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Bai Z, Yan C, Chang D. Prediction and therapeutic targeting of the tumor microenvironment-associated gene CTSK in gastric cancer. Discov Oncol 2023; 14:200. [PMID: 37930479 PMCID: PMC10628060 DOI: 10.1007/s12672-023-00821-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 11/02/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Cathepsin-K (CTSK) is overexpressed in Gastric cancer (GC) and the mechanism of its overexpression in GC is still unclear. The present work found CTSK as a potential predictive biomarker and immunotherapeutic target for GC based on the tumor microenvironment (TME). METHODS From public databases, gene expression profiles and clinical data of GC were downloaded to analyze the distribution of stromal and immune cells and tumor abundance in TME. Differentially expressed genes (DEGs) associated with TME were obtained by differential analysis, followed by cross-screening to obtain CTSK as a gene associated with TME. Next, a series of methods and tools were employed to explore the relationships between clinicopathological features of GC and CTSK expression as well as prognosis, tumor immune microenvironment, immune checkpoints and drug sensitivity. And GSEA was used to investigate the potential role of CTSK in the tumor microenvironment of GC. RESULTS From the dataset, we obtained a total of 656 DEGs associated with TME and the stromal component of TME was found to be closely involved in GC prognosis. CTSK was cross-screened as the key gene associated with TME by the PPI network and univariate Cox regression analysis. Pan-cancer analysis revealed significant high expression of CTSK in a variety of cancers. Subsequently, we hypothesized that high-expressed CTSK was closely correlated with poor prognosis and lymph node metastasis of tumors, and that CTSK, a GC TME-related gene, was largely involved in a range of biological behaviors of tumors, with a significant correlation between several immune cells. CONCLUSION CTSK was validated as a potential prognostic biomarker related to TME of GC and could be a promising next-generation immunotherapeutic target for GC.
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Affiliation(s)
- Zilong Bai
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shanxi, China
| | - Chunyu Yan
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shanxi, China
| | - Dongmin Chang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shanxi, China.
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Wu Z, Zheng J, Zhang H, Shen N, Luo X, Shen C, Song P, Zhang Y, Zhang M, Yang S, Guo G, Xue X, Zhang F, Feng S. Molecular characteristics, oncogenic roles, and relevant immune and pharmacogenomic features of NEK2 in gastric cancer. Int Immunopharmacol 2023; 116:109737. [PMID: 36738674 DOI: 10.1016/j.intimp.2023.109737] [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: 11/22/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 02/05/2023]
Abstract
Gastric cancer (GC) is the most common form of gastrointestinal cancer, with a high mortality rate and limited treatment options. High levels of NEK2 are associated with malignant progression and a poor prognosis in several tumors; however, the role of NEK2 in GC remains unclear. We aimed to explore the potential role of NEK2 in the oncogenesis of GC and in the shaping of the tumor microenvironment (TME). The expression levels of NEK2 were analyzed using immunohistochemistry and real-time quantitative polymerase chain reaction. We found that NEK2 expression was upregulated in GC and was a predictor of a poor prognosis. Based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene set enrichment analyses, multiple tumor pathways were hyperactivated in patients with high NEK2 mRNA expression. Immunological characteristics indicated that NEK2 upregulation might lead to decreased immune cell infiltration and weakened immune activity in the cancer immunity cycle. Additionally, higher frequencies of amplifications and deletions were observed in the high NEK2 expression subpopulation. Based on the TME classification, patients with high expression of NEK2 were more susceptible to targeted therapy with drugs targeting the cell cycle and DNA replication. Following verification, a NEK2-derived genomic model reliably predicted the patient prognosis; A nomogram (radiation therapy, tumor/node/metastasis staging, and the NEK2-derived risk score) was used to better estimate an individual's survival probability. In summary, our findings indicate that NEK2 plays a vital role in the tumorigenesis of GC.
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Affiliation(s)
- Zhonghan Wu
- School of the First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingjing Zheng
- The Fifth Affiliated Hospital of Wenzhou Medical University& Lishui Municipal Central Hospital, Lishui, Zhejiang, China
| | - Haoke Zhang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ningzhe Shen
- First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaohui Luo
- School of the First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chenfang Shen
- The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Peining Song
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yu Zhang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Min Zhang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shaopeng Yang
- School of the First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gangqiang Guo
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Fabiao Zhang
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Department of Hepatic-Biliary-Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zheiang, China.
| | - Shiyu Feng
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Li HX, Wang SQ, Lian ZX, Deng SL, Yu K. Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer. Cells 2022; 12:cells12010064. [PMID: 36611857 PMCID: PMC9818185 DOI: 10.3390/cells12010064] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.
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Affiliation(s)
- Huan-Xiang Li
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shu-Qi Wang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shou-Long Deng
- National Health Commission (NHC) of China Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
- Correspondence: (S.-L.D.); (K.Y.)
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
- Correspondence: (S.-L.D.); (K.Y.)
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An Immunity-Associated lncRNA Signature for Predicting Prognosis in Gastric Adenocarcinoma. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:3035073. [PMID: 35509706 PMCID: PMC9061059 DOI: 10.1155/2022/3035073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/05/2022] [Accepted: 03/31/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric adenocarcinoma (GAD) is one of the most common tumors in the world and the prognosis is still very poor. Objective We sought to identify reliable prognostic biomarkers for the progression of GAD and the sensitivity to drug therapy. Method The RNA sequencing data of GAD was downloaded from the Cancer Genome Atlas (TCGA) database and used for analysis. Differentially expressed, immune-related lncRNA (DEIRlncRNA) was characterized by differential analysis and correlation analysis. Univariate Cox regression analysis was used to identify DEIRlncRNA associated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression analysis allowed us to determine a signature composed of eight IRlncRNAs. Based on this signature, we further performed gene set enrichment analysis (GSEA) and somatic mutation analysis to evaluate the ability of this signature to predict prognosis. Results In total, 72 immune-related lncRNAs (DEIRlncRNAs) with prognostic value were identified. These lncRNAs were used to construct a model containing eight immune-related lncRNAs (8-IRlncRNAs). Based on this risk model, we divided GAD patients into high-risk and low-risk groups. The analysis showed that the prognosis of the two groups was different and that the high-risk group had worse overall survival (OS). Immune cell infiltration analysis showed that the proportion of memory B cells increased in the high-risk group while the proportion of macrophages M1, T cells, CD4 memory-activated cells, and T cell follicular helpers decreased. GSEA results showed that 8-IRlncRNA was significantly enriched in tumorigenesis pathways such as myc. The results of somatic mutation analysis showed that the CDH1 gene was significantly mutated in the high-risk group. Conclusion A prognostic signature of 8-IRlncRNAs in GAD was established and this signature was able to predict the prognosis of GAD patients.
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Senchukova MA, Tomchuk O, Shurygina EI. Helicobacter pylori in gastric cancer: Features of infection and their correlations with long-term results of treatment. World J Gastroenterol 2021; 27:6290-6305. [PMID: 34712033 PMCID: PMC8515796 DOI: 10.3748/wjg.v27.i37.6290] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/21/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is a spiral-shaped bacterium responsible for the development of chronic gastritis, gastric ulcer, gastric cancer (GC), and MALT-lymphoma of the stomach. H. pylori can be present in the gastric mucosa (GM) in both spiral and coccoid forms. However, it is not known whether the severity of GM contamination by various vegetative forms of H. pylori is associated with clinical and morphological characteristics and long-term results of GC treatment. AIM To establish the features of H. pylori infection in patients with GC and their correlations with clinical and morphological characteristics of diseases and long-term results of treatment. METHODS Of 109 patients with GC were included in a prospective cohort study. H. pylori in the GM and tumor was determined by rapid urease test and by immunohistochemically using the antibody to H. pylori. The results obtained were compared with the clinical and morphological characteristics and prognosis of GC. Statistical analysis was performed using the Statistica 10.0 software. RESULTS H. pylori was detected in the adjacent to the tumor GM in 84.5% of cases, of which a high degree of contamination was noted in 50.4% of the samples. Coccoid forms of H. pylori were detected in 93.4% of infected patients, and only coccoid-in 68.9%. It was found that a high degree of GM contamination by the coccoid forms of H. pylori was observed significantly more often in diffuse type of GC (P = 0.024), in poorly differentiated GC (P = 0.011), in stage T3-4 (P = 0.04) and in N1 (P = 0.011). In cases of moderate and marked concentrations of H. pylori in GM, a decrease in 10-year relapse free and overall survival from 55.6% to 26.3% was observed (P = 0.02 and P = 0.07, respectively). The relationship between the severity of the GM contamination by the spiral-shaped forms of H. pylori and the clinical and morphological characteristics and prognosis of GC was not revealed. CONCLUSION The data obtained indicates that H. pylori may be associated not only with induction but also with the progression of GC.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Olesya Tomchuk
- Department of Histology, Cytology, Embryology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Elena I Shurygina
- Department of Pathology, Orenburg State Medical University, Orenburg 460000, Russia
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Ma C, Zhang X, Zhao X, Zhang N, Zhou S, Zhang Y, Li P. Predicting the Survival and Immune Landscape of Colorectal Cancer Patients Using an Immune-Related lncRNA Pair Model. Front Genet 2021; 12:690530. [PMID: 34552614 PMCID: PMC8451271 DOI: 10.3389/fgene.2021.690530] [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: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Background Accumulating evidence has demonstrated that immune-related long non-coding ribonucleic acids (irlncRNAs) can be used as prognostic indicators of overall survival (OS) in patients with colorectal cancer (CRC). Our aim in this research, therefore, was to construct a risk model using irlncRNA pairs with no requirement for a specific expression level, in hope of reliably predicting the prognosis and immune landscape of CRC patients. Methods Clinical and transcriptome profiling data of CRC patients downloaded from the Cancer Genome Atlas (TCGA) database were analyzed to identify differentially expressed (DE) irlncRNAs. The irlncRNA pairs significantly correlated with the prognosis of patients were screened out by univariable Cox regression analysis and a prognostic model was constructed by Lasso and multivariate Cox regression analyses. A receiver operating characteristic (ROC) curve was then plotted, with the area under the curve calculated to confirm the reliability of the model. Based on the optimal cutoff value, CRC patients in the high- or low-risk groups were distinguished, laying the ground for evaluating the risk model from the following perspectives: survival, clinicopathological traits, tumor-infiltrating immune cells (TIICs), antitumor drug efficacy, kinase inhibitor efficacy, and molecules related to immune checkpoints. Results A prognostic model consisting of 15 irlncRNA pairs was constructed, which was found to have a high correlation with patient prognosis in a cohort from the TCGA (p < 0.001, HR = 1.089, 95% CI [1.067-1.112]). According to both univariate and multivariate Cox analyses, this model could be used as an independent prognostic indicator in the TCGA cohort (p < 0.001). Effective differentiation between high- and low-risk patients was also accomplished, on the basis of aggressive clinicopathological characteristics, sensitivity to antitumor drugs, and kinase inhibitors, the tumor immune infiltration status, and the expression levels of specific molecules related to immune checkpoints. Conclusion The prognostic model established with irlncRNA pairs is a promising indicator for prognosis prediction in CRC patients.
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Affiliation(s)
- Chao Ma
- Medical School of Chinese PLA, Beijing, China.,Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xin Zhang
- State Key Laboratory of Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xudong Zhao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Nan Zhang
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Sixin Zhou
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yonghui Zhang
- Medical School of Chinese PLA, Beijing, China.,Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Peiyu Li
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Hosseinkhani N, Derakhshani A, Shadbad MA, Argentiero A, Racanelli V, Kazemi T, Mokhtarzadeh A, Brunetti O, Silvestris N, Baradaran B. The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead. Front Immunol 2021; 12:676181. [PMID: 34093577 PMCID: PMC8172140 DOI: 10.3389/fimmu.2021.676181] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoints (ICs) have pivotal roles in regulating immune responses. The inhibitory ICs in the tumor microenvironment (TME) have been implicated in the immune evasion of tumoral cells. Therefore, identifying and targeting these inhibitory ICs might be critical for eliminating tumoral cells. V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory IC that is expressed on myeloid cells, lymphoid cells, and tumoral cells; therefore, VISTA can substantially regulate innate and adaptive anti-tumoral immune responses. Besides, growing evidence indicates that VISTA blockade can enhance the sensitivity of tumoral cells to conventional IC-based immunotherapy, e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. In this regard, the current study aimed to review the current evidence about the structure and expression pattern of VISTA, its role in TME, the clinicopathological significance of VISTA, and its prognostic values in various cancers. Besides, this review intended to collect the lessons from the recent pre-clinical and clinical studies and propose a strategy to overcome tumor immune-resistance states.
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Affiliation(s)
- Negar Hosseinkhani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Mahdi Abdoli Shadbad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Antonella Argentiero
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Oronzo Brunetti
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Nicola Silvestris
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
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