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Deng RZ, Zheng X, Lu ZL, Yuan M, Meng QC, Wu T, Tian Y. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer. World J Gastrointest Oncol 2024; 16:4354-4368. [PMID: 39554751 PMCID: PMC11551631 DOI: 10.4251/wjgo.v16.i11.4354] [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: 07/23/2024] [Revised: 08/24/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Run-Zhi Deng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Xin Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Zhong-Lei Lu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, Fujian Province, China
| | - Ming Yuan
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Qi-Chang Meng
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Tao Wu
- Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Yu Tian
- Department of Thoracic Surgery, Yancheng No. 1 People’s Hospital, Affiliated Hospital of Nanjing University Medical School, The First People’s Hospital of Yancheng, Yancheng 224000, Jiangsu Province, China
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Orozco-Castaño C, Mejia-Garcia A, Zambrano Y, Combita AL, Parra-Medina R, Bonilla DA, González A, Odriozola A. Construction of an immune gene expression meta signature to assess the prognostic risk of colorectal cancer patients. ADVANCES IN GENETICS 2024; 112:207-254. [PMID: 39396837 DOI: 10.1016/bs.adgen.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Despite recent advancements in colorectal cancer (CRC) treatment, particularly with the introduction of immunotherapy and checkpoint inhibitors, the efficacy of these therapies remains limited to a subset of patients. To address this challenge, our study aimed to develop a prognostic biomarker based on immune-related genes to predict better outcomes in CRC patients and aid in treatment decision-making. We comprehensively analysed immune gene expression signatures associated with CRC prognosis to construct an immune meta-signature with prognostic potential. Utilising data from The Cancer Genome Atlas (TCGA), we employed Cox regression to identify immune-related genes with prognostic significance from multiple studies. Subsequently, we compared the expression levels of immune genes, levels of immune cell infiltration, and various immune-related molecules between high-risk and low-risk patient groups. Functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses provided insights into the biological pathways associated with the identified prognostic genes. Finally, we validated our findings using a separate CRC cohort from the Gene Expression Omnibus (GEO). Integration of the prognostic genes revealed significant disparities in survival outcomes. Differential expression analysis identified a set of immune-associated genes, which were further refined using LASSO penalisation and Cox regression. Univariate Cox regression analyses confirmed the autonomy of the gene signature as a prognostic indicator for CRC patient survival. Our risk prediction model effectively stratified CRC patients based on their prognosis, with the high-risk group showing enrichment in pro-oncogenic terms and pathways. Immune infiltration analysis revealed an augmented presence of certain immunosuppressive subsets in the high-risk group. Finally, we validated the performance of our prognostic model by applying the risk score equation to a different CRC patient dataset, confirming its prognostic potential in this new cohort. Overall, our study presents a novel immune-related gene signature with promising implications for predicting cancer progression and prognosis, thereby enabling more personalised management strategies for CRC patients.
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Affiliation(s)
- Carlos Orozco-Castaño
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Grupo de Apoyo y Seguimiento para la Investigación GASPI, Instituto Nacional de Cancerología (INC), Bogotá, Colombia.
| | - Alejandro Mejia-Garcia
- Department of Human Genetics, McGill University, Montreal, QC, Canada, McGill University, Genome Centre, Montreal, QC, Canada
| | - Yina Zambrano
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia
| | - Alba Lucia Combita
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Grupo de Apoyo y Seguimiento para la Investigación GASPI, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Departamento de Microbiología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Rafael Parra-Medina
- Research Institute, Fundación Universitaria de Ciencias de la Salud-FUCS, Bogotá, Colombia; Department of Pathology, Instituto Nacional de Cancerología, Electronic address, Bogotá, Colombia
| | - Diego A Bonilla
- Research Division, Dynamical Business & Science Society - DBSS International SAS, Bogotá, Colombia; Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrián Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Kim J, Pena JV, McQueen HP, Kong L, Michael D, Lomashvili EM, Cook PR. Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA. Cancer Gene Ther 2024; 31:28-42. [PMID: 37990062 DOI: 10.1038/s41417-023-00678-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 08/22/2023] [Accepted: 10/11/2023] [Indexed: 11/23/2023]
Abstract
Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress anti-tumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This finding was unexpected given previous reports that type I interferon alpha (IFN-α) inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with type I interferon beta (IFN-β) upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), a hub adaptor protein through which multiple dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has also been associated with multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This finding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells.
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Affiliation(s)
- Jihyun Kim
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Jocelyn V Pena
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Hannah P McQueen
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Lingwei Kong
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Dina Michael
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Elmira M Lomashvili
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Pamela R Cook
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA.
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Che R, Wang Q, Li M, Shen J, Ji J. Quantitative Proteomics of Tissue-Infiltrating T Cells From CRC Patients Identified Lipocalin-2 Induces T-Cell Apoptosis and Promotes Tumor Cell Proliferation by Iron Efflux. Mol Cell Proteomics 2024; 23:100691. [PMID: 38072118 PMCID: PMC10792491 DOI: 10.1016/j.mcpro.2023.100691] [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: 04/25/2023] [Revised: 09/25/2023] [Accepted: 12/07/2023] [Indexed: 01/02/2024] Open
Abstract
T cells play the most pivotal roles in antitumor immunity; the T-cell proteome and the differentially expressed proteins in the tumor immune microenvironment have rarely been identified directly from the clinical samples, especially for tumors that lack effective immunotherapy targets, such as colorectal cancer (CRC). In this study, we analyzed the protein expression pattern of the infiltrating T cells isolated from CRC patients using quantitative proteomics. CD4+ and CD8+ T cells were isolated from clinical samples and labeled by tandem mass tag reagents, and the differentially expressed proteins were quantified by mass spectrometry. The T-cell proteome profiling revealed dysfunctions in these tumor-infiltrating T cells. Specifically, antitumor immunity was suppressed because of differentially expressed metal ion transporters and immunity regulators. For the first time, lipocalin-2 (LCN2) was shown to be significantly upregulated in CD4+ T cells. Quantitative proteomic analysis of LCN2-overexpressed Jurkat cells showed that LCN2 damaged T cells by changes in iron transport. LCN2 induced T-cell apoptosis by reducing cellular iron concentration; moreover, the iron that was transported to the tumor microenvironment aided tumor cell proliferation, promoting tumor development. Meanwhile, LCN2 also influenced tumor progression through immune cytokines and cholesterol metabolism. Our results demonstrated that LCN2 has immunosuppressive functions that can promote tumor development; therefore, it is a potential immunotherapy target for CRC.
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Affiliation(s)
- Rui Che
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Qingsong Wang
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
| | - Minzhe Li
- General Surgery Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jian Shen
- General Surgery Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
| | - Jianguo Ji
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
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Hajebi Khaniki S, Shokoohi F, Esmaily H, Kerachian MA. Analyzing aberrant DNA methylation in colorectal cancer uncovered intangible heterogeneity of gene effects in the survival time of patients. Sci Rep 2023; 13:22104. [PMID: 38092774 PMCID: PMC10719305 DOI: 10.1038/s41598-023-47377-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 11/13/2023] [Indexed: 12/17/2023] Open
Abstract
Colorectal cancer (CRC) involves epigenetic alterations. Irregular gene-methylation alteration causes and advances CRC tumor growth. Detecting differentially methylated genes (DMGs) in CRC and patient survival time paves the way to early cancer detection and prognosis. However, CRC data including survival times are heterogeneous. Almost all studies tend to ignore the heterogeneity of DMG effects on survival. To this end, we utilized a sparse estimation method in the finite mixture of accelerated failure time (AFT) regression models to capture such heterogeneity. We analyzed a dataset of CRC and normal colon tissues and identified 3406 DMGs. Analysis of overlapped DMGs with several Gene Expression Omnibus datasets led to 917 hypo- and 654 hyper-methylated DMGs. CRC pathways were revealed via gene ontology enrichment. Hub genes were selected based on Protein-Protein-Interaction network including SEMA7A, GATA4, LHX2, SOST, and CTLA4, regulating the Wnt signaling pathway. The relationship between identified DMGs/hub genes and patient survival time uncovered a two-component mixture of AFT regression model. The genes NMNAT2, ZFP42, NPAS2, MYLK3, NUDT13, KIRREL3, and FKBP6 and hub genes SOST, NFATC1, and TLE4 were associated with survival time in the most aggressive form of the disease that can serve as potential diagnostic targets for early CRC detection.
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Affiliation(s)
- Saeedeh Hajebi Khaniki
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV, 89154, USA
| | - Farhad Shokoohi
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV, 89154, USA.
| | - Habibollah Esmaily
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Li M, Song J, Wang L, Wang Q, Huang Q, Mo D. Natural killer cell-related prognosis signature predicts immune response in colon cancer patients. Front Pharmacol 2023; 14:1253169. [PMID: 38026928 PMCID: PMC10679416 DOI: 10.3389/fphar.2023.1253169] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Background: Natural killer (NK) cells are crucial components of the innate immune system that fight tumors and viral infections. Patients with colorectal cancer (CRC) have a poor prognosis, and immunotherapeutic tools play a key role in the treatment of CRC. Methods: Public data on CRC patients was collected from the TCGA and the GEO databases. Tissue data of CRC patients were collected from Guangxi Medical University Affiliated Cancer Hospital. An NK-related prognostic model was developed by the least absolute shrinkage and selection operator (LASSO) and Cox regression method. Validation data were collected from different clinical subgroups and an external independent validation cohort to verify the model's accuracy. In addition, multiple external independent immunotherapy datasets were collected to further examine the value of NK-related risk scores (NKRS) in the prediction of immunotherapy response. Potential biological functions of key genes were examined by methods of cell proliferation, apoptosis and Western blotting. Results: A novel prognostic model for CRC patients based on NK-related genes was developed and NKRS was generated. There was a significantly poorer prognosis among the high-NKRS group. Based on immune response prediction, patients with low NKRS may be more suitable for immunotherapy and they are more sensitive to immunotherapy. The proliferation rate of CRC cells was significantly reduced and apoptosis of CRC cells was increased after SLC2A3 was knocked down. SLC2A3 was also found to be associated with the TGF-β signaling pathway. Conclusion: NKRS has potential applications for predicting prognostic status and response to immunotherapy in CRC patients. SLC2A3 has potential as a therapeutic target for CRC.
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Affiliation(s)
- Meiqin Li
- Department of Clinical Laboratory, Guang Xi Medical University Cancer Hospital, Nanning, China
| | - Jingqing Song
- Department of Gastrointestinal Surgery, Guang Xi Medical University Cancer Hospital, Nanning, China
| | - Lin Wang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Qi Wang
- Department of Basic Medicine, Guangxi Health Science College, Nanning, China
| | - Qinghua Huang
- Department of Breast Surgery, Wuzhou Red Cross Hospital, Wuzhou, China
| | - Dan Mo
- Department of Breast, Maternal and Child Healthcare Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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Xiao Y, Jiang C, Li H, Xu D, Liu J, Huili Y, Nie S, Guan X, Cao F. Genes associated with inflammation for prognosis prediction for clear cell renal cell carcinoma: a multi-database analysis. Transl Cancer Res 2023; 12:2629-2645. [PMID: 37969384 PMCID: PMC10643973 DOI: 10.21037/tcr-23-1183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/19/2023] [Indexed: 11/17/2023]
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is the largest subtype of kidney tumour, with inflammatory responses characterising all stages of the tumour. Establishing the relationship between the genes related to inflammatory responses and ccRCC may help the diagnosis and treatment of patients with ccRCC. Methods First, we obtained the data for this study from a public database. After differential analysis and Cox regression analysis, we obtained the genes for the establishment of a prognostic model for ccRCC. As we used data from multiple databases, we standardized all the data using the surrogate variable analysis (SVA) package to make the data from different sources comparable. Next, we used a least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model of genes related to inflammation. The data used for modelling and internal validation came from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) series (GSE29609) databases. ccRCC data from the International Cancer Genome Consortium (ICGC) database were used for external validation. Tumour data from the E-MTAB-1980 cohort were used for external validation. The GSE40453 and GSE53757 datasets were used to verify the differential expression of inflammation-related gene model signatures (IRGMS). The immunohistochemistry of IRGMS was queried through the Human Protein Atlas (HPA) database. After the adequate validation of the IRGM, we further explored its application by constructing nomograms, pathway enrichment analysis, immunocorrelation analysis, drug susceptibility analysis, and subtype identification. Results The IRGM can robustly predict the prognosis of samples from patients with ccRCC from different databases. The verification results show that nomogram can accurately predict the survival rate of patients. Pathway enrichment analysis showed that patients in the high-risk (HR) group were associated with a variety of tumorigenesis biological processes. Immune-related analysis and drug susceptibility analysis suggested that patients with higher IRGM scores had more treatment options. Conclusions The IRGMS can effectively predict the prognosis of ccRCC. Patients with higher IRGM scores may be better candidates for treatment with immune checkpoint inhibitors and have more chemotherapy options.
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Affiliation(s)
- Yonggui Xiao
- School of Clinical Medicine, Affiliated Hospital, North China University of Science and Technology, Tangshan, China
| | - Chonghao Jiang
- Department of Urology, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Hubo Li
- School of Clinical Medicine, Affiliated Hospital, North China University of Science and Technology, Tangshan, China
| | - Danping Xu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinzheng Liu
- School of Clinical Medicine, Affiliated Hospital, North China University of Science and Technology, Tangshan, China
| | - Youlong Huili
- School of Clinical Medicine, Affiliated Hospital, North China University of Science and Technology, Tangshan, China
| | - Shiwen Nie
- School of Clinical Medicine, Affiliated Hospital, North China University of Science and Technology, Tangshan, China
| | - Xiaohai Guan
- Department of Urology, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Fenghong Cao
- Department of Urology, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
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Huang L, Sha Y, Liang W, Mo C, Li C, Deng Y, Gong W, Hou X, Ou M. High-throughput sequencing reveals Jatrorrhizine inhibits colorectal cancer growth by ferroptosis-related genes. BMC Med Genomics 2023; 16:217. [PMID: 37710311 PMCID: PMC10500743 DOI: 10.1186/s12920-023-01619-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/30/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND Colorectal cancer is a malignant tumor that poses a serious threat to human health. The main objective of this study is to investigate the mechanism by which Jatrorrhizine (JAT), a root extract from Stephania Epigaea Lo, exerts its anticancer effects in colorectal cancer. METHODS We initially assessed the inhibitory properties of JAT on SW480 cells using MTT and cell scratch assays. Flow cytometry was employed to detect cell apoptosis. Differentially expressed genes were identified through high-throughput sequencing, and they were subjected to functional enrichment and signaling pathway analysis and PPI network construction. RT-qPCR was used to evaluate gene expression and identify critical differentially expressed genes. Finally, the function and role of differentially expressed genes produced by JAT-treated SW480 cells in colorectal cancer will be further analyzed using the TCGA database. RESULTS Our study demonstrated that JAT exhibits inhibitory effects on SW480 cells at concentrations of 12.5µM, 25µM, 50µM, and 75µM without inducing cell apoptosis. Through high-throughput sequencing, we identified 244 differentially expressed genes. KEGG and GO analysis of high-throughput sequencing results showed that differentially expressed genes were significantly enriched in MAPK, Wnt, and P53 signaling pathways. Notably, JAT significantly altered the expression of genes associated with ferroptosis. Subsequent RT-qPCR showed that the expression of ferroptosis genes SLC2A3 and ASNS was significantly lower in JAT-treated SW480 cells than in the control group. Analysis by TCGA data also showed that ferroptosis genes SLC2A3 and ASNS were significantly highly expressed in COAD. The prognosis of SLC2A3 was significantly worse in COAD compared to the normal group. SLC2A3 may be a core target of JAT for the treatment of COAD. CONCLUSIONS JAT can inhibit COAD growth by ferroptosis-related genes. And it is a potential natural substance for the treatment of COAD.
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Affiliation(s)
- Lingyu Huang
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
- Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection, College of Life Science, Ministry of Education of China, Guangxi Normal University, Guilin, 541000 China
| | - Yu Sha
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Wenken Liang
- Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection, College of Life Science, Ministry of Education of China, Guangxi Normal University, Guilin, 541000 China
| | - Chune Mo
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Chunhong Li
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Yecheng Deng
- Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection, College of Life Science, Ministry of Education of China, Guangxi Normal University, Guilin, 541000 China
| | - Weiwei Gong
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Xianliang Hou
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
| | - Minglin Ou
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541000 China
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Chen M, Zhang Q, Xu F, Li Z, Li J, Wang W, Wang S, Wang M, Qiu T, Li J, Zhang H, Wang W. Ti 3C 2 and Ti 2C MXene materials for high-performance isolation of extracellular vesicles via coprecipitation. Anal Chim Acta 2023; 1269:341426. [PMID: 37290854 DOI: 10.1016/j.aca.2023.341426] [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: 12/28/2022] [Revised: 04/28/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023]
Abstract
Two-dimensional (2D) materials such as MXenes, are usually well utilized in the field of catalysts and battery due to their good hydrophilicity and diversified surface terminals. However, their potential applications in the treatment of biological samples have not been widely concerned. Extracellular vesicles (EVs) contain unique molecular signatures and could be used as biomarkers for the detection of severe diseases such as cancer, as well as monitoring the therapeutic response. In this work, two kinds of MXene materials (Ti3C2 and Ti2C) were successfully synthesized and employed in the isolation of EVs from the biological samples by taking advantage of the affinity interaction between the titanium (Ti) in MXenes and the phospholipid membrane of EVs. Compared with Ti2C MXene materials, TiO2 beads and the other EVs isolation methods, Ti3C2 MXene materials exhibited excellent isolation performance via the coprecipitation with EVs due to the abundant unsaturated coordination of Ti2+/Ti3+, and the dosage of materials was the lowest. Meanwhile, the whole isolation process could be done within 30 min and integrated well with the following analysis of proteins and ribonucleic acids (RNAs), which was also convenient and economic. Furthermore, the Ti3C2 MXene materials were used to isolate the EVs from the blood plasma of colorectal cancer (CRC) patients and healthy donors. Proteomics analysis of EVs showed that 67 proteins were up-regulated, in which most of them were closely related to CRC progression. These findings indicate that the MXene material-based EVs isolation method via coprecipitation provides an efficient tool for early diagnosis of diseases.
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Affiliation(s)
- Mengxi Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Qi Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Fang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Zhi Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Jiaxi Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Wenjing Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Shuang Wang
- Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou, 450001, China
| | - Mengmeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Tian Qiu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Jiawei Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Haiyang Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
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Xu Y, Wang D, Zhao G. Potassium voltage‑gated channel subfamily E member 4 facilitates the malignant progression of colon cancer by enhancing EGF containing fibulin extracellular matrix protein 2 expression. Exp Ther Med 2023; 26:392. [PMID: 37456174 PMCID: PMC10347171 DOI: 10.3892/etm.2023.12091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/28/2023] [Indexed: 07/18/2023] Open
Abstract
Colon cancer is a highly invasive and metastatic cancer with a poor prognosis. The University of Alabama at Birmingham Cancer data analysis portal (UALCAN) database indicates that potassium voltage-gated channel subfamily E member 4 (KCNE4) is highly expressed in colon cancer tissues. UALCAN data also show that KCNE4 expression is positively associated with individual cancer stages and negatively associated with patient survival. Therefore, the aim of the current study was to elucidate the functional role of KCNE4 in the biological behaviors of colon cancer cells and to investigate the underlying molecular mechanism. The gene EGF containing fibulin extracellular matrix protein 2 (EFEMP2) was found to be positively correlated with KCNE4 in colon cancer based on analysis performed using the LinkedOmics database; notably, upregulated EFEMP2 expression has been reported to be closely associated with the malignant phenotypes of colon cancer cells. The differences in the expression levels of KCNE4 and EFEMP2 between human colon cancer and normal colonic mucosa cell lines were assessed via reverse transcription-quantitative PCR and western blot assays. In addition, the proliferation, migration and invasion of colon cancer cells were determined using Cell Counting kit-8, colony formation, would healing and Transwell assays, and a co-immunoprecipitation assay was performed to confirm the interaction between KCNE4 and EFEMP2. The results of the study demonstrated that KCNE4 and EFEMP2 are markedly upregulated in colon cancer cells. In addition, KCNE4 interacted with and bound to EFEMP2. The suppressive effects of KCNE4 knockdown on the proliferation, colony formation, migration and invasion of colon cancer cells were attenuated by EFEMP2 overexpression. On the basis of these findings, it may be concluded that KCNE4 acts as an oncogene in colon cancer via the promotion of EFEMP2 expression.
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Affiliation(s)
- Yujie Xu
- Department of Gastrointestinal Surgery, Haikou People's Hospital, Haikou, Hainan 570208, P.R. China
| | - Dingmao Wang
- Department of Gastrointestinal Surgery, Haikou People's Hospital, Haikou, Hainan 570208, P.R. China
| | - Guodong Zhao
- Department of Gastrointestinal Surgery, Haikou People's Hospital, Haikou, Hainan 570208, P.R. China
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11
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KCNE4 expression is correlated with the pathological characteristics of colorectal cancer patients and associated with the radioresistance of cancer cells. Pathol Res Pract 2023; 241:154234. [PMID: 36459833 DOI: 10.1016/j.prp.2022.154234] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is a common malignancy, and radioresistance limits the effectiveness of radiotherapy for rectal cancer. This study is performed to investigate the role and regulatory mechanism of Potassium Voltage-Gated Channel Subfamily E Regulatory Subunit 4 (KCNE4) in the radioresistance of CRC cells. METHODS Immunohistochemical staining results of KCNE4 in normal tissues and CRC tissues were obtained from the Human Protein Atlas (HPA) database. The UALCAN database was used for analyzing KCNE4 mRNA expression in normal tissue samples and CRC tissue samples and its relationship with tumor stage. The relationship of KCNE4 expression with prognosis was analyzed utilizing the data of GEPIA database. LinkedOmics database was searched to analyze the co-expressed gene sets of KCNE4 in CRC, and to analyze the signaling pathways related with KCNE4 in CRC. GO and KEGG enrichment analyses were carried out on the co-expressed genes of KCNE4 with DAVID database. Ionizing radiation (IR)-resistant cell lines (HCT116/IR and HT29/IR) were established; cell viability was assessed via cell counting kit-8 (CCK-8) and EdU assays, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was performed for detecting cell apoptosis. Western blotting was carried out to detect the expressions of p-p85 and p-AKT. RESULTS KCNE4 was highly expressed in CRC tissues and linked to advanced tumor stage, lymph node metastasis and poor prognosis of CRC patients. KCNE4 overexpression promoted HCT116/IR cell proliferation and inhibited the apoptosis, while KCNE4 knockdown suppressed HT29/IR cell proliferation and facilitated the apoptosis. Furthermore, high KCNE4 expression was associated with the activation of the PI3K/AKT signal pathway. CONCLUSION KCNE4 is associated with the clinicopathological characteristics of CRC patients, and its high expression level contributes to the radioresistance of cancer cells via activating the PI3K/AKT signal pathway.
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12
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Comprehensive Analysis of the Role of SLC2A3 on Prognosis and Immune Infiltration in Head and Neck Squamous Cell Carcinoma. Anal Cell Pathol (Amst) 2022; 2022:2371057. [PMID: 36247875 PMCID: PMC9553684 DOI: 10.1155/2022/2371057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/01/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
Background. SLC2A3 is upregulated in various cancer types and promotes proliferation, invasion, and metabolism. However, its role in the prognosis and immune regulation of head and neck squamous cell carcinoma (HNSCC) is still obscure. This study is aimed at exploring the prognostic and immunotherapeutic potential of SLC2A3 in HNSCC. Methods. All data were downloaded from TCGA database and integrated via R software. SLC2A3 expression was evaluated using R software, TIMER, CPTAC, and HPA databases. The association between SLC2A3 expression and clinicopathologic characteristics was assessed by R software. The effect of SLC2A3 on survival was analyzed by R software and Kaplan-Meier Plotter. Genomic alterations in SLC2A3 were investigated using the cBioPortal database. Coexpression of SLC2A3 was studied using LinkedOmics and STRING, and enrichment analyses were performed with R software. The relationship between SLC2A3 expression and immune infiltration was determined using TIMER and TISIDB databases. Immune checkpoints and ESTIMATE score were analyzed via the SangerBox database. Results. SLC2A3 expression was upregulated in HNSCC tissues compared to normal tissues. It was significantly related to TNM stage, histological grade, and alcohol history. High SLC2A3 expression was associated with poor prognosis in HNSCC. Coexpression analysis indicated that SLC2A3 mostly participated in the HIF-1 signaling pathway and glycolysis. Furthermore, SLC2A3 expression strongly correlated with tumor-infiltrating lymphocytes in HNSCC. Conclusion. SLC2A3 could serve as a potential prognostic biomarker for tumor immune infiltration in HNSCC.
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13
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Siddhuraj P, Jönsson J, Alyamani M, Prabhala P, Magnusson M, Lindstedt S, Erjefält JS. Dynamically upregulated mast cell CPA3 patterns in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Front Immunol 2022; 13:924244. [PMID: 35983043 PMCID: PMC9378779 DOI: 10.3389/fimmu.2022.924244] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundThe mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown.MethodsUsing a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF).ResultsMast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p < 0.001, pulmonary vessels p < 0.01, and alveolar parenchyma p < 0.01) compared to controls, while granule-stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both mast cell density, CPA3 mRNA (p < 0.001) and protein (p < 0.05), in the fibrotic alveolar tissue. Spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Elevated CPA3 mRNA also correlated to lung tissue eosinophils, CD3 T cells, and declined lung function. Single-cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers.ConclusionThis study shows that lung tissue mast cell populations in COPD and IPF lungs have spatially complex and markedly upregulated CPA3 expression profiles that correlate with immunopathological alterations and lung function. Given the proposed roles of CPA3 in tissue homeostasis, remodeling, and inflammation, these alterations are likely to have clinical consequences.
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Affiliation(s)
- Premkumar Siddhuraj
- Unit of Airway Inflammation, Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | | | - Manar Alyamani
- Unit of Airway Inflammation, Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | - Pavan Prabhala
- Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Mattias Magnusson
- Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sandra Lindstedt
- Department of Thoracic Surgery, Lund University Skane University Hospital, Lund, Sweden
| | - Jonas S. Erjefält
- Unit of Airway Inflammation, Department of Experimental Medical Sciences, Lund University, Lund, Sweden
- Department of Allergology and Respiratory Medicine, Lund University, Skane University Hospital, Lund, Sweden
- *Correspondence: Jonas S. Erjefält,
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14
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Li J, Han T, Wang X, Wang Y, Chen X, Chen W, Yang Q. Construction of a Novel Immune-Related mRNA Signature to Predict the Prognosis and Immune Characteristics of Human Colorectal Cancer. Front Genet 2022; 13:851373. [PMID: 35401707 PMCID: PMC8984163 DOI: 10.3389/fgene.2022.851373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 03/02/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Anti-cancer immunotherapeutic approaches have gained significant efficacy in multiple cancer types. However, not all patients with colorectal cancer (CRC) could benefit from immunotherapy due to tumor heterogeneity. The purpose of this study was to construct an immune-related signature for predicting the immune characteristics and prognosis of CRC. Methods: RNA-sequencing data and corresponding clinical information of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and immune-related genes (IRGs) were downloaded from the Immunology Database and Analysis Portal (ImmPort). Then, we utilized univariate, lasso regression, and multivariate cox regression to identify prognostic IRGs and develop the immune-related signature. Subsequently, a nomogram was established based on the signature and other prognostic factors, and its predictive capacity was assessed by receiver operating characteristic (ROC) and decision curve analysis (DCA). Finally, associations between the signature and the immune characteristics of CRC were assessed. Results: In total, 472 samples downloaded from TCGA were divided into the training cohort (236 samples) and internal validation cohort (236 samples), and the GEO cohort was downloaded as an external validation cohort (122 samples). A total of 476 differently expressed IRGs were identified, 17 of which were significantly correlated to the prognosis of CRC patients. Finally, 10 IRGs were filtered out to construct the risk score signature, and patients were divided into low- and high-risk groups according to the median of risk scores in the training cohort. The high-risk score was significantly correlated with unfavorable survival outcomes and aggressive clinicopathological characteristics in CRC patients, and the results were further confirmed in the internal validation cohort, entire TCGA cohort, and external validation cohort. Immune infiltration analysis revealed that patients in the low-risk group infiltrated with high tumor-infiltrating immune cell (TIIC) abundances compared to the high-risk group. Moreover, we also found that the immune checkpoint biomarkers were significantly overexpressed in the low-risk group. Conclusion: The prognostic signature established by IRGs showed a promising clinical value for predicting the prognosis and immune characteristics of human CRC, which contribute to individualized treatment decisions.
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15
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Atiakshin DA, Kostin AA, Trotsenko ID, Shishkina VV, Tiemann M, Buchwalow IB. Carboxypeptidase A3 in the structure of the protease phenotype of mast cells: cytophysiological aspects. RUDN JOURNAL OF MEDICINE 2022. [DOI: 10.22363/2313-0245-2022-26-1-9-32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Carboxypeptidase A3 (CPA3) is a specific protease of mast cells (MC) with variable expression and appears to be one of the preformed components of the secretome. CPA3 is involved in regulation of the state of a specifi tissue microenvironment and components of the integrative-buffer metabolic environment in adaptive and pathological processes; it affects implementation of the innate immunity, mechanisms of angiogenesis, processes of the extracellular matrix remodeling, etc. CPA3 identification using protocols of multiplex immunohistochemistry allows specifying details of the organ-specific mast cell population features, including the protease phenotype, mechanisms of biogenesis with cyto- and histotopographic criteria, and features of secretory pathways. Numerous biological effects of CPA3, including participation in the regulation of the pulmonary parenchyma and systemic blood flow, in biogenesis and remodeling of the fibrous component of the extracellular matrix, in epigenetic reprogramming, determine the importance of fundamental investigation of the biological activity and regulation of pathological processes of CPA3. Further studies will contribute to the detection of the true value of the mast cell CPA3 expression features as a prognostic factor and a promising molecular target for treatment of socially significant diseases.
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16
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Atiakshin D, Kostin A, Trotsenko I, Samoilova V, Buchwalow I, Tiemann M. Carboxypeptidase A3—A Key Component of the Protease Phenotype of Mast Cells. Cells 2022; 11:cells11030570. [PMID: 35159379 PMCID: PMC8834431 DOI: 10.3390/cells11030570] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 11/16/2022] Open
Abstract
Carboxypeptidase A3 (CPA3) is a specific mast cell (MC) protease with variable expression. This protease is one of the preformed components of the secretome. During maturation of granules, CPA3 becomes an active enzyme with a characteristic localization determining the features of the cytological and ultrastructural phenotype of MC. CPA3 takes part in the regulation of a specific tissue microenvironment, affecting the implementation of innate immunity, the mechanisms of angiogenesis, the processes of remodeling of the extracellular matrix, etc. Characterization of CPA3 expression in MC can be used to refine the MC classification, help in a prognosis, and increase the effectiveness of targeted therapy.
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Affiliation(s)
- Dmitri Atiakshin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, 117198 Moscow, Russia; (D.A.); (A.K.); (I.T.)
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, Studencheskaya Str. 10, 394036 Voronezh, Russia
| | - Andrey Kostin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, 117198 Moscow, Russia; (D.A.); (A.K.); (I.T.)
| | - Ivan Trotsenko
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, 117198 Moscow, Russia; (D.A.); (A.K.); (I.T.)
| | - Vera Samoilova
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany; (V.S.); (M.T.)
| | - Igor Buchwalow
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, 117198 Moscow, Russia; (D.A.); (A.K.); (I.T.)
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany; (V.S.); (M.T.)
- Correspondence: ; Tel.: +49-(040)-7070-85317; Fax: +49-(040)-7070-85110
| | - Markus Tiemann
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany; (V.S.); (M.T.)
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17
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Guo T, Wang Z, Liu Y. Establishment and verification of a prognostic tumor microenvironment-based and immune-related gene signature in colon cancer. J Gastrointest Oncol 2021; 12:2172-2191. [PMID: 34790383 DOI: 10.21037/jgo-21-522] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/16/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastrointestinal malignant cancers affect many sites in the intestinal tract, including the colon. In this study, we purposed to improve prognostic predictions for colon cancer (CC) patients by establishing a novel biosignature of immune-related genes (IRGs) based on the tumor microenvironment (TME). Methods Using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, we calculated the stromal and immune scores of every CC patient extracted from The Cancer Genome Atlas (TCGA). We then identified 4 immune-related messenger RNA (mRNA) biosignatures through a Cox and least absolute shrinkage and selection operator (LASSO) univariate analysis, and a Cox multivariate analysis. Relationships between tumor immune infiltration and the risk score were evaluated through the CIBERSORT algorithm and Tumor Immune Estimation Resource (TIMER) database. Results Our studies showed that individuals who had a high immune score (P=0.017) and low stromal score (P=0.041) had a favorable overall survival (OS) rate. By comparing high/low scores cohort, 220 differentially expressed genes (DEGs) were determined. Then an immune-related four-mRNA biosignature, including PDIA2, NAFTC1, VEGFC, and CD1B was identified. Kaplan-Meier, calibration, and receiver operating characteristic (ROC) curves verified the model's performance. By using univariate and multivariate Cox analyses, we found each biosignature was an independent risk factor for assessing a CC patient's survival. Three external GEO cohorts validated its good efficiency in estimating OS among individuals with CC. Moreover, the signature was also related to infiltration of several cells of the immune system in the tumor microenvironment. Conclusions The resultant model in our study included 4 IRGs associated with the TME. These IRGs can be utilized as an auxiliary variable to estimate and help improve the prognosis of individuals with CC.
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Affiliation(s)
- Tianyu Guo
- Department of Hepatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Zhe Wang
- Department of Gastrointestinal Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yefu Liu
- Department of Hepatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
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18
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Shi J, Bao M, Wang W, Wu X, Li Y, Zhao C, Liu W. Integrated Profiling Identifies PLOD3 as a Potential Prognostic and Immunotherapy Relevant Biomarker in Colorectal Cancer. Front Immunol 2021; 12:722807. [PMID: 34646265 PMCID: PMC8503557 DOI: 10.3389/fimmu.2021.722807] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022] Open
Abstract
Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3) is related to a variety of human diseases. However, its function in Colorectal cancer (CRC) remains uncertain. PLOD3 expression was analyzed using The Cancer Genome Atlas (TCGA) pan-cancer data. DAVID was used for enrichment analysis of PLOD3-related genes. The correlation between PLOD3 expression and immune cell infiltration was evaluated. Four expression profile datasets (GSE17536, GSE39582, GSE74602, and GSE113513) from Gene Expression Omnibus, and two proteomic datasets were used as validation cohorts for assessing the diagnostic and prognostic value of PLOD3 in CRC. What's more, we performed immunohistochemistry (IHC) staining for PLOD3 in 160 paired CRC specimens and corresponding adjacent non-tumor tissues. PLOD3 was highly expressed in many tumors including CRC. PLOD3 was upregulated in advanced stage CRCs, and high PLOD3 expression was associated with poor survival. High PLOD3 expression was associated with low levels of B cells, CD4+ T cells, M1 macrophages, CD8+ T cells, and multiple immunerelated characteristics. In addition, the high PLOD3 expression group had a higher TIDE score and a lower tumor mutation burden and microsatellite instability, indicating that patients with high PLOD3 expression may be resistant to immunotherapy. Additional datasets and IHC analysis were used to validate the diagnostic and prognostic value of PLOD3 at the mRNA and protein levels in CRC. Patients with non-response to immunotherapy showed increased PLOD3 expression in an immunotherapy treated dataset. PLOD3 is a potential biomarker for CRC diagnosis and prognosis prediction. CRCs with high PLOD3 expression may be resistant to immune checkpoint therapy.
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Affiliation(s)
- Junhong Shi
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Meiyu Bao
- Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Weifeng Wang
- Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Xuan Wu
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yueying Li
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changdong Zhao
- Department of Gastroenterology, Second People's Hospital of Lianyungang City, Lianyungang, China
| | - Weiwei Liu
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
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19
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Broholm M, Degett TH, Furbo S, Fiehn AMK, Bulut M, Litman T, Eriksen JO, Troelsen JT, Gjerdrum LMR, Gögenur I. Colonic Stent as Bridge to Surgery for Malignant Obstruction Induces Gene Expressional Changes Associated with a More Aggressive Tumor Phenotype. Ann Surg Oncol 2021; 28:8519-8531. [PMID: 34467497 DOI: 10.1245/s10434-021-10226-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/25/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Colonic stent is recommended as a bridge to elective surgery for malignant obstruction to improve short-term clinical outcomes for patients with colorectal cancer. However, since the oncological outcomes remain controversial, this study aimed to investigate the impact of self-expandable metallic stent (SEMS) on the tumor microenvironment. METHODS Patients treated with colonic stent as a bridge to surgery from 2010 to 2015 were identified from hospital records. Tumor biopsies and resected tumor samples of the eligible patients were retrieved retrospectively. Gene expression analysis was performed using the NanoString nCounter PanCancer IO 360 gene expression panel. RESULTS Of the 164 patients identified, this study included 21 who underwent colonic stent placement as a bridge to elective surgery. Gene expression analysis revealed 82 differentially expressed genes between pre- and post-intervention specimens, of which 72 were upregulated and 10 downregulated. Among the significantly upregulated genes, 46 are known to have protumor functions, of which 26 are specifically known to induce tumorigenic mechanisms such as proliferation, migration, invasion, angiogenesis, and inflammation. In addition, ten differentially expressed genes were identified that are known to promote antitumor functions. CONCLUSION SEMS induces gene expressional changes in the tumor microenvironment that are associated with tumor progression in colorectal cancer and may potentiate a more aggressive phenotype. Future studies are warranted to establish optimal timing of surgery after SEMS insertion in patients with obstructive colorectal cancer.
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Affiliation(s)
- Malene Broholm
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark. .,Department of Science and Environment, Roskilde University, Roskilde, Denmark.
| | - Thea Helene Degett
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
| | - Sara Furbo
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
| | - Anne-Marie Kanstrup Fiehn
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark.,Department of Pathology, Zealand University Hospital, Køge, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Mustafa Bulut
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Litman
- Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jens Ole Eriksen
- Department of Pathology, Zealand University Hospital, Køge, Denmark
| | - Jesper T Troelsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Lise Mette Rahbek Gjerdrum
- Department of Pathology, Zealand University Hospital, Køge, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Siddhuraj P, Clausson CM, Sanden C, Alyamani M, Kadivar M, Marsal J, Wallengren J, Bjermer L, Erjefält JS. Lung Mast Cells Have a High Constitutive Expression of Carboxypeptidase A3 mRNA That Is Independent from Granule-Stored CPA3. Cells 2021; 10:cells10020309. [PMID: 33546258 PMCID: PMC7913381 DOI: 10.3390/cells10020309] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 12/12/2022] Open
Abstract
The mast cell granule metalloprotease CPA3 is proposed to have important tissue homeostatic functions. However, the basal CPA3 mRNA and protein expression among mast cell populations has remained poorly investigated. Using a novel histology-based methodology that yields quantitative data on mRNA and protein expression at a single-cell level, the present study maps CPA3 mRNA and protein throughout the MCT and MCTC populations in healthy skin, gut and lung tissues. MCTC cells had both a higher frequency of CPA3 protein-containing cells and a higher protein-staining intensity than the MCT population. Among the tissues, skin MCs had highest CPA3 protein intensity. The expression pattern at the mRNA level was reversed. Lung mast cells had the highest mean CPA3 mRNA staining. Intriguingly, the large alveolar MCT population, that lack CPA3 protein, had uniquely high CPA3 mRNA intensity. A broader multi-tissue RNA analysis confirmed the uniquely high CPA3 mRNA quantities in the lung and corroborated the dissociation between chymase and CPA3 at the mRNA level. Taken together, our novel data suggest a hitherto underestimated contribution of mucosal-like MCT to baseline CPA3 mRNA production. The functional consequence of this high constitutive expression now reveals an important area for further research.
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Affiliation(s)
- Premkumar Siddhuraj
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
| | - Carl-Magnus Clausson
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
| | - Caroline Sanden
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
- Medetect AB, Medicon Village, 223 81 Lund, Sweden
| | - Manar Alyamani
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
| | - Mohammad Kadivar
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
| | - Jan Marsal
- Department of Gastroenterology, Lund University, Skane University Hospital, 221 85 Lund, Sweden;
| | - Joanna Wallengren
- Department of Dermatology, Lund University Skane University Hospital, 221 85 Lund, Sweden;
| | - Leif Bjermer
- Department of Allergology and Respiratory Medicine, Lund University, Skane University Hospital, 221 85 Lund, Sweden;
| | - Jonas S. Erjefält
- Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden; (P.S.); (C.-M.C.); (C.S.); (M.A.); (M.K.)
- Department of Allergology and Respiratory Medicine, Lund University, Skane University Hospital, 221 85 Lund, Sweden;
- Correspondence: ; Tel.: +46-462-220-960
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