patients were classified with the consensus clustering algorithm, and the associated biological functions and immune microenvironment infiltration were explored based on the expression of ICD-associated genes. A risk score signature consisting of 11 ICD-related genes was established via the least absolute shrinkage and selection operator regression (LASSO) method. We have retrieved similar studies in recent years and compared them with our study using the time-dependent receiver operating characteristic (ROC) curves. Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA) were performed to explore the association between the signature and tumor microenvironment (TME). Two distinct subtypes associated with ICD in GC were identified, each with a different prognosis. The ICD-high expression subtype was associated with higher immune cell infiltration and a better prognosis. The ICD-related gene signature containing 11 genes (CGB5, Z84468.1, APOA5, EPHA8, CLEC18C, TLR7, MUC7, MUC15, CTLA4, CALB2, and UGT2B28), could independently and accurately predict the prognosis of GC. In this study, an ICD-based classification was conducted to assist in the diagnosis and personalized therapy for GC. The ICD-related genes risk score model was established to predict prognosis.
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Affiliation(s)
- Yajun Meng
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Ze Jin
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Mengmeng Wang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Di Chen
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Mengpei Zhu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Yumei Huang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Shang Xia
- Department of Internal Medicine and Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
| | - Zhifang Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China.
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Leowattana W, Leowattana P, Leowattana T. Immunotherapy for advanced gastric cancer. World J Methodol 2023; 13:79-97. [PMID: 37456977 PMCID: PMC10348086 DOI: 10.5662/wjm.v13.i3.79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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7
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Li Y, Pan Q, Cheng M, Wu Z. Identification and validation of anoikis-associated gene SNCG as a prognostic biomarker in gastric cancer. Aging (Albany NY) 2023; 15:2541-2553. [PMID: 36996495 PMCID: PMC10120907 DOI: 10.18632/aging.204626] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/20/2023] [Indexed: 04/01/2023]
Abstract
Anoikis is a newly discovered form of apoptosis that was originally identified in the extracellular matrix (ECM). Recent studies have reported that anoikis is central to cancer metastasis. Here, SNCG was identified as hub anoikis-associated gene in GC and associated with prognosis of patients with GC. To screen the hub anoikis-associated genes connected to GC, the database of Cancer Genome Atlas (TCGA) was employed. For further validating these identified genes, the Gene Expression Omnibus (GEO) dataset was applied, and Western blotting and quantitative Real-Time PCR were carried out. To identify hub genes, we conducted the analyses of univariate Cox regression, differential expression, and weighted gene co-expression network analysis (WGCNA). According to the identified hub genes, we constructed a model of prognosis. Following complex analysis, SNCG was finally identified as hub anoikis-associated gene in GC. Indeed, K-M and receiver operating characteristic analyses suggested that the expression patterns of SNCG can be used as prognostic factors for GC survival. The expression and survival trends of SNCG were verified in the validation cohort and in vitro experimental analyses. The analysis of immune cell infiltration showed that the infiltrated immune cells varied among patients with GC and gene SNCG. Furthermore, due to the significant association of the constructed risk signature with patient age and survival, this risk signature can be used to predict the prognosis of GC. We suggest that SNCG was served as hub anoikis-associated gene in GC. Meanwhile, SNCG may have prognostic potential for overall patient survival.
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Affiliation(s)
- Yi Li
- Department of Operating Room, The First People’s Hospital of Linping District, Hangzhou, Zhejiang 311199, China
| | - Qin Pan
- Department of Anesthesiology, The First People’s Hospital of Linping District, Hangzhou, Zhejiang 311199, China
| | - Mingxia Cheng
- Department of Anesthesiology, The First People’s Hospital of Linping District, Hangzhou, Zhejiang 311199, China
| | - Zhengyuan Wu
- Department of Hand Plastic Surgery, The First People’s Hospital of Linping District, Hangzhou, Zhejiang 311199, China
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8
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Zhao Y, Bai Y, Shen M, Li Y. Therapeutic strategies for gastric cancer targeting immune cells: Future directions. Front Immunol 2022; 13:992762. [PMID: 36225938 PMCID: PMC9549957 DOI: 10.3389/fimmu.2022.992762] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.
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Affiliation(s)
- Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuansong Bai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meili Shen
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
| | - Yapeng Li
- The National and Local Joint Engineering Laboratory for Synthesis Technology of High Performance Polymer, College of Chemistry, Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
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9
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Faghfuri E, Shadbad MA, Faghfouri AH, Soozangar N. Cellular immunotherapy in gastric cancer: adoptive cell therapy and dendritic cell-based vaccination. Immunotherapy 2022; 14:475-488. [PMID: 35232264 DOI: 10.2217/imt-2021-0285] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most frequently diagnosed malignancies. Recent studies have highlighted cellular immunotherapy (CI) as a promising approach for treating this disease. Among the CI-based approaches, adoptive cell therapy and dendritic cell-based vaccination are commonly studied in preclinical and clinical trials. Here we review the current evidence on the potentiality of CI in treating GC, the targets for adoptive cell therapy, ongoing clinical trials, constraints and the future outlook. The results suggest that there is a need to identify novel biomarkers that predict which GC patients will most likely respond to these approaches. Also, CI plus chemotherapy or immune checkpoint inhibitors can improve the survival of patients with late-stage GC. Therefore, this approach can be promising for treating these patients.
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Affiliation(s)
- Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | | | - Narges Soozangar
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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10
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Ansari R, Caimi P, Zhengyi C, Rashidi A. Renal Outcomes after Chimeric Antigen Receptor T-Cell (CAR-T) therapy: A Single Center Perspective. Nephrol Dial Transplant 2022; 37:1777-1779. [PMID: 35218198 DOI: 10.1093/ndt/gfac048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Indexed: 11/12/2022] Open
Affiliation(s)
- Rehan Ansari
- Division of Nephrology and Hypertension, University Hospitals Cleveland Medical Center, USA
| | - Paolo Caimi
- Department of Hematology and Medical Oncology, Cleveland Clinic, USA
| | - Chen Zhengyi
- Department of Population and Quantitative Health Science, Case Western Reserve University, USA
| | - Arash Rashidi
- Division of Nephrology and Hypertension, University Hospitals Cleveland Medical Center, USA
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11
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Zhang S, Yang H, Xiang X, Liu L, Huang H, Tang G. THBS2 is Closely Related to the Poor Prognosis and Immune Cell Infiltration of Gastric Cancer. Front Genet 2022; 13:803460. [PMID: 35186032 PMCID: PMC8853287 DOI: 10.3389/fgene.2022.803460] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
Background: The potential functions of Thrombospondin 2 (THBS2) in the progression and immune infiltration of gastric cancer (GC) remain unclear. The purpose of this study was to clarify the role of THBS2 in GC prognosis and the relationship between THBS2 and GC immune cell infiltration. Material and Methods: The differential expression levels of THBS2 in the GC and cancer-adjacent tissues were identified using the TCGA databases and verified using real-time polymerase chain reaction (PCR), immunohistochemical staining and two datasets from Gene Expression Omnibus (GEO). THBS2 related differential expressed genes (DEGs) were identified and used for further functional enrichment analysis and Gene Set Enrichment Analysis (GSEA). Furthermore, a THBS2-related immune infiltration analysis was also performed. Kaplan-Meier and Cox regression analyses were utilized to illustrate the effects of THBS2 on the prognosis and clinical variables of GC. Finally, a nomogram was constructed to predict the survival probability of patients with GC. Results: The THBS2 expression in GC was significantly higher than that in cancer-adjacent tissues (p < 0.001), which was verified using real-time PCR, immunohistochemical staining and datasets from GEO. The 599 identified DEGs were primarily enriched in pathways related to tumorigenesis and tumor progression, including the focal adhesion pathway, signaling by vascular endothelial growth factor, and Wnt signaling. THBS2 expression was positively correlated with the enrichment of the macrophages (r = 0.590, p < 0.001), which was also confirmed by immunohistochemistry; however, negatively correlated with the enrichment of Th17 cells (r = 0.260, p < 0.001). The high expression of THBS2 was significantly correlated with the pathological grade (p < 0.01), histological grade (p < 0.05), histological type (p < 0.05), T stage (p < 0.001), and poor overall survival (OS) (P = 0.003) of GC. The constructed nomogram can well predict the 1-, 3-, and 5-years OS probability of patients with GC (C-index [95% confidence interval] = 0.725 [0.701–0.750]). Conclusion: THBS2 is closely related to the poor prognosis and immune infiltration of gastric cancer.
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Affiliation(s)
- Shiyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Huiying Yang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xuelian Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Huali Huang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guodu Tang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- *Correspondence: Guodu Tang,
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12
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Gastric cancer cell death analyzed by live cell imaging of spheroids. Sci Rep 2022; 12:1488. [PMID: 35087119 PMCID: PMC8795446 DOI: 10.1038/s41598-022-05426-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is the third cause of cancer-related mortality worldwide and is often diagnosed at advanced stages of the disease. This makes the development of more comprehensive models and efficient treatments crucial. One option is based on repurposing already marketed drugs as adjuvants to chemotherapy. Accordingly, we have previously developed the combination of docetaxel and the cholesterol-lowering drug, lovastatin, as a powerful trigger of HGT-1 human GC cells' apoptosis using 2D cultures. Because 3D models, known as spheroids, are getting recognized as possibly better suited than 2Ds in toxicological research, we aimed to investigate the efficacy of this drug combination with such a model. We established monocellular spheroids from two human (GC) cell lines, HGT-1 and AGS, and bicellular spheroids from these cells mixed with cancer-associated fibroblasts. With these, we surveyed drug-induced cytotoxicity with MTT assays. In addition, we used the Incucyte live imaging and analysis system to follow spheroid growth and apoptosis. Taken together, our results showed that the lovastatin + docetaxel combination was an efficient strategy to eliminate GC cells grown in 2D or 3D cultures, lending further support in favor of repurposing lovastatin as an adjuvant to taxane-based anticancer treatment.
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Huo B, Song Y, Tan B, Li J, Zhang J, Zhang F, Chang L. Research on the mechanisms of taraxerol for the treatment of gastric cancer effect based on network pharmacology. Int J Immunopathol Pharmacol 2022; 36:20587384211063962. [PMID: 34986036 PMCID: PMC8743941 DOI: 10.1177/20587384211063962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Modern pharmacological studies have shown that traditional Chinese medicine (TCM) Taraxacum mongolicum possesses anti-cancer activity. Taraxerol (TRX) is a pentacyclic triterpene isolated from T. mongolicum, which is widely used in clinical treatment, and its anti-cancer effects have been extensively studied. However, the effects and molecular mechanism of TRX in gastric cancer (GC) have not been fully explicated. METHODS We used public databases to derive information on potential targets of TRX and proteins related to GC. Also, STRING and R3.6.2 software were used to analyze the protein-protein interaction (PPI). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were done to explain the potential mechanism underlying the regulatory role of TRX in GC. The role of TRX in GC was verified by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, apoptosis analysis, Transwell assay, and wound healing assay, and the key signaling pathways were verified. RESULTS We identified 135 potential targets for the treatment of GC via network pharmacological analysis. GO and KEGG enrichment analysis showed that steroid hormone receptor activity and the PI3K/AKT signaling pathway were the biological processes and pathways with the highest degree of enrichment. Additionally, cellular experiments revealed that TRX inhibited the proliferation, migration, and invasion of GC cells as well as induced G1 phase arrest and apoptosis in GC cells. CONCLUSION Here, we used multi-target and multi-pathway network pharmacological analysis to verify the anti-cancer activity of TRX in GC. Also, in vitro experimental data were used to derive the potential molecular mechanism.
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Affiliation(s)
- Bingjie Huo
- Department of Traditional Chinese Medicine, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Yanru Song
- Department of Traditional Chinese Medicine, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Bibo Tan
- Department of General Surgery, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Jianbo Li
- Department of Traditional Chinese Medicine, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Jie Zhang
- Department of Traditional Chinese Medicine, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Fengbin Zhang
- Department of Gastroenterology Pharmacology, 117878The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Liang Chang
- HeBei University of Chinese Medicine, No. 3 Xing yuan Road, Lu quan District, Shijiazhuang, Hebei 050200, P. R. China
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14
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Identification of Differentially Expressed Genes Reveals BGN Predicting Overall Survival and Tumor Immune Infiltration of Gastric Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:5494840. [PMID: 34868341 PMCID: PMC8641985 DOI: 10.1155/2021/5494840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 01/12/2023]
Abstract
Gastric cancer (GC) is one of the most widely occurring malignancies worldwide. Although the diagnosis and treatment strategies of GC have been greatly improved in the past few decades, the morbidity and lethality rates of GC are still rising due to lacking early diagnosis strategies and powerful treatments. In this study, a total of 37 differentially expressed genes were identified in GC by analyzing TCGA, GSE118897, GSE19826, and GSE54129. Using the PPI database, we identified 17 hub genes in GC. By analyzing the expression of hub genes and OS, MFAP2, BGN, and TREM1 were related to the prognosis of GC. In addition, our results showed that higher levels of BGN exhibited a significant correlation with shorter OS time in GC. Nomogram analysis showed that the dysregulation of BGN could predict the prognosis of GC. Moreover, we revealed that BGN had a markedly negative correlation with B cells but had positive correlations with CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in GC samples. The pan-cancer analysis demonstrated that BGN was differentially expressed and related to tumor-infiltrating immune cells across human cancers. This study for the first time comprehensively revealed that BGN was a potential biomarker for the prediction of GC prognosis and tumor immune infiltration.
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15
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Qu Y, Wang X, Bai S, Niu L, Zhao G, Yao Y, Li B, Li H. The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer. Int J Cancer 2021; 150:1373-1391. [PMID: 34766338 PMCID: PMC9298834 DOI: 10.1002/ijc.33873] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 12/16/2022]
Abstract
TNFR2+ regulatory T cells preferentially accumulate in the tumor microenvironment, express high levels of immunosuppressive molecules and possess strong suppressive activity. Our study aimed to explore the characteristics and role of TNFR2+ Tregs in the microenvironment and progression of gastric cancer via polychromatic immunofluorescence, single-cell RNA sequencing and flow cytometry assays. The TNFR2+ Treg infiltration level in the tumor microenvironment increased significantly as gastric cancer progressed and was demonstrated to be a prognostic marker. Single-cell RNA sequencing revealed high levels of TNFR2 in tumor-infiltrating Tregs. The TNF-α/TNFR2 signaling pathway was activated, accompanied by the upregulation of costimulatory molecules. Unlike blood Tregs, tumor-infiltrating Tregs existed in activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4-1BB, OX40 and GITR, tumor-infiltrating Tregs were also characterized by high expression levels of immune checkpoints such as CTLA-4 and TIGIT and chemokines such as CCR6. In vitro studies showed that the TNF-α/TNFR2 pathway increased the Foxp3 expression in CD4+ CD25+ T cells and the latent TGF-β production in Tregs as well as enhanced the immunosuppressive function of Tregs. In summary, our study revealed high infiltration levels of TNFR2+ Tregs that were in activated and effector states in the tumor microenvironment. The infiltration level of TNFR2+ Tregs is a prognostic marker and an independent risk factor for gastric cancer. Activation of the TNF-α/TNFR2 pathway promotes the immunosuppressive phenotype and function of Tregs. Our study provides a new theoretical basis for TNFR2+ Tregs as a therapeutic target in gastric cancer.
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Affiliation(s)
- Yang Qu
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Xianhao Wang
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Shuai Bai
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Liling Niu
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Yuan Yao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
| | - Bin Li
- National Clinical Research Center for Cancer, Tianjin, China.,Gastric Surgery Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China
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16
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Development and Validation of a Novel Ferroptosis-Related Gene Signature for Predicting Prognosis and the Immune Microenvironment in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6014202. [PMID: 34708125 PMCID: PMC8545527 DOI: 10.1155/2021/6014202] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 09/18/2021] [Indexed: 01/21/2023]
Abstract
Ferroptosis is a mode of regulated cell death that depends on iron and plays pivotal roles in regulating various biological processes in human cancers. However, the role of ferroptosis in gastric cancer (GC) remains unclear. In our study, a total of 2721 differentially expressed genes (DEGs) were filtered based on The Cancer Genome Atlas (TCGA) (n = 375) dataset. Weighted gene coexpression network (WGCNA) analysis was then used and identified 7 modules, of which the blue module with the most significant enrichment result was selected. By taking the intersections of the blue module and ferroptosis-related genes (FRGs), we obtained 23 common genes. Functional analysis was performed to explore the biological function of the genes of interest, and with univariate Cox regression (UCR) analysis, survival genes were screened to construct a prognostic model based on 3 genes (SLC1A5, ANGPTL4, and CGAS), which could play a role in predicting the survival of GC patients. UCR and multivariate Cox regression (MCR) analysis revealed that the prognostic index could be used as an independent prognostic indicator and validated using another GSE84437 dataset. Notably, patients in the high-risk group had higher mutation frequencies, such as TTN and TP53. TIMER analysis demonstrated that the risk score strongly correlated with macrophage and CD4+ T cell infiltration. In addition, the high- and low-risk groups illustrated different distributions of different immune statuses. Furthermore, the low-risk group had a higher immunophenoscore (IPS), which meant a better response to immune checkpoint inhibitors (ICIs). Finally, gene set enrichment analysis (GSEA) revealed several significant pathways involved in GC. In this study, a novel FRG signature was built that could predict GC prognosis and reflect the status of the tumor immune microenvironment.
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17
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Songjang W, Nensat C, Pongcharoen S, Jiraviriyakul A. The role of immunogenic cell death in gastrointestinal cancer immunotherapy (Review). Biomed Rep 2021; 15:86. [PMID: 34512974 PMCID: PMC8411483 DOI: 10.3892/br.2021.1462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
Modern cancer immunotherapy techniques are aimed at enhancing the responses of the patients' immune systems to fight against the cancer. The main promising strategies include active vaccination of tumor antigens, passive vaccination with antibodies specific to cancer antigens, adoptive transfer of cancer-specific T cells and manipulation of the patient's immune response by inhibiting immune checkpoints. The application of immunogenic cell death (ICD) inducers has been proven to enhance the immunity of patients undergoing various types of immunotherapy. The dying, stressed or injured cells release or present molecules on the cell surface, which function as either adjuvants or danger signals for detection by the innate immune system. These molecules are now termed 'damage-associated molecular patterns'. The term 'ICD' indicates a type of cell death that triggers an immune response against dead-cell antigens, particularly those derived from cancer cells, and it was initially proposed with regards to the effects of anticancer chemotherapy with conventional cytotoxic drugs. The aim of the present study was to review and discuss the role and mechanisms of ICD as a promising combined immunotherapy for gastrointestinal tumors.
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Affiliation(s)
- Worawat Songjang
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
| | - Arunya Jiraviriyakul
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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18
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Zhang M, Wang X, Wang Z. Early Study of Tumor Abnormal Protein in Gastric Adenocarcinoma. Onco Targets Ther 2021; 14:1719-1726. [PMID: 33707954 PMCID: PMC7943549 DOI: 10.2147/ott.s297413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/13/2021] [Indexed: 12/25/2022] Open
Abstract
Objective To study the correlation between tumor abnormal protein (TAP) and tumor markers, blood glucose, uric acid and coagulation function in gastric adenocarcinoma and to evaluate the clinical application of TAP in the diagnosis of gastric adenocarcinoma. Methods A total of 34 nontumor patients and 95 gastric adenocarcinoma patients admitted to the First Affiliated Hospital of Jinzhou Medical University were enrolled in this study. Fresh blood from patients' fingertips was collected, all blood samples were examined with TAP testing kit, and then searched and measured the condensed particulate matter. Results The comparison of TAP between nontumor patients and gastric adenocarcinoma patients was statistically significant (P<0.05). Bivariate correlation analysis was conducted between TAP and other related tumor markers (alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9 (CA199), carbohydrate antigen 72-4 (CA72-4)), blood glucose, uric acid, and coagulation function-related indicators, and the results showed that the correlation between TAP and CA199, CA72-4, and activated partial prothrombin time was statistically significant. In addition, according to the analysis results, there was no significant difference among TAP and age, height and weight in the tumor population and the nontumor population. Conclusion TAP can be used for the screening and diagnosis of gastric adenocarcinoma, and the effect of TAP combined with other indicators is more significant than TAP alone.
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Affiliation(s)
- Ming Zhang
- Department of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People's Republic of China
| | - Xiaoyu Wang
- Department of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People's Republic of China
| | - Zhenghua Wang
- Department of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People's Republic of China
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19
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Chen S, Chen C, Hu Y, Zhu C, Luo X, Wang L, Wang X, Sun X, Chen X, Xie W, Lou H, Huang X, Li C, Xu J, Xue X, Shen X. Three-Dimensional Ex Vivo Culture for Drug Responses of Patient-Derived Gastric Cancer Tissue. Front Oncol 2021; 10:614096. [PMID: 33659211 PMCID: PMC7917258 DOI: 10.3389/fonc.2020.614096] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies with high mortality and substantial morbidity. Although the traditional treatment strategies for GC revolve around surgery, radiotherapy, and chemotherapy, none have been able to optimally treat most affected patients. To improve clinical outcomes and overcome potential GC resistance, we established a three-dimensional (3D) culturing platform that accurately predicts drug responses in a time- and cost-effective manner. We collected tumor tissues from patients following surgeries and cultured them for 3 days using our protocol. We first evaluated cell proliferation, viability, and apoptosis using the following markers: Ki67 and cleaved caspase 3 (Cas3). We demonstrated that cell viability was maintained for 72 h in culture and that the tumor microenvironments and vascular integrities of the tissues were intact throughout the culture period. We then administered chemotherapeutics to assess drug responses and found differential sensitivity across different patient-derived tissues, enabling us to determine individualized medication plans. Overall, our study validated this rapid, cost-effective, scalable, and reproducible protocol for GC tissue culture that can be employed for drug response assessments. Our 3D culture platform paves a new way for personalized medication in GC and other tumors and can greatly impact future oncological research.
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Affiliation(s)
- Sian Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Chenbin Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Yuanbo Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Ce Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozhi Luo
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China.,Department of Pathology, The Second Affiliated Hospital & Yuying Children's, Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lizhu Wang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xiang Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangwei Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xiaodong Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Wangkai Xie
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Han Lou
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xielin Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chao Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jun Xu
- The First School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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20
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Integrated analysis identifies oxidative stress genes associated with progression and prognosis in gastric cancer. Sci Rep 2021; 11:3292. [PMID: 33558567 PMCID: PMC7870842 DOI: 10.1038/s41598-021-82976-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/27/2021] [Indexed: 12/25/2022] Open
Abstract
Oxidative stress (OS) reactions are reported to be associated with oncogenesis and tumor progression. However, little is known about the potential diagnostic value of OS in gastric cancer (GC). This study identified hub OS genes associated with the prognosis and progression of GC and illustrated the underlying mechanisms. The transcriptome data and corresponding GC clinical information were collected from The Cancer Genome Atlas (TCGA) database. Aberrantly expressed OS genes between tumors and adjacent normal tissues were screened, and 11 prognosis-associated genes were identified with a series of bioinformatic analyses and used to construct a prognostic model. These genes were validated in the Gene Expression Omnibus (GEO) database. Furthermore, weighted gene co-expression network analysis (WGCNA) was subsequently conducted to identify the most significant hub genes for the prediction of GC progression. Analysis revealed that a good prognostic model was constructed with a better diagnostic accuracy than other clinicopathological characteristics in both TCGA and GEO cohorts. The model was also significantly associated with the overall survival of patients with GC. Meanwhile, a nomogram based on the risk score was established, which displayed a favorable discriminating ability for GC. In the WGCNA analysis, 13 progression-associated hub OS genes were identified that were also significantly associated with the progression of GC. Furthermore, functional and gene ontology (GO) analyses were performed to reveal potential pathways enriched with these genes. These results provide novel insights into the potential applications of OS-associated genes in patients with GC.
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21
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miR-7641 depletion suppresses proliferation of gastric cancer cells by targeting ARID1A. Anticancer Drugs 2021; 31:368-376. [PMID: 31913196 DOI: 10.1097/cad.0000000000000881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data showed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.
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22
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Huang X, Zhang J, Zheng Y. ANTXR1 Is a Prognostic Biomarker and Correlates With Stromal and Immune Cell Infiltration in Gastric Cancer. Front Mol Biosci 2020; 7:598221. [PMID: 33385012 PMCID: PMC7770144 DOI: 10.3389/fmolb.2020.598221] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.
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Affiliation(s)
- Xiaodong Huang
- Department of General Surgery, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Jie Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongbin Zheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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23
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El Rami FE, Barsoumian HB, Khneizer GW. Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell. Ther Adv Med Oncol 2020; 12:1758835920967238. [PMID: 33193828 PMCID: PMC7607792 DOI: 10.1177/1758835920967238] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC.
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Affiliation(s)
- Fadi E El Rami
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Gebran W Khneizer
- Department of Internal Medicine, Indiana University Hospital, 550 N University Blvd, Suite 1501, Indianapolis, IN 46202, USA
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24
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Zeng Q, Li L, Feng Z, Luo L, Xiong J, Jie Z, Cao Y, Li Z. LCP1 is a prognostic biomarker correlated with immune infiltrates in gastric cancer. Cancer Biomark 2020; 30:105-125. [PMID: 32986657 DOI: 10.3233/cbm-200006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Previous studies have identified LCP1 as a diagnostic and prognostic marker in several cancers. However, the role of LCP1 in gastric cancer (GC) and its effect on tumor immune infiltration remain unclear. OBJECTIVE The aim was to explore the role of LCP1 in GC and its effect on tumor immune infiltration. METHODS We explored the expression of LCP1 relative to clinicopathology in GC patients by bioinformatics analysis and immunohistochemistry. Using cBioportal database, we analyzed the characteristic genetic variations of LCP1 in GC. In addition, we evaluated the correlation between LCP1 expression and tumor-infiltrating lymphocytes (TILs) using R software, TIMER and TISIDB databases. Finally, we analyzed the biological functions in which LCP1 may participate and the signaling pathways it may regulate. RESULTS Here, we showed that LCP1 expression is significantly correlated with tumor aggressiveness and poor prognosis in GC patients. Additionally, the results indicated that LCP1 was associated with TILs, including both immunosuppressive and immunosupportive cells, and was strongly correlated with various immune marker sets in GC. GSEA analysis demonstrated that LCP1 expression played an important role in lymphocyte formation and immune reaction. CONCLUSIONS LCP1 may be a potential prognostic biomarker for GC patients and a marker for tumor immunotherapy.
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Affiliation(s)
- Qingwen Zeng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Leyan Li
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Zongfeng Feng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Lianghua Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Jianbo Xiong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Zhigang Jie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Cao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Zhengrong Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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Identification of Key Genes in Gastric Cancer by Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7658230. [PMID: 33015179 PMCID: PMC7525308 DOI: 10.1155/2020/7658230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/12/2020] [Accepted: 09/01/2020] [Indexed: 12/22/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies of the digestive system with few genetic markers for its early detection and prevention. In this study, differentially expressed genes (DEGs) were analyzed using GEO2R from GSE54129 and GSE13911 of the Gene Expression Omnibus (GEO). Then, gene enrichment analysis, protein-protein interaction (PPI) network construction, and topological analysis were performed on the DEGs by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, STRING, and Cytoscape. Finally, we performed survival analysis of key genes through the Kaplan-Meier plotter. A total of 1034 DEGs were identified in GC. GO and KEGG results showed that DEGs mainly enriched in plasma membrane, cell adhesion, and PI3K-Akt signaling pathway. Subsequently, the PPI network with 44 nodes and 333 edges was constructed, and 18 candidate genes in the network were focused on by centrality analysis and module analysis. Furthermore, data showed that high expressions of fibronectin 1(FN1), the tissue inhibitor of metalloproteinases 1 (TIMP1), secreted phosphoprotein 1 (SPP1), apolipoprotein E (APOE), and versican (VCAN) were related to poor overall survivals in GC patients. In summary, this study suggests that FN1, TIMP1, SPP1, APOE, and VCAN may act as the key genes in GC.
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Liang LB, Huang XY, He H, Liu JY. Prognostic Values of Radiosensitivity Genes and CD19 Status in Gastric Cancer: A Retrospective Study Using TCGA Database. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:365-373. [PMID: 32982372 PMCID: PMC7490048 DOI: 10.2147/pgpm.s265121] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/11/2020] [Indexed: 02/05/2023]
Abstract
Background The correlation between the radiosensitivity genes combined with CD19 status and clinical outcome was investigated to identify gastric cancer (GC) patients who would benefit from radiotherapy combined with CAR-T cell therapy. Methods The gene expression and clinical features were downloaded from The Cancer Genome Atlas (TCGA) Stomach Cancer (STAD). To identify the hub radiosensitivity genes and CD19 status, 407 patients were categorized into two groups: radiosensitivity (RS) and radioresistance (RR) based on the prognosis. The chi-square test, Mann-Whitney test, and Kaplan-Meier survival analysis were applied to compare the differential expression in these groups and analyze the correlation between the gene expression and clinical outcome and features. Finally, the influencing factors for the prognosis of GC were investigated by multiple Cox regression, especially in RS patients. Results A total of 15 differential expression genes, containing two communities with 8 hub radiosensitivity genes, were identified. We also identified a 2-gene signature model with a negative coefficient and calculated the risk score for the prognosis of GC. Also, Helicobacter pylori infection was validated, and the high-risk score of radiosensitivity genes was the risk factor, and high CD19 expression was the protective factor for the prognosis. Conclusion The radiosensitivity gene signature and CD19 expression predicted the clinical outcome of GC patients.
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Affiliation(s)
- Li-Bo Liang
- Department of International Medical Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Xin-Yan Huang
- West China School of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China
| | - Ji-Yan Liu
- Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People's Republic of China.,Department of Oncology, The First People's Hospital of Ziyang, Ziyang 641300, Sichuan Province, People's Republic of China
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Wei Q, Yuan X, Li J, Xu Q, Ying J. PD-1 inhibitor combined with apatinib for advanced gastric or esophagogastric junction cancer: a retrospective study. Transl Cancer Res 2020; 9:5315-5322. [PMID: 35117897 PMCID: PMC8798944 DOI: 10.21037/tcr-20-1333] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/14/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND Nivolumab and pembrolizumab were approved as immune checkpoint inhibitors for third-line treatment of advanced gastric or esophagogastric junction cancer (GC/EGJC) in 2017. However, immunotherapy monotherapy has low efficacy. Apatinib has been proven effective in advanced GC/EGJC. Numerous studies have shown that immunotherapy has a synergistic effect when combined with targeted drug therapy. Based on these facts and to assess the efficacy and safety of programmed death 1 (PD-1) inhibitor and apatinib as combination therapy in patients (pts) with unresectable locally advanced or metastatic GC/EGJC, a retrospective clinical research study was carried out. METHODS Pts (n=24) received PD-1 inhibitor and apatinib (250 mg once daily) as second- or third-line therapy in this observational, retrospective study. The primary objectives were efficacy and safety. RESULTS At data cut-off (December 31, 2019), 24 pts were enrolled. Of the 19 pts who were evaluable, the objective response rate (ORR) was 26.3% (5/19), the median progression-free survival (PFS) was 3.0 (95% CI: 1.3 to 4.7) months, and the median overall survival (OS) was not reached. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 3 (15.8%) of the 19 pts. These adverse events (AEs) included pruritus, rash, hand-foot syndrome, and increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). No treatment-related deaths occurred. CONCLUSIONS Combination therapy of PD-1 inhibitor and apatinib showed encouraging clinical activity and demonstrated tolerable toxicity in pts with advanced GC/EGJC. Hence, our work provide rationale for the combination of PD-1 inhibitor and apatinib in advanced GC/EGJC.
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Affiliation(s)
- Qing Wei
- Department of Abdominal Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Xing Yuan
- Department of Abdominal Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Jingjing Li
- Department of Abdominal Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Qi Xu
- Department of Abdominal Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Jieer Ying
- Department of Abdominal Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
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Peng Z, Cheng S, Kou Y, Wang Z, Jin R, Hu H, Zhang X, Gong JF, Li J, Lu M, Wang X, Zhou J, Lu Z, Zhang Q, Tzeng DTW, Bi D, Tan Y, Shen L. The Gut Microbiome Is Associated with Clinical Response to Anti-PD-1/PD-L1 Immunotherapy in Gastrointestinal Cancer. Cancer Immunol Res 2020; 8:1251-1261. [PMID: 32855157 DOI: 10.1158/2326-6066.cir-19-1014] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/27/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti-PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti-PD-1/PD-L1 immunotherapy in melanoma, non-small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti-PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti-PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti-PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti-PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses.See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243.
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Affiliation(s)
- Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Siyuan Cheng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | | | - Ziqi Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Rong Jin
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Medical Immunology (Ministry of Health), Peking University, Beijing, China
| | | | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ji-Fang Gong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - ZhiHao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | | | | | | | | | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
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Bioinformatics Analysis of Key Genes and circRNA-miRNA-mRNA Regulatory Network in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2862701. [PMID: 32908877 PMCID: PMC7463386 DOI: 10.1155/2020/2862701] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/29/2020] [Accepted: 08/04/2020] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world, with morbidity and mortality ranking second among all cancers. Accumulating evidences indicate that circular RNAs (circRNAs) are closely correlated with tumorigenesis. However, the mechanisms of circRNAs still remain unclear. This study is aimed at determining hub genes and circRNAs and analyzing their potential biological functions in GC. Expression profiles of mRNAs and circRNAs were downloaded from the Gene Expression Omnibus (GEO) data sets of GC and paracancer tissues. Differentially expressed genes (DEGs) and differentially expressed circRNAs (DE-circRNAs) were identified. The target miRNAs of DE-circRNAs and the bidirectional interaction between target miRNAs and DEGs were predicted. Functional analysis was performed, and the protein-protein interaction (PPI) network and the circRNA-miRNA-mRNA network were established. A total of 456 DEGs and 2 DE-circRNAs were identified with 3 mRNA expression profiles and 2 circRNA expression profiles. GO analysis indicated that DEGs were mainly enriched in extracellular matrix and cell adhesion, and KEGG confirmed that DEGs were mainly associated with focal adhesion, the PI3K-Akt signaling pathway, extracellular matrix- (ECM)- receptor interaction, and gastric acid secretion. 15 hub DEGs (BGN, COL1A1, COL1A2, FBN1, FN1, SPARC, SPP1, TIMP1, UBE2C, CCNB1, CD44, CXCL8, COL3A1, COL5A2, and THBS1) were identified from the PPI network. Furthermore, the survival analysis indicate that GC patients with a high expression of the following 9 hub DEGs, namely, BGN, COL1A1, COL1A2, FBN1, FN1, SPARC, SPP1, TIMP1, and UBE2C, had significantly worse overall survival. The circRNA-miRNA-mRNA network was constructed based on 1 circRNA, 15 miRNAs, and 45 DEGs. In addition, the 45 DEGs included 5 hub DEGs. These results suggested that hub DEGs and circRNAs could be implicated in the pathogenesis and development of GC. Our findings provide novel evidence on the circRNA-miRNA-mRNA network and lay the foundation for future research of circRNAs in GC.
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30
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Novel Immunotherapeutic Approach in Gastric Cancer. ACTA MEDICA BULGARICA 2020. [DOI: 10.2478/amb-2020-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Gastric cancer (GC) is suitable for immunotherapy because 80% of it display microsatellite and chromosomal instability, some mutations and DNA hypermethylation. Therefore, GC is more immunogenic. The immunotherapy with monoclonal antibodies, adoptive cell therapy and checkpoint inhibition are discussed. The commonly used monoclonal antibodies are Trastuzumab targeting HER2 and Bevacizumab suppressing VEGF and tumor angiogenesis. Treatment with tumor-specific T cells is called adoptive cell therapy. There is experience with the application of tumor infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs) and cytokine-induced killer cells (CIK). This review discusses the therapy with innate immune cells with anti-tumor activity such as dendritic cells and NK cells. The checkpoint inhibition was also reviewed. In conclusion, it could be stated that the immunotherapy of GC has the potential to provide a more favorable outcome to patients with GC, but it also have some limitations which need to be considered.
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Olguín JE, Medina-Andrade I, Rodríguez T, Rodríguez-Sosa M, Terrazas LI. Relevance of Regulatory T Cells during Colorectal Cancer Development. Cancers (Basel) 2020; 12:E1888. [PMID: 32674255 PMCID: PMC7409056 DOI: 10.3390/cancers12071888] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called "phenotypic plasticity", where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC.
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Affiliation(s)
- Jonadab E. Olguín
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
| | - Itzel Medina-Andrade
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
| | - Tonathiu Rodríguez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
| | - Miriam Rodríguez-Sosa
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
| | - Luis I. Terrazas
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios # 1, Tlalnepantla 54090, Mexico; (J.E.O.); (I.M.-A.); (T.R.); (M.R.-S.)
- Unidad de Biomedicina, FES Iztacala, UNAM, Av. De los Barrios # 1, Tlalnepantla 54090, Mexico
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Mao M, Yu Q, Huang R, Lu Y, Wang Z, Liao L. Stromal score as a prognostic factor in primary gastric cancer and close association with tumor immune microenvironment. Cancer Med 2020; 9:4980-4990. [PMID: 32432377 PMCID: PMC7367639 DOI: 10.1002/cam4.2801] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/15/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Gastric cancer remains one of the major causes for tumor‐related deaths worldwide. Our study aimed to provide an understanding of primary gastric cancer and prompt its clinical diagnosis and treatment. Methods We integrated the expression profiles and overall survival information of primary gastric cancer in TCGA and GEO database and estimated the stromal score of each sample by the estimate R package. Stromal score and clinicopathologic characteristics associated with overall survival were analyzed by using Cox regression and the Kaplan‐Meier method. Gene set enrichment analysis (GSEA) and KEGG analysis were performed to explore the potential molecular mechanism in TCGA dataset. The relationship between immunotherapy‐associated markers or immune cell types and stromal score was explored by using Pearson correlation analysis. Results A total of 796 samples were collected for the analysis. Patients with stromal score‐high showed poor overall survival (P < .01, HR: 1.407, 95% CI: 1.144‐1.731) and identified as an independent prognostic factor. KEGG analysis revealed that stromal score actively involved in diverse tumor‐associated pathways. GSEA analysis also revealed stromal score associated with diverse immune‐related biological processes. Furthermore, stromal score was related with immunotherapy‐associated markers and multiple immune cells. Conclusion Our results showed that stromal score could serve as a potential prognostic biomarker in primary gastric cancer and play an important role in the recognition, surveillance, and prognosis of gastric cancer.
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Affiliation(s)
- Min Mao
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Qingliang Yu
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Rongzhi Huang
- Department of Orthopedic Surgery, The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou First People's Hospital, Qinzhou, China
| | - Yunxin Lu
- First Clinical Medical College, Guangxi Medical University, Nanning, China
| | - Zhen Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liang Liao
- Department of Traumatic Orthopedics and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Refolo MG, Lotesoriere C, Messa C, Caruso MG, D'Alessandro R. Integrated immune gene expression signature and molecular classification in gastric cancer: New insights. J Leukoc Biol 2020; 108:633-646. [PMID: 32170872 DOI: 10.1002/jlb.4mr0120-221r] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/03/2020] [Accepted: 01/24/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is characterized by extreme heterogeneity due to histopathological differences, molecular characteristics, and immune gene expression signature. Until recently, several targeted therapies failed due to this complexity. The recent immunotherapy resulted in more effective and safe approaches in several malignancies. All tumors could be considered potentially immunogenic and the new knowledge regarding the interactions among tumor cells, immune cells, and tumor microenvironment (TME) allowed to reverse possible immune resistance. The immune response is a complex multisteps process that finely regulates the balance between the recognition of non-self and the prevention of autoimmunity. Cancer cells can use these pathways to suppress tumor immunity as a major mechanism of immune resistance. The recent molecular classifications of GCs by The Cancer Genome Atlas (TCGA) and by the Asian Cancer Research (ACRG) networks, together with the identification of multiple biomarkers, open new perspectives for stratification of patients who might benefit from a long-term immune checkpoint therapy. One of the major processes that contribute to an immunosuppressive microenvironment is represented by tumor angiogenesis. The cellular mechanisms inducing both angiogenesis and immunosuppressive responses are often reached by the same cell types and soluble factors, such as vascular endothelial growth factor A (VEGFA). Recent studies point out that combinatorial strategies should be adapted as useful therapeutic approach to reverse the immunosuppressive status of microenvironment occurring in a relevant percentage of gastric tumors.
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Affiliation(s)
- Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Bari, Italy
| | - Caterina Messa
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
| | - Maria Gabriella Caruso
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Bari, Italy
| | - Rosalba D'Alessandro
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
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Ji L, Qian W, Gui L, Ji Z, Yin P, Lin GN, Wang Y, Ma B, Gao WQ. Blockade of β-Catenin-Induced CCL28 Suppresses Gastric Cancer Progression via Inhibition of Treg Cell Infiltration. Cancer Res 2020; 80:2004-2016. [PMID: 32156780 DOI: 10.1158/0008-5472.can-19-3074] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/07/2020] [Accepted: 03/05/2020] [Indexed: 11/16/2022]
Abstract
Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of the tumor immune microenvironment is essential for understanding tumorigenesis and for the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates the tumor immune microenvironment in the stomach. Here, we identify CCL28 as a direct transcriptional target gene of β-catenin/T-cell factor (TCF). Protein levels of β-catenin and CCL28 positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 recruited regulatory T (Treg) cells in a transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and N-methyl-N-nitrosourea (MNU) treatment, inhibition of β-catenin/TCF activity by a pharmacologic inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, an anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings reveal an immunoregulatory role of β-catenin signaling in stomach tumors and highlight the therapeutic potential of CCL28 blockade for the treatment of gastric cancer. SIGNIFICANCE: These findings demonstrate an immunosuppressive role of tumor-intrinsic β-catenin signaling and the therapeutic potential of CCL28 blockade in gastric cancer.
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Affiliation(s)
- Lu Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Qian
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Liming Gui
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongzhong Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Pan Yin
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Guan Ning Lin
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - You Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Ma
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. .,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. .,Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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Chen X, Chen R, Jin R, Huang Z. The role of CXCL chemokine family in the development and progression of gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:484-492. [PMID: 32269686 PMCID: PMC7137023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 02/06/2020] [Indexed: 06/11/2023]
Abstract
The chemokine (C-X-C motif) ligand (CXCL) family plays an important role in inflammation. In order to understand the role of CXC chemokine family in carcinogenesis, this study explored a group of early gastric cancer (GC) patients, and assessed the level of CXC chemokine ligand (CXCL) in blood samples of patients representing systemic circulation and tumor microenvironment, detected the expression of CXC chemokine receptor (CXCR) in tumor tissues, and measured tumor infiltrating immune cell subsets. 69 patients with GC were included in a single center prospective study and were followed up for 6 years. The level of CXCL1-14 was determined by ELISA and the concentration gradient of chemokine was calculated. Western blot was used to detect the expression of CXCR1, CXCR2, CXCR3, and CXCR4 in tumor tissue. CXCL1-14 expression was inhibited by siRNA in HGC27 cells and then the migration ability of HGC27 cells was detected by cell scratch test. The results of this study showed that the chemokine concentrations of CXCL1, CXCL2, CXCL5, CXCL8, CXCL11, and CXCL13 in peripheral blood and tumor drainage blood of patients without recurrence after treatment were significantly lower than those before treatment. The concentrations of CXCL1, CXCL2, CXCL4, CXCL5, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13, and CXCL14 in peripheral blood and tumor drainage blood were significantly higher than those in patients without recurrence. Patients with low expression of CXCR1 and CXCR3 had lower AFP (alpha fetoprotein), smaller tumor volume, and lower TNM tumor stage. Patients with lower expression of CXCR2 and CXCR4 had higher AFP (alpha fetoprotein) level, larger tumor volume, and higher TNM tumor stage. After down-regulation of CXCLs expression, the migration ability of most cell lines was significantly inhibited. This study suggests that CXCL chemokine family plays an important role in the pathogenesis of GC and can be used as a marker for the development of GC.
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Affiliation(s)
- Xuyan Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Renpin Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Ruifang Jin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
| | - Zhiming Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University Zhejiang, P. R. China
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Li Y, Liu H, Chen H, Shao J, Su F, Zhang S, Cai X, He X. DERL3 functions as a tumor suppressor in gastric cancer. Comput Biol Chem 2020; 84:107172. [DOI: 10.1016/j.compbiolchem.2019.107172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/13/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023]
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HAVCR1 Affects the MEK/ERK Pathway in Gastric Adenocarcinomas and Influences Tumor Progression and Patient Outcome. Gastroenterol Res Pract 2019; 2019:6746970. [PMID: 31885544 PMCID: PMC6914876 DOI: 10.1155/2019/6746970] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 08/16/2019] [Accepted: 10/03/2019] [Indexed: 01/09/2023] Open
Abstract
The hepatitis A virus cellular receptor 1 (HAVCR1) gene as a sensitive and specific biomarker has been reported in various diseases. Especially, HAVCR1 overexpression promotes the development and progression of several human cancers. Hence, we aimed to detect the effects of HAVCR1 on gastric adenocarcinoma (GAC). We first determined the expression of HAVCR1 in GAC tissues compared with normal gastric tissues based on the Cancer Genome Atlas (TCGA) database using bioinformatics analysis methods. Then, we assessed the biological function of HAVCR1 in GAC cells using quantitative real-time reverse transcription-PCR (qRT-PCR), western blot, cell counting kit-8- (CCK-) 8, colony formation assay, wound healing assay, and transwell assay. Our results showed that HAVCR1 expression was upregulated in GAC tissues and positively associated with poor survival. Loss-of-function analyses indicated that knockdown of HAVCR1 inhibited the proliferation, colony formation, migration, and invasion of GAC cells. Furthermore, reduction of HAVCR1 in GAC cells can decrease the expression of phosphorylated MEK/ERK. These findings suggested that HAVCR1 may represent a potential biomarker for GAC prognosis, as well as a novel therapeutic target for GAC treatment.
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Cavaliere A, Merz V, Casalino S, Zecchetto C, Simionato F, Salt HL, Contarelli S, Santoro R, Melisi D. Novel Biomarkers for Prediction of Response to Preoperative Systemic Therapies in Gastric Cancer. J Gastric Cancer 2019; 19:375-392. [PMID: 31897341 PMCID: PMC6928085 DOI: 10.5230/jgc.2019.19.e39] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/02/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.
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Affiliation(s)
- Alessandro Cavaliere
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Valeria Merz
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Simona Casalino
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Zecchetto
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Francesca Simionato
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Hayley Louise Salt
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaela Santoro
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Davide Melisi
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
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Zhou Z, Zhang H, Deng T, Ning T, Liu R, Liu D, Bai M, Ying G, Ba Y. Exosomes Carrying MicroRNA-155 Target Forkhead Box O3 of Endothelial Cells and Promote Angiogenesis in Gastric Cancer. MOLECULAR THERAPY-ONCOLYTICS 2019; 15:223-233. [PMID: 31828217 PMCID: PMC6889542 DOI: 10.1016/j.omto.2019.10.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) has a poor prognosis due to its relentless proliferation and metastasis. One of the reasons for this plight is the formidable angiogenesis ability of GC. Considering the important role of cancer exosomes as carriers and communicators in the tumor microenvironment, we explored the role of exosome-microRNA (miRNA) in regulating angiogenesis. Western blotting and quantitative real-time PCR were used to measure the protein and mRNA levels of the miRNA target gene. To detect changes in cellular biological functions, we pretreated human umbilical vein endothelial cells (HUVECs) that were severally cocultured with GC-derived exosomes and transfected them with different miRNAs directly. Also, we used the mouse xenograft model to verify the effect of miR-155 on angiogenesis of GC tissues in vivo. Our study confirmed that miR-155, as a driver of angiogenesis, encapsulated by exosomes from GC can enhance the generation of new vessels for GC in vitro through inhibiting the expression of Forkhead box O3 (FOXO3a) protein, which led to the progression of GC. Therefore, miR-155 is probable to become a potential biomarker for the detection of migration and angiogenesis of GC, and serves as a novel target for anti-angiogenesis therapy.
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Affiliation(s)
- Zhengyang Zhou
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Haiyang Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Ting Deng
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Tao Ning
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Rui Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Dongying Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Ming Bai
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Guoguang Ying
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Yi Ba
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
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40
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Feng L, Li J, Li F, Li H, Bei S, Zhang X, Yang Z. Long noncoding RNA VCAN-AS1 contributes to the progression of gastric cancer via regulating p53 expression. J Cell Physiol 2019; 235:4388-4398. [PMID: 31637706 DOI: 10.1002/jcp.29315] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 09/30/2019] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is one of the most frequent malignancies worldwide. Long noncoding RNAs (lncRNAs) are found to be largely implicated in various cancers, including GC. However, the function of lncRNA VCAN antisense RNA 1 (VCAN-AS1) in GC remains unclear. Herein, we observed a low level of VCAN-AS1 in normal gastric tissues through NCBI and UCSC, and that VCAN-AS1 upregulation in GC tissues was related to poor prognosis by TCGA. Furthermore, VCAN-AS1 was found markedly enhanced in GC tissues and cell lines, while its upregulation was related with clinical outcomes of GC patients. Besides this, silencing VCAN-AS1 represses cell proliferation, migration, and invasion but enhances apoptosis. More important, we discovered that VCAN-AS1 expression was negatively correlated with wild-type p53 levels in GC tissues and that p53 was negatively modulated by VCAN-AS1 in GC cells. Furthermore, p53 suppression reversed the repression of VCAN-AS1 silence on the biological processes of AGS cells. Intriguingly, we identified that both VCAN-AS1 and TP53 can bind with eIF4A3, one of the core proteins in the exon junction complex. Also, we confirmed that VCAN-AS1 negatively regulates TP53 expression by competitively binding with eIF4A3. Our findings disclosed that VCAN-AS1 contributes to GC progression through interacting with eIF4A3 to downregulate TP53 expression, indicating that VCAN-AS1 is a novel therapeutic strategy for GC treatment.
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Affiliation(s)
- Li Feng
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Jian Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Fan Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Huanqin Li
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Songhua Bei
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaohong Zhang
- Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, China
| | - Zhen Yang
- Surgical Department, Minhang Hospital, Fudan University, Shanghai, China
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Li F, Sun Y, Huang J, Xu W, Liu J, Yuan Z. CD4/CD8 + T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med 2019; 8:7330-7344. [PMID: 31631566 PMCID: PMC6885892 DOI: 10.1002/cam4.2596] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 08/28/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The tumor microenvironment represents an abnormal niche containing numerous factors, such as T cells, dendritic cells (DCs), regulatory T cells (Tregs), and indoleamine 2,3-dioxygenase (IDO), involved in maintaining immune homeostasis and tolerance. All these factors may influence the choice of therapy and the clinical outcomes. METHODS Flow cytometry was performed to identify CD4+/CD8 + T cells and DCs, and immunohistochemistry was used to evaluate IDO and Forkhead Box P3 (Foxp3) expression; these experiments were performed in order to explore the clinical and prognostic significance of CD4/CD8 + T cells, DCs, Tregs, and IDO expression in gastric carcinoma. RESULTS Smaller tumor size was correlated with higher expression levels of peripheral CD4 + T cells (P = .003) and CD8 + T cells (P = .002), and lower IDO expression (P = .044) in tumors. Well-differentiated gastric carcinomas displayed higher peripheral (P = .029) and tumor-infiltrating CD4 + T cell (P = .009) populations and a higher tumor-infiltrating DC1/DC2 ratio (P = .048). Gastric cancer in the early T stages exhibited higher populations of peripheral DC2s (P = .044) and a higher tumor-infiltrating DC1/DC2 ratio (P = .012). Gastric cancer at the N0 stage had lower tumor-infiltrating DC2s (P = .032) and a higher DC1/DC2 ratio (P = .037). IDO expression was positively correlated with tumor-infiltrating Foxp3 + Tregs (P < .001) as well as DC2s (P < .001), whereas it was negatively correlated with the tumor-infiltrating CD4/CD8 + T cell ratio (P = .023). Tumor-infiltrating Foxp3 + Treg was positively correlated with tumor-infiltrating DC2s (r2 = 0.772; P < .001). At T, N, and TNM stages, the expression levels of peripheral DC2s, tumor-infiltrating DC1/DC2 ratios, Foxp3 + Tregs, and IDO were significantly correlated with prognosis (P < .05). The T stage and peripheral DC2s were significant risk factors for overall survival. CONCLUSION Immunocompetent cells and humoral immune factors, including DC2s, CD4+/CD8 + T cells, Foxp3 + Tregs, and IDO, interact with each other to compose a complex community of tumor immune microenvironment, ultimately affecting tumor progression and survival of gastric cancer.
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Affiliation(s)
- Fangxuan Li
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yao Sun
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Jinchao Huang
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Juntian Liu
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhiyong Yuan
- Department of Radiotherapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
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Roviello G, D’Angelo A, Generali D, Pittacolo M, Ganzinelli M, Iezzi G, Manzini ND, Sobhani N. Avelumab in gastric cancer. Immunotherapy 2019; 11:759-768. [PMID: 31060469 DOI: 10.2217/imt-2019-0011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third cause of cancer-related deaths worldwide. Currently, surgery and chemotherapy remain the main therapeutic options and the prognosis of the disease is still poor in the metastatic setting. Avelumab is a human IgG1 antibody directed against PD-L1 approved for Merkel cell carcinoma and urothelial carcinoma that could be useful also for the treatment of GC. This review describes the chemical structure, the pharmacologic properties and the current knowledge of the efficacy of avelumab in the treatment of GC from the data available on the first and later phase clinical trials. The ongoing studies testing this drug either alone or in combination with other drugs are also described.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy
| | - Alberto D’Angelo
- Department of Biology & Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
| | - Daniele Generali
- Breast Cancer Unit, ASST Cremona, Viale Concordia 1, 26100 Cremona, Italy
| | - Matteo Pittacolo
- Department of Orthopedics & Orthopedic Oncology, University of Padova, Italy
| | - Monica Ganzinelli
- Thoracic Unit, Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Nicolò de Manzini
- General Surgery Unit, Department of Medical, Surgical and Health Sciences Cattinara University Hospital, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy
| | - Navid Sobhani
- Breast Cancer Unit, ASST Cremona, Viale Concordia 1, 26100 Cremona, Italy
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Controlling Nutritional Status (CONUT) as a prognostic immunonutritional biomarker for gastric cancer after curative gastrectomy: a propensity score-matched analysis. Surg Endosc 2019; 33:4143-4152. [PMID: 30838449 DOI: 10.1007/s00464-019-06723-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND In clinical practice, it is not unusual to treat oncologic patients whose tumor markers are within normal range, even with advanced cancer. The Controlling Nutritional Status (CONUT) score could provide a useful nutritional and immunological prognostic biomarker for cancer patients. In this study, we assessed the prognostic value of the CONUT score for patients with gastric cancer, including a subgroup analysis with stratification based on serum carcinoembryonic antigen (CEA) level. METHODS We retrospectively reviewed the medical records of 368 consecutive patients who underwent curative laparoscopy-assisted gastrectomy. The prognostic value of the CONUT score was compared between patients with a low (≤ 2) and high (≥ 3) score, with propensity score matching (PSM) used to control for biasing covariates (Depth of tumor, Lymph node metastasis, pathological TNM (pTNM) stage). RESULTS Overall survival (OS) among all patients was independently predicted by the tumor stage (hazard ratio (HR): 2.231, p = 0.001), the CONUT score (HR: 2.254, p = 0.001), and serum CEA level (HR: 1.821, p = 0.025). Among patients with a normal preoperative serum CEA level, tumor stage (HR: 2.350, p = 0.007), and the CONUT score (HR: 1.990, p = 0.028) were independent prognostic factors of OS. In the high serum CEA level group, tumor size (HR: 2.930, p = 0.015) and the CONUT score (HR: 3.707, p = 0.004) were independent prognostic factors of OS. CONCLUSIONS It is advantageous to use both CEA level and the CONUT score to assess the prognosis of patients with gastric cancer, which reflect both tumor-related factors and host-related factors, respectively.
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Han L, Hao Y, Wang J, Wang Z, Yang H, Wu X. Knockdown of LINC02465 Suppresses Gastric Cancer Cell Growth and Metastasis Via PI3K/AKT Pathway. HUM GENE THER CL DEV 2019; 30:19-28. [PMID: 30632400 DOI: 10.1089/humc.2018.177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Liang Han
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
| | - Yanping Hao
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
| | - Jianhua Wang
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
| | - Zhengjiang Wang
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
| | - Hongmei Yang
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
| | - Xudong Wu
- Department of Gastroenterology, First People's Hospital of Yancheng City, Yancheng, Jiangsu Province, China
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45
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Zhandossov O, Kaussova G, Koten A. Combined treatment for gastric cancer: Immunological approach. TURKISH JOURNAL OF GASTROENTEROLOGY 2018; 29:151-156. [PMID: 29749320 DOI: 10.5152/tjg.2018.17398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Gastric cancer is one of the most common oncological diseases. It can develop in any part of the stomach and spread to other organs, especially the esophagus, lungs, and liver. The aim of our study was to investigate the effectiveness of our proposed therapy. MATERIALS AND METHODS Our research promises more effective neoadjuvant therapy, including immunotherapy and multi-agent chemotherapy. Of the 62 patients involved in our study, 32 underwent neoadjuvant chemotherapy in combination with surgery, whereas the rest underwent neoadjuvant chemoimmunotherapy with surgery. RESULTS Investigation of T-cell-mediated and humoral immunity in patients with gastric cancer over the course of treatment found a reduction of the main indices of cell-mediated and humoral immunity in the patients who underwent standard therapy, which greatly caused a decline of antitumor, anti-infective, and antitoxic protection of the patients' organisms. CONCLUSION This study can contribute to the development of new therapies for gastric cancer as well as other types of cancer.
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Affiliation(s)
- Olzhas Zhandossov
- Department of Oncology, Kazakhstan Medical University High School of Public Health, Almaty, Kazakhstan
| | - Galina Kaussova
- Department of Public Health and Social Sciences, Kazakhstan Medical University High School of Public Health, Almaty, Kazakhstan
| | - Avraam Koten
- Department of Oncology, Medical Center "CarmelMC", Haifa, Israel
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Zhou Q, Wu X, Wen C, Wang H, Wang H, Liu H, Peng J. Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells. Biochem Biophys Res Commun 2018; 505:261-266. [DOI: 10.1016/j.bbrc.2018.09.093] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 09/14/2018] [Indexed: 01/19/2023]
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47
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Tirino G, Pompella L, Petrillo A, Laterza MM, Pappalardo A, Caterino M, Orditura M, Ciardiello F, Galizia G, De Vita F. What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives. Int J Mol Sci 2018; 19:E2659. [PMID: 30205505 PMCID: PMC6165492 DOI: 10.3390/ijms19092659] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 02/05/2023] Open
Abstract
Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called "precision medicine" even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.
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Affiliation(s)
- Giuseppe Tirino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Luca Pompella
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Angelica Petrillo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Maria Maddalena Laterza
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Annalisa Pappalardo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Marianna Caterino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Gennaro Galizia
- Division of GI Tract Surgical Oncology, Department of Cardio-Thoracic and Respiratory Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
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48
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Lazăr DC, Avram MF, Romoșan I, Cornianu M, Tăban S, Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer. World J Gastroenterol 2018; 24:3583-3616. [PMID: 30166856 PMCID: PMC6113718 DOI: 10.3748/wjg.v24.i32.3583] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/05/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with different clinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
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Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Sorina Tăban
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
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Ji J, Zhen W, Si Y, Ma W, Zheng L, Li C, Zhang Y, Qin S, Zhang T, Liu P, Zheng X, Liu Y. Increase in CIP2A expression is associated with cisplatin chemoresistance in gastric cancer. Cancer Biomark 2018; 21:307-316. [PMID: 29103022 DOI: 10.3233/cbm-170416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein which involves in the progression of several human malignancies. Development of cisplatin (DDP) resistance is the obstacle to an effective control of gastric cancer (GC) clinically. OBJECTIVE We thus assessed whether CIP2A expression is associated with sensitivity of GC to DDP. METHODS Real-time quantitative PCR, immunohistochemical analysis, or western blotting was performed to detect CIP2A expression in GC patients' tissues. SGC7901/DDP cells were transfected with CIP2A siRNA. MTT assay was used to determine the DDP-sensitivity of cells. Flow cytometry was used to measure cell apoptosis. RESULTS CIP2A has higher expression in DDP-resistant GC patients. DDP-resistant GC patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. CIP2A knockdown in DDP-resistant GC cells resulted in attenuated proliferative abilities and increased apoptosis level. CIP2A depletion sensitizes DDP-resistant cells to DDP and CIP2A overexpression antagonizes DDP-sensitive cells to DDP. CIP2A influences the expression of multidrug resistance-related proteins in GC cells. CONCLUSIONS Our results suggested that CIP2A oncoprotein plays an important role in DDP resistance of GC and could serve as a novel therapeutic target for the treatment of GC patients with DDP resistance.
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Affiliation(s)
- Juanli Ji
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, China.,Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Weiguo Zhen
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.,Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Yuan Si
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Wenjing Ma
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Lanlan Zheng
- Laboratory of Medicinal Plant, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Chen Li
- Laboratory of Medicinal Plant, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Yonghong Zhang
- Laboratory of Medicinal Plant, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Shanshan Qin
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Te Zhang
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Pengfei Liu
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Xin Zheng
- Department of Gastrointestinal Surgery, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Ying Liu
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China
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50
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Peng J. si-TP73-AS1 suppressed proliferation and increased the chemotherapeutic response of GC cells to cisplatin. Oncol Lett 2018; 16:3706-3714. [PMID: 30127981 PMCID: PMC6096144 DOI: 10.3892/ol.2018.9107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 04/16/2018] [Indexed: 12/20/2022] Open
Abstract
Previous studies have revealed that long noncoding RNAs (lncRNAs) function as crucial regulators in various biological processes, including tumorigenesis. Although the expression of lncRNA TP73-antisense RNA1 (AS1) has been identified in hepatocellular carcinoma and glioma, the biological function of TP73-AS1 in gastric cancer (GC) remains unclear. Thus, the present study employed a comprehensive analysis on the function of lncRNA TP73-AS1 in GC. The aim of the present study was to determine the clinical significance and biological function of TP73-AS1 in human GC tissues and cells. Additionally, the expression of TP73-AS1 was increased in GC tissues and cell lines and increased expression level of TP73-AS1 was associated with poor prognosis in patients with GC. Functional assays revealed that silencing of TP73-AS1 may suppress cell proliferation and enhance the chemotherapeutic response of GC cells to cisplatin through targeting the high mobility group 1/receptor for advanced glycation endproducts signaling pathway. Collectively, the results of the present study demonstrated that TP73-AS1 may be a novel lncRNA for the clinical prognosis of GC and a potential therapeutic target for the treatment of GC.
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Affiliation(s)
- Jianjun Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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