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Zhang Y, Zhu WL, Wu M, Gao TY, Hu HX, Xu ZY. Using bioinformatics methods to elucidate fatty acid-binding protein 4 as a potential biomarker for colon adenocarcinoma. World J Gastrointest Oncol 2025; 17:103113. [DOI: 10.4251/wjgo.v17.i4.103113] [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: 11/12/2024] [Revised: 01/07/2025] [Accepted: 02/14/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) ranks second in terms of cancer-related deaths. We found that fatty acid-binding protein 4 (FABP4), which is related to cell adhesion and immunity, affects the occurrence and development of COAD. This study focused on the possibility of using FABP4 as a biomarker for COAD and constructed a nomogram for predicting the survival of COAD patients.
AIM To verify the possibility of using FABP4 as a biomarker for COAD.
METHODS A total of 453 COAD tissue samples, along with 41 normal tissue samples, were obtained from The Cancer Genome Atlas database. The difference in FABP4 expression between COAD tissues and normal tissues was analyzed, and the results were verified by immunohistochemistry. The WGCNA algorithm links FABP4 expression with an enrichment analysis and with immune cell infiltration pathways. The biological functions of FABP4 and its coexpressed genes were explored through enrichment analyses. The ESTIMATE, CIBERSORT and ssGSEA methods were used for the immune infiltration analysis. Finally, risk scores were calculated by a Cox analysis. A nomogram was constructed by combining risk scores with routine clinicopathological factors. We assessed the accuracy of survival predictions based on the C-index. The C-index ranges from 0.5 to 1.0, and in general, a C-index value greater than 0.65 indicates a reasonable estimate. The results were validated using the Gene Expression Omnibus (GEO) database.
RESULTS FABP4 was significantly differentially expressed in COAD. It is a promising auxiliary biomarker for screening and diagnosis. Enrichment analyses suggested that FABP4 may influence the invasion and progression of COAD through cell adhesion. The immunological analysis revealed that FABP4 expression in COAD was significantly positively correlated with immune cell infiltration. Moreover, a nomogram to predict the survival of COAD patients was successfully constructed by integrating the calculated risk scores of 15 candidate genes and routine clinicopathological factors. This nomogram could effectively predict 1-year, 3-year, and 5-year survival (C-index = 0.786) and was verified (C-index = 0.73).
CONCLUSION This study established FABP4 as an effective biomarker for screening, assisting in the diagnosis and determining the prognosis.
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Affiliation(s)
- Yun Zhang
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
| | - Wen-Li Zhu
- Seven Inpatient Ward, The Fourth People's Hospital of Wuhu, Wuhu 241002, Anhui Province, China
| | - Min Wu
- Sixteen Inpatient Ward, The Fourth People's Hospital of Wuhu, Wuhu 241002, Anhui Province, China
| | - Tian-Yuan Gao
- Department of Pathology, The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, Anhui Province, China
| | - Hui-Xian Hu
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
| | - Zheng-Yuan Xu
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
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Owida HA, Abed AY, Altalbawy FMA, H M, Abbot V, Jakhonkulovna SM, Mohammad SI, Vasudevan A, Khalaf RM, Zwamel AH. NLRP3 inflammasome-based therapies by natural products: a new development in the context of cancer therapy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04030-0. [PMID: 40116873 DOI: 10.1007/s00210-025-04030-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/06/2025] [Indexed: 03/23/2025]
Abstract
The leucine-rich repeat containing protein (NLR) canonical inflammasome family includes Nod-like receptor protein 3 (NLRP3). Via the mediation of apoptosis proteins and immunological reactions, it controls the pathogenesis of malignancy. Experimental studies showed a relationship among lymphogenesis, cancer metastasis, and NLRP3 expression. Natural products have also been used as lead-based substances in a number of investigations to speed up the creation of novel, specific NLRP3 inhibitors. Via the mediation of apoptotic proteins and immunological responses, it controls the pathogenesis of malignancy. Moreover, it was recently noted that among human cancers, chemotherapy activates NLRP3. Induction of NLRP3 could encourage the generation of IL-1β and IL-22 to facilitate the propagation of malignancy. Additionally, prior research has demonstrated that the usage of NLRP3 in cancer therapy may result in resistance to drugs. The depletion of NLRP3 could affect the survival of cells. Natural products have been used as lead materials in a number of studies to help generate novel, specific NLRP3 antagonists more quickly. In the present review, we examine the mechanism behind the beneficial effects of the natural substances on the inhibition of cancer growth and progression, with special focus on NLRP3 regulation.
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Affiliation(s)
- Hamza Abu Owida
- Department of Medical Engineering, Faculty of Engineering, Al-Ahliyya Amman University, Amman, 19328, Jordan
| | - Ahmed Yaseen Abed
- Department of Medical Laboratories Techniques, College of Health and Medical Technology, University of Al Maarif, Ramadi, Al Anbar, 31001, Iraq.
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Vikrant Abbot
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, 140307, Punjab, India
| | | | - Suleiman Ibrahim Mohammad
- Electronic Marketing and Social Media, Economic and Administrative Sciences, Zarqa University, Zarqa, Jordan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
| | | | - Ahmed Hussein Zwamel
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Dai H, Zhang X, Zhao Y, Nie J, Hang Z, Huang X, Ma H, Wang L, Li Z, Wu M, Fan J, Jiang K, Luo W, Qin C. ADME gene-driven prognostic model for bladder cancer: a breakthrough in predicting survival and personalized treatment. Hereditas 2025; 162:42. [PMID: 40108724 PMCID: PMC11921678 DOI: 10.1186/s41065-025-00409-4] [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: 01/15/2025] [Accepted: 03/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Genes that participate in the absorption, distribution, metabolism, excretion (ADME) processes occupy a central role in pharmacokinetics. Meanwhile, variability in clinical outcomes and responses to treatment is notable in bladder cancer (BLCA). METHODS Our study utilized expansive datasets from TCGA and the GEO to explore prognostic factors in bladder cancer. Utilizing both univariate Cox regression and the lasso regression techniques, we identified ADME genes critical for patient outcomes. Utilizing genes identified in our study, a model for assessing risk was constructed. The evaluation of this model's predictive precision was conducted using Kaplan-Meier survival curves and assessments based on ROC curves. Furthermore, we devised a predictive nomogram, offering a straightforward visualization of crucial prognostic indicators. To explore the potential factors mediating the differences in outcomes between high and low risk groups, we performed comprehensive analyses including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)-based enrichment analyses, immune infiltration variations, somatic mutation landscapes, and pharmacological sensitivity response assessment etc. Immediately following this, we selected core genes based on the PPI network and explored the prognostic potential of the core genes as well as immune modulation, and pathway activation. And the differential expression was verified by immunohistochemistry and qRT-PCR. Finally we explored the potential of the core genes as pan-cancer biomarkers. RESULTS Our efforts culminated in the establishment of a validated 17-gene ADME-centered risk prediction model, displaying remarkable predictive accuracy for BLCA prognosis. Through separate cox regression analyses, the importance of the model's risk score in forecasting BLCA outcomes was substantiated. Furthermore, a novel nomogram incorporating clinical variables alongside the risk score was introduced. Comprehensive studies established a strong correlation between the risk score and several key indicators: patterns of immune cell infiltration, reactions to immunotherapy, landscape of somatic mutation and profiles of drug sensitivity. We screened the core prognostic gene CYP2C8, explored its role in tumor bioregulation and validated its upregulated expression in bladder cancer. Furthermore, we found that it can serve as a reliable biomarker for pan-cancer. CONCLUSION The risk assessment model formulated in our research stands as a formidable instrument for forecasting BLCA prognosis, while also providing insights into the disease's progression mechanisms and guiding clinical decision-making strategies.
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Affiliation(s)
- Haojie Dai
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xi Zhang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- Department of Urology, The First Affliated Hospital of Nanjing Medical University, Nanjing, China
| | - You Zhao
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Jun Nie
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Zhenyu Hang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Xin Huang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Hongxiang Ma
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Li Wang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Zihao Li
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ming Wu
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Jun Fan
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ke Jiang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China.
| | - Weiping Luo
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China.
| | - Chao Qin
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- Department of Urology, The First Affliated Hospital of Nanjing Medical University, Nanjing, China
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Zhao Y, Ye J, Liang Y, Chen J. SCN3B is an Anti-breast Cancer Molecule with Migration Inhibition Effect. Biochem Genet 2025:10.1007/s10528-025-11059-6. [PMID: 40072811 DOI: 10.1007/s10528-025-11059-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025]
Abstract
Breast cancer is a prevalent and highly heterogeneous malignancy that continues to be a major global health concern. Voltage-gated sodium channels are primarily known for their role in neuronal excitability, but emerging evidence suggests their involvement in the pathogenesis of various cancers, including breast cancer. However, the effect of β-subunits on breast cancer cells is not yet studied. SCN3B, as a modulatory subunit, is of particular interest due to its less understood role in cancer biology. This research comprehensively investigates the clinical associations, diagnostic potential, and functional role of SCN3B in breast cancer, shedding light on its diverse implications from patient outcomes to molecular mechanisms. Our methods included clinical data analysis from The Cancer Genome Atlas (TCGA) breast cancer dataset, diagnostic analysis through ROC curves, differential gene expression analysis, SCN3B expression assessment in cell lines, overexpression experiments, and functional assays. Additionally, we constructed a protein-protein interaction network to explore potential mechanisms underlying SCN3B's impact. The study revealed significant clinical associations between SCN3B expression and various parameters such as tumor stage, race, age, histological type, molecular subtype, and hormone receptor status. SCN3B demonstrated strong diagnostic potential with an AUC of 0.95. It influenced the expression of over 800 genes, primarily associated with cell migration and extracellular matrix interactions. SCN3B exhibited distinct expression patterns between normal and breast cancer cell lines and successfully overexpressed in various breast cancer cell lines. This overexpression inhibited cell migration and invasion. Our research emphasizes SCN3B's clinical relevance, diagnostic potential, and influence on cell behavior in breast cancer, offering insights into its multifaceted role and therapeutic implications.
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Affiliation(s)
- Yinfeng Zhao
- Department of Thyroid and Breast Surgery, Suizhou Hospital, Hubei University Of Medicine, Suizhou City, Hubei Province, China
| | - Jianzhong Ye
- Department of Gynecology, Suizhou Hospital, Hubei University Of Medicine, Suizhou City, Hubei Province, China
| | - Yun Liang
- Department of Thyroid and Breast Surgery, Suizhou Hospital, Hubei University Of Medicine, Suizhou City, Hubei Province, China.
| | - Jia Chen
- Department of Gynecology, People's Hospital of Jianshi, Enshi Tujia and Miao Autonomous Prefecture, Enshi City, Hubei Province, China.
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Li D, Zheng P, Huang S. SLC12A9 is an immunological and prognostic biomarker for glioma. Gene 2025; 937:149136. [PMID: 39622394 DOI: 10.1016/j.gene.2024.149136] [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: 08/03/2024] [Revised: 11/20/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Glioma is one of the most common malignant brain tumors. It has a high rate of progression and a poor prognosis, and effective biomarkers still need to be identified. The solute carrier family 12 (SLC12) family has been reported to be involved in various physiological and pathological processes, but their functional roles in glioma remain unclear. METHODS Using public datasets, we studied the mutation and expression level of SLC12 family genes in glioma and identified the significantly differentially expressed member solute carrier family 12 member 9 (SLC12A9). We further predicted the prognostic role of SLC12A9 in glioma by using the Kaplan-Meier method and Cox regression analysis. Then, we performed biological functional enrichment analysis. We focused on the relationships between SLC12A9 expression and immune infiltration in glioma. Meanwhile, we conducted in vitro experiments to evaluate the effect of SLC12A9 expression on glioma cells. RESULTS Among the members of the SLC12 family, SLC12A9 had the highest mutation rate in glioma, with gene amplification as the major mutation type, and its expression was significantly upregulated in glioma. Higher SLC12A9 expression was significantly associated with older age, higher grade, wild-type isocitrate dehydrogenase (IDH), and a worse prognosis. The functional enrichment analysis indicated that SLC12A9 is mainly related to ion channel annotation. Gene set enrichment analysis (GSEA) revealed that SLC12A9 was mainly related to the DNA replication pathway. Furthermore, we found that SLC12A9 correlated with tumor-infiltrating immune cells and immune checkpoints. Thus, SLC12A9 may be involved in regulating the immune response of glioma. Finally, our in vitro experiments revealed that silencing SLC12A9 dramatically inhibited glioma cell growth and migration. CONCLUSIONS We showed that SLC12A9 may be a new predictive biomarker for glioma diagnosis, prognosis, and immunotherapy response, offering helpful guidelines to advance glioma treatment.
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Affiliation(s)
- Danting Li
- College of Life Sciences, Anhui Agricultural University, Hefei 230036, China; School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Peilin Zheng
- Department of General Practice, People's Hospital of Longhua, Shenzhen 518109, Guangdong, China.
| | - Shoujun Huang
- College of Life Sciences, Anhui Agricultural University, Hefei 230036, China.
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Qian X, Yang L, Shi Y. Investigation of the impact of magnetic resonance imaging-assisted surgery on immune cell cytokine levels and efficacy in patients with gliomas. Curr Probl Surg 2025; 63:101640. [PMID: 39922633 DOI: 10.1016/j.cpsurg.2024.101640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 02/10/2025]
Affiliation(s)
- Xueshan Qian
- Department of CT&MRI Room, Qianjiang Central Hospital, Qianjiang, Hubei Province, China
| | - Li Yang
- Department of Radiology, Mianyang Central Hospital, Mianyang, Sichuan Province, China
| | - Yonghui Shi
- Department of Radiology, the Affiliated Hospital of Tibet Minzu University, Xianyang, Shaanxi Province, China.
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Sergeev AV, Malyshev DP, Genatullina AI, Pavlova GV, Gromova ES, Zvereva MI. Single-Molecule Nanopore Sequencing of the CpG Island from the Promoter of O6-Methylguanine-DNA Methyltransferase Provides Insights into the Mechanism of De Novo Methylation of G/C-Rich Regions. EPIGENOMES 2025; 9:4. [PMID: 39982246 PMCID: PMC11843895 DOI: 10.3390/epigenomes9010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/14/2025] [Accepted: 01/22/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND The methylation of cytosine residues at CpG sites within the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a key biomarker in glioblastoma therapy. The MGMT promoter (MGMTp) contains multiple guanine-rich sequences capable of folding into G-quadruplexes (G4s), but their relevance for MGMTp methylation is poorly understood. OBJECTIVES Our study explores the impact of potential G-quadruplex-forming sequences (PQS) in the MGMT promoter CpG island on the activity of de novo DNA methyltransferase Dnmt3a. Additionally, we investigate their influence on the accuracy of methylation pattern detection using nanopore sequencing. METHODS Nanopore sequencing was employed to analyze the methylation of 94 clinically significant CpG sites in the human MGMTp using an in vitro de novo methylation system. Circular dichroism spectroscopy was used to identify G4 structures within the MGMTp CpG island. Interactions between the catalytic domain of Dnmt3a and the PQS from the MGMTp were examined by biolayer interferometry. RESULTS Guanine-rich DNA strands of the PQSs in the MGMTp were hypomethylated, while the complementary cytosine-rich strands were methylated by DNA methyltransferase Dnmt3a with higher efficiency. The accuracy of detecting modified bases in the PQS was significantly lower compared to surrounding sequences. Single-stranded guanine-rich DNA sequences from the MGMTp exhibited strong binding to Dnmt3a-CD, with an affinity approximately 10 times higher than their cytosine-rich complements (Kd = 3 × 10-8 M and 3 × 10-7 M, respectively). By binding to Dnmt3a, G4-forming oligonucleotides from MGMTp effectively inhibited the methylation reaction (IC50 6 × 10-7 M). CONCLUSIONS The obtained data indicate the role of PQSs in establishing de novo methylation of the MGMT promoter. They also highlight the challenges of sequencing guanine-rich regions and the impact of specific de novo methylation patterns on clinical data interpretation.
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Affiliation(s)
- Alexander V. Sergeev
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia; (D.P.M.); (A.I.G.); (E.S.G.); (M.I.Z.)
| | - Daniil P. Malyshev
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia; (D.P.M.); (A.I.G.); (E.S.G.); (M.I.Z.)
| | - Adelya I. Genatullina
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia; (D.P.M.); (A.I.G.); (E.S.G.); (M.I.Z.)
| | - Galina V. Pavlova
- Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences, 117485 Moscow, Russia;
- Burdenko National Medical Research Institute for Neurosurgery, 125047 Moscow, Russia
| | - Elizaveta S. Gromova
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia; (D.P.M.); (A.I.G.); (E.S.G.); (M.I.Z.)
| | - Maria I. Zvereva
- Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia; (D.P.M.); (A.I.G.); (E.S.G.); (M.I.Z.)
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Liu H, Karsidag M, Chhatwal K, Wang P, Tang T. Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers. PLoS One 2025; 20:e0314745. [PMID: 39820192 PMCID: PMC11737691 DOI: 10.1371/journal.pone.0314745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/14/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND Cancer remains one of the most significant public health challenges worldwide. A widely recognized hallmark of cancer is the ability to sustain proliferative signaling, which is closely tied to various cell cycle processes. Centromere Protein A (CENPA), a variant of the standard histone H3, is crucial for selective chromosome segregation during the cell cycle. Despite its importance, a comprehensive pan-cancer bioinformatic analysis of CENPA has not yet been conducted. METHODS Data on genomes, transcriptomes, and clinical information were retrieved from publicly accessible databases. We analyzed CENPA's genetic alterations, mRNA expression, functional enrichment, association with stemness, mutations, expression across cell populations and cellular locations, link to the cell cycle, impact on survival, and its relationship with the immune microenvironment. Additionally, a prognostic model for glioma patients was developed to demonstrate CENPA's potential as a biomarker. Furthermore, drugs targeting CENPA in cancer cells were identified and predicted using drug sensitivity correlations and protein-ligand docking. RESULTS CENPA exhibited low levels of gene mutation across various cancers. It was found to be overexpressed in nearly all cancer types analyzed in TCGA, relative to normal controls, and was predominantly located in the nucleus of malignant cells. CENPA showed a strong association with the cancer cell cycle, particularly as a biomarker for the G2 phase. It also emerged as a valuable diagnostic and prognostic biomarker across multiple cancer types. In glioma, CENPA demonstrated reliable prognostic potential when used alongside other prognostic factors. Additionally, CENPA was linked to the immune microenvironment. Drugs such as CD-437, 3-Cl-AHPC, Trametinib, BI-2536, and GSK461364 were predicted to target CENPA in cancer cells. CONCLUSION CENPA serves as a crucial biomarker for the cell cycle in cancers, offering both diagnostic and prognostic value.
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Affiliation(s)
- Hengrui Liu
- Cancer Research Institute, Jinan University, Guangzhou, Guangdong, China
- Yinuo Biomedical Co., Ltd, Tianjin, China
| | - Miray Karsidag
- Canyon Crest Academy, San Diego, CA, United States of America
| | - Kunwer Chhatwal
- Hopkinton High School, Hopkinton, MA, United States of America
| | - Panpan Wang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Tao Tang
- Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
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Tang H, Yang X, Li G, Peng K, Sun Y, Jiang L, Huang Y. Development and experimental validation of dephosphorylation-related biomarkers to assess prognosis and immunotherapeutic response in gliomas. Front Immunol 2025; 15:1488894. [PMID: 39830513 PMCID: PMC11739095 DOI: 10.3389/fimmu.2024.1488894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025] Open
Abstract
Background Gliomas are common aggressive brain tumors with poor prognosis. Dephosphorylation-related biomarkers are in a void in gliomas. This study aims to construct a validated prognostic risk model for dephosphorylation, which will provide new directions for clinical treatment, prognostic assessment, and temozolomide (TMZ) resistance in glioma patients. Methods Screening dephosphorylation-related genes (DRGs) and transcriptome expression data from The Cancer Genome Atlas (TCGA), Molecular signatures database (MSigDB) and constructing risk scoring models. Kaplan-Meier (K-M), nomogram and ROC curve were used to assess the predictive efficacy of the model. Gene set enrichment analysis (GSEA), immune cell infiltration, immunotherapy response and chemotherapeutic drug sensitivity analysis were performed in this study. The correlation between chemotherapeutic drugs and the half maximal inhibitory concentration (IC50) values of 12 DRGs was analyzed. Cell division cycle 25A (CDC25A) and TMZ were screened and verified by experiments. Quantitative Real-Time PCR (qRT-PCR) detection of mRNA expression of 12 genes in human normal glial cells and two glioma cell lines. Transfection techniques overexpressed and knocked down CDC25A. qRT-PCR and Western Blot (WB) were used to detect the mRNA and protein expression levels of CDC25A. Subsequently, verify the effect of CDC25A on TMZ resistance in glioma cells. Results The model established in this study was able to accurately predict the prognosis of glioma patients. Besides, there were significant differences in GSEA, immune cell infiltration, immunotherapeutic response and chemotherapeutic drug sensitivity analysis between glioma patients in the high and low risk groups. The results of CCK8 experiments showed that overexpression of CDC25A increased the susceptibility of U251 and LN229 cells to TMZ, and knockdown of CDC25A attenuated the susceptibility of U251 and LN229 cells to TMZ.
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Affiliation(s)
- Hui Tang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xuping Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Guoqian Li
- Department of Pharmacy, Chengdu Chengnan Jinhua Hospital, Chengdu, China
| | - Ke Peng
- Department of Pharmacy, Renshou County Traditional Chinese Medicine Hospital, Meshan, China
| | - Yang Sun
- Department of Pharmaceutical Analysis, Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, China
| | - Longyang Jiang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yilan Huang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
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10
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Wang H, Chen D, He M. Efficacy and Safety of Recombinant Human Thrombopoietin (rhTPO) on Coagulation Function and Inflammatory Factors in the Treatment of Patients with Sepsis-Related Thrombocytopenia. Clin Appl Thromb Hemost 2025; 31:10760296251315173. [PMID: 39901742 PMCID: PMC11792032 DOI: 10.1177/10760296251315173] [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: 10/20/2024] [Revised: 12/31/2024] [Accepted: 01/08/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND this study aimed to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in the treatment of sepsis-associated thrombocytopenia, and to evaluate its impact on coagulation function, inflammatory markers, platelet (Plt) count, and patient prognosis. METHODS a total of 144 patients with sepsis-associated thrombocytopenia, admitted to our hospital between 2022 and 2023, were selected for the study. The patients were randomly divided into two groups using a random number table: the control group (Group C, n = 72) and the research group (Group R, n = 72). The Group C received standard treatment, while the Group R received rhTPO in addition to standard care. We compared the general demographic data, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, coagulation parameters, serum levels of Toll-like receptor 4 (TLR4), interleukin-6 (IL-6), serum creatinine (SCr), tumor necrosis factor-alpha (TNF-α), Plt count, transfusion volume, treatment duration, incidence of complications, and mortality rates between the two groups. RESULTS there were no significant differences in the general demographic characteristics between the two groups (P > 0.05). After treatment, the APACHE II scores in both groups significantly decreased, with a more pronounced reduction observed in the Group R. Coagulation function indicators, including activated partial thromboplastin time (APTT), fibrinogen (FIB), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (AT-III), protein C, thrombomodulin (TM), and Plt factor 4 (PF4), showed greater improvement in the Group R compared to the Group C (P < 0.05). The serum levels of TLR4, IL-6, and TNF-α in the Group R were significantly lower than those in the Group C (P < 0.05), whereas no significant difference in SCr levels was observed between the groups (P > 0.05). The Plt count in the Group R began to significantly increase on day 3 of treatment, and was consistently higher than that in the Group C on days 3, 5, and 7 (P < 0.05). The Group R required significantly fewer red blood cell transfusions compared to the Group C and did not require Plt suspension (P < 0.05). No significant differences were found between the groups in terms of mechanical ventilation time, intensive care unit (ICU) length of stay, and total hospital stay (P > 0.05). However, the ICU and overall hospital mortality rates were significantly lower in the Group R than in the Group C (P < 0.05). Multivariate logistic regression analysis indicated that rhTPO treatment was an independent protective factor for reducing mortality (OR = 0.475, P = 0.042). CONCLUSION rhTPO treatment effectively improves coagulation function and inflammatory status in patients with sepsis-associated thrombocytopenia, increases Plt count, reduces transfusion requirements, and lowers mortality. These findings suggest that rhTPO has significant clinical application value in the management of this condition.
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Affiliation(s)
- Huijuan Wang
- Department of Intensive Care Unit (ICU), First People's Hospital of Linping District, Hangzhou, China
| | - Dong Chen
- Department of Colorectal Surgery, First People's Hospital of Linping District, Hangzhou, China
| | - Ming He
- Department of Intensive Care Unit (ICU), First People's Hospital of Linping District, Hangzhou, China
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Wang Y, Chu D, Li H, Fan J, Zhu X, Ma Y, Gu Z, Xie N, Jing P. A comprehensive investigation of PRMT5 in the prognosis and ion channel features of lung cancer. Front Oncol 2024; 14:1478672. [PMID: 39678513 PMCID: PMC11638061 DOI: 10.3389/fonc.2024.1478672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/07/2024] [Indexed: 12/17/2024] Open
Abstract
The increasing incidence and mortality associated with lung cancer (LC) is a significant global health challenge. The underlying mechanisms contributing to LC remain inadequately understood. However, emerging evidence suggests that the epigenetic modifier protein arginine methyltransferase 5 (PRMT5) plays a complex role in various cellular processes, including DNA repair, gene transcription, and alternative splicing, through its function in catalyzing the symmetric dimethylation of both histone and non-histone proteins. In this study, we examined the functional role of PRMT5 utilizing LC-related datasets (GSE30219, GSE50081, and TCGA LC cohort) through a series of analyses. Our findings revealed that PRMT5 was significantly overexpressed in LC samples compared to normal tissues and was correlated with overall survival and disease-free survival rates. Additionally, PRDM1 was identified as a key protein exhibiting a strong interaction with PRMT5. The prognostic model that integrated PRMT5 with clinical factors demonstrated robust performance in assessing survival outcomes. Elevated levels of PRMT5 were associated with poor prognosis in LC, as evidenced by analyses of the GSE30219, GSE50081, and TCGA-LC datasets. Furthermore, we identified 27 ion channel (IC) genes exhibited a correlation with PRMT5 in lung adenocarcinoma (LUAD), of which 9 genes were identified as statistically significant with KM survival analysis. Strikingly, all of the 9 genes, including LRRC8A, the same as PRMT5, were associated with poor prognosis in LUAD. Our research highlights the potential of PRMT5 as a novel prognostic biomarker and its relationship with IC genes in LC.
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Affiliation(s)
- Yan Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Daifang Chu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Haichao Li
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Jiangjiang Fan
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Ximing Zhu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Yulong Ma
- Department of Thoracic Surgery, Yicheng County People’s Hospital, Linfen, Shanxi, China
| | - Zhongping Gu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Nianlin Xie
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
| | - Pengyu Jing
- Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi’an, China
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12
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Xu Z, Rasteh AM, Dong A, Wang P, Liu H. Identification of molecular targets of Hypericum perforatum in blood for major depressive disorder: a machine-learning pharmacological study. Chin Med 2024; 19:141. [PMID: 39385284 PMCID: PMC11465934 DOI: 10.1186/s13020-024-01018-5] [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: 06/05/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Hypericum perforatum (HP) is a traditional herb that has been shown to have antidepressant effects, but its mechanism is unclear. This study aims to identify the molecular targets of HP for the treatment of MDD. METHODS We performed differential analysis and weighted gene co-expression network analysis (WGCNA) with blood mRNA expression cohort of MDD and healthy control to identify DEGs and significant module genes (gene list 1). Three databases, CTD, DisGeNET, and GeneCards, were used to retrieve MDD-related gene intersections to obtain MDD-predicted targets (gene list 2). The validated targets were retrieved from the TCMSP database (gene list 3). Based on these three gene lists, 13 key pathways were identified. The PPI network was constructed by extracting the intersection of genes and HP-validated targets on all key pathways. Key therapeutic targets were obtained using MCODE and machine learning (LASSO, SVM-RFE). Clinical diagnostic assessments (Nomogram, Correlation, Intergroup expression), and gene set enrichment analysis (GSEA) were performed for the key targets. In addition, immune cell analysis was performed on the blood mRNA expression cohort of MDD to explore the association between the key targets and immune cells. Finally, molecular docking prediction was performed for the targets of HP active ingredients on MDD. RESULTS Differential expression analysis and WGCNA module analysis yielded 933 potential targets for MDD. Three disease databases were intersected with 982 MDD-predicted targets. The TCMSP retrieved 275 valid targets for HP. Separate enrichment analysis intersected 13 key pathways. Five key targets (AKT1, MAPK1, MYC, EGF, HSP90AA1) were finally screened based on all enriched genes and HP valid targets. Combined with the signaling pathway and immune cell analysis suggested the effect of peripheral immunity on MDD and the important role of neutrophils in immune inflammation. Finally, the binding of HP active ingredients (quercetin, kaempferol, and luteolin) and all 5 key targets were predicted based on molecular docking. CONCLUSIONS The active constituents of Hypericum perforatum can act on MDD and key targets and pathways of this action were identified.
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Affiliation(s)
- Zewen Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | | | | | - Panpan Wang
- The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Hengrui Liu
- Cancer Research Institute, Jinan University, Guangzhou, China.
- Tianjin Yinuo Biomedical Co., Ltd, Tianjin, China.
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13
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Kaynar A, Kim W, Ceyhan AB, Zhang C, Uhlén M, Turkez H, Shoaie S, Mardinoglu A. Unveiling the Molecular Mechanisms of Glioblastoma through an Integrated Network-Based Approach. Biomedicines 2024; 12:2237. [PMID: 39457550 PMCID: PMC11504402 DOI: 10.3390/biomedicines12102237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, the average survival time is around 15-18 months, underscoring the fatality of GBM. This study aims to investigate the impact of sample heterogeneity on gene expression in GBM, identify key metabolic pathways and gene modules, and explore potential therapeutic targets. Methods: In this study, we analysed GBM transcriptome data derived from The Cancer Genome Atlas (TCGA) using genome-scale metabolic models (GEMs) and co-expression networks. We examine transcriptome data incorporating tumour purity scores (TPSs), allowing us to assess the impact of sample heterogeneity on gene expression profiles. We analysed the metabolic profile of GBM by generating condition-specific GEMs based on the TPS group. Results: Our findings revealed that over 90% of genes showing brain and glioma specificity in RNA expression demonstrate a high positive correlation, underscoring their expression is dominated by glioma cells. Conversely, negatively correlated genes are strongly associated with immune responses, indicating a complex interaction between glioma and immune pathways and non-tumorigenic cell dominance on gene expression. TPS-based metabolic profile analysis was supported by reporter metabolite analysis, highlighting several metabolic pathways, including arachidonic acid, kynurenine and NAD pathway. Through co-expression network analysis, we identified modules that significantly overlap with TPS-correlated genes. Notably, SOX11 and GSX1 are upregulated in High TPS, show a high correlation with TPS, and emerged as promising therapeutic targets. Additionally, NCAM1 exhibits a high centrality score within the co-expression module, which shows a positive correlation with TPS. Moreover, LILRB4, an immune-related gene expressed in the brain, showed a negative correlation and upregulated in Low TPS, highlighting the importance of modulating immune responses in the GBM mechanism. Conclusions: Our study uncovers sample heterogeneity's impact on gene expression and the molecular mechanisms driving GBM, and it identifies potential therapeutic targets for developing effective treatments for GBM patients.
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Affiliation(s)
- Ali Kaynar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
| | - Woonghee Kim
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Atakan Burak Ceyhan
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Mathias Uhlén
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Hasan Turkez
- Medical Biology Department, Faculty of Medicine, Atatürk University, Erzurum 25240, Türkiye;
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
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14
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Zheng H, Zheng J, Shen Y. Targeting SEZ6L2 in Colon Cancer: Efficacy of Bexarotene and Implications for Survival. J Gastrointest Cancer 2024; 55:1291-1305. [PMID: 38954188 DOI: 10.1007/s12029-024-01085-9] [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] [Accepted: 06/19/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Bexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer. METHODS We utilized both TCGA data and a cohort of Chinese patients. In a meticulous analysis of 478 colon cancer cases, SEZ6L2 expression levels were examined in relation to clinical characteristics, staging parameters, and treatment outcomes. Additionally, we investigated the pharmacological impact of bexarotene on SEZ6L2, demonstrating a significant downregulation of SEZ6L2 at both mRNA and protein levels in colon cancer patients following bexarotene treatment. RESULTS SEZ6L2 consistently overexpresses in colon cancer, serving as a potential universal biomarker with prognostic significance, validated in a diverse Chinese cohort. In vitro, SEZ6L2 promotes cell viability without affecting migration. Bexarotene treatment inhibits SEZ6L2 expression, correlating with reduced viability both in vitro and in vivo. SEZ6L2 overexpression accelerates declining survival rates in an in vivo context. Bexarotene's efficacy is context-dependent, effective in parental cells but not with SEZ6L2 overexpression. Computational predictions suggest a direct SEZ6L2-bexarotene interaction, warranting further experimental exploration. CONCLUSION The study provides valuable insights into SEZ6L2 as a prognostic biomarker in colon cancer, revealing its intricate relationship with clinical parameters, treatment outcomes, and bexarotene effects. Context-dependent therapeutic responses emphasize the nuanced understanding required for SEZ6L2's role in colon cancer, paving the way for targeted therapeutic strategies.
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Affiliation(s)
- Huajun Zheng
- Digestive System Department, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, 318 Chaowang Road, Gongshu District, Hangzhou City, Zhejiang Province, China.
| | - Jianying Zheng
- Operation Department, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou City, Zhejiang Province, China
| | - Yan Shen
- Digestive System Department, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, 318 Chaowang Road, Gongshu District, Hangzhou City, Zhejiang Province, China
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15
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Liu H, Dong A, Rasteh AM, Wang P, Weng J. Identification of the novel exhausted T cell CD8 + markers in breast cancer. Sci Rep 2024; 14:19142. [PMID: 39160211 PMCID: PMC11333736 DOI: 10.1038/s41598-024-70184-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
Cancer is one of the most concerning public health issues and breast cancer is one of the most common cancers in the world. The immune cells within the tumor microenvironment regulate cancer development. In this study, single immune cell data sets were used to identify marker gene sets for exhausted CD8 + T cells (CD8Tex) in breast cancer. Machine learning methods were used to cluster subtypes and establish the prognostic models with breast cancer bulk data using the gene sets to evaluate the impacts of CD8Tex. We analyzed breast cancer overexpressing and survival-associated marker genes and identified CD8Tex hub genes in the protein-protein-interaction network. The relevance of the hub genes for CD8 + T-cells in breast cancer was evaluated. The clinical associations of the hub genes were analyzed using bulk sequencing data and spatial sequencing data. The pan-cancer expression, survival, and immune association of the hub genes were analyzed. We identified biomarker gene sets for CD8Tex in breast cancer. CD8Tex-based subtyping systems and prognostic models performed well in the separation of patients with different immune relevance and survival. CRTAM, CLEC2D, and KLRB1 were identified as CD8Tex hub genes and were demonstrated to have potential clinical relevance and immune therapy impact. This study provides a unique view of the critical CD8Tex hub genes for cancer immune therapy.
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Affiliation(s)
- Hengrui Liu
- Cancer Research Institute, Jinan University, Guangzhou, China
| | | | | | - Panpan Wang
- The First Affiliated Hospital of Jinan University, Guangzhou, China.
| | - Jieling Weng
- Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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16
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Geng D, Liu M, Wu D, Yue B. The relationship between serum levels of epidermal growth factor and β-human chorionic gonadotropin and the type and prognosis of ectopic pregnancy. Arch Gynecol Obstet 2024; 310:1179-1187. [PMID: 38683393 DOI: 10.1007/s00404-024-07523-0] [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: 01/09/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024]
Abstract
PURPOSE This work aimed to explore the relationship between epidermal growth factor (EGF) and β-human chorionic gonadotropin (β-HCG) and ectopic pregnancy types and impact on prognosis. METHODS Twenty women with normal pregnancies (NPs) were recruited as control group, and twenty women each with tubal pregnancy (TP) and cervical pregnancy (CP) were recruited. Blood samples were collected to detect EGF and β-HCG. Data on length of hospital stay and incidence of complications were collected. The differences in serum EGF and β-HCG levels were compared among groups and within various types of ectopic pregnancy using analysis of variance and Pearson correlation analysis. RESULTS Serum EGF and β-HCG were notably lower in TP and CP group vs. controls (P < 0.05). In subgroup analysis within the types of ectopic pregnancy, serum EGF levels were drastically higher in TP group vs. CP group (P < 0.05). Serum EGF levels were negatively correlated with pregnancy outcomes and incidence of complications (P < 0.05). In patients with TP and CP, serum EGF and β-HCG recovery time and hospital stay differed drastically (P < 0.05). Serum EGF and β-HCG levels showed optimal cutoff values identified at 2.65 μg/L and 11,745.35 IU/L, respectively. The corresponding area under the curve (AUC) values were 0.885 and 0.841. CONCLUSION Elevated levels of EGF may be associated with the occurrence of ectopic pregnancy and may impact the type of ectopic pregnancy, pregnancy outcomes, and the incidence of complications. Further clinical research is warranted to investigate these findings.
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Affiliation(s)
- Dandan Geng
- Department of Gynecology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No 39, 12 Qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China.
- Department of Traditional Chinese Medicine, The Forth Hospital of Shijiazhuang, Shijiazhuang, 050000, China.
| | - Manfang Liu
- Department of Traditional Chinese Medicine, The Forth Hospital of Shijiazhuang, Shijiazhuang, 050000, China
| | - Dongyan Wu
- Department of Gynecology, The Forth Hospital of Shijiazhuang, Shijiazhuang, 050000, China
| | - Benming Yue
- Department of Gynecology, The Forth Hospital of Shijiazhuang, Shijiazhuang, 050000, China
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Martija AA, Krauß A, Bächle N, Doth L, Christians A, Krunic D, Schneider M, Helm D, Will R, Hartmann C, Herold-Mende C, von Deimling A, Pusch S. EMP3 sustains oncogenic EGFR/CDK2 signaling by restricting receptor degradation in glioblastoma. Acta Neuropathol Commun 2023; 11:177. [PMID: 37936247 PMCID: PMC10629159 DOI: 10.1186/s40478-023-01673-z] [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: 04/18/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023] Open
Abstract
Epithelial membrane protein 3 (EMP3) is an N-glycosylated tetraspanin with a putative trafficking function. It is highly expressed in isocitrate dehydrogenase-wild-type glioblastoma (IDH-wt GBM), and its high expression correlates with poor survival. However, the exact trafficking role of EMP3 and how it promotes oncogenic signaling in GBM remain unclear. Here, we show that EMP3 promotes EGFR/CDK2 signaling by regulating the trafficking and enhancing the stability of EGFR. BioID2-based proximity labeling revealed that EMP3 interacts with endocytic proteins involved in the vesicular transport of EGFR. EMP3 knockout (KO) enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7 + late endosomes, thereby promoting EGFR degradation. Increased EGFR degradation is rescued by the RAB7 negative regulator and novel EMP3 interactor TBC1D5. Phosphoproteomic and transcriptomic analyses further showed that EMP3 KO converges into the inhibition of the cyclin-dependent kinase CDK2 and the repression of EGFR-dependent and cell cycle transcriptional programs. Phenotypically, EMP3 KO cells exhibit reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to the pan-kinase inhibitor staurosporine and the EGFR inhibitor osimertinib. Furthermore, EGFR-dependent patient-derived glioblastoma stem cells display a transcriptomic signature consistent with reduced CDK2 activity, as well as increased susceptibility to CDK2 inhibition upon EMP3 knockdown. Lastly, using TCGA data, we showed that GBM tumors with high EMP3 expression have increased total and phosphorylated EGFR levels. Collectively, our findings demonstrate a novel EMP3-dependent mechanism by which EGFR/CDK2 activity is sustained in GBM. Consequently, EMP3's stabilizing effect provides an additional layer of tumor cell resistance against targeted kinase inhibition.
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Affiliation(s)
- Antoni Andreu Martija
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Alexandra Krauß
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
- Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Natalie Bächle
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Laura Doth
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Arne Christians
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
- Canopy Biosciences, Bruker Nano Group, Hannover, Germany
| | - Damir Krunic
- Light Microscopy Facility, DKFZ, Heidelberg, Germany
| | | | - Dominic Helm
- Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Rainer Will
- Cellular Tools Core Facility, DKFZ, Heidelberg, Germany
| | - Christian Hartmann
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
| | | | - Andreas von Deimling
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Pusch
- Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
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Liu H, Tang T. MAPK signaling pathway-based glioma subtypes, machine-learning risk model, and key hub proteins identification. Sci Rep 2023; 13:19055. [PMID: 37925483 PMCID: PMC10625624 DOI: 10.1038/s41598-023-45774-0] [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: 04/24/2023] [Accepted: 10/24/2023] [Indexed: 11/06/2023] Open
Abstract
An early diagnosis and precise prognosis are critical for the treatment of glioma. The mitogen‑activated protein kinase (MAPK) signaling pathway potentially affects glioma, but the exploration of the clinical values of the pathway remains lacking. We accessed data from TCGA, GTEx, CGGA, etc. Up-regulated MAPK signaling pathway genes in glioma were identified and used to cluster the glioma subtypes using consensus clustering. The subtype differences in survival, cancer stemness, and the immune microenvironment were analyzed. A prognostic model was trained with the identified genes using the LASSO method and was validated with three external cohorts. The correlations between the risk model and cancer-associated signatures in cancer were analyzed. Key hub genes of the gene set were identified by hub gene analysis and survival analysis. 47% of the MAPK signaling pathway genes were overexpressed in glioma. Subtypes based on these genes were distinguished in survival, cancer stemness, and the immune microenvironment. A risk model was calculated with high confidence in the prediction of overall survival and was correlated with multiple cancer-associated signatures. 12 hub genes were identified and 8 of them were associated with survival. The MAPK signaling pathway was overexpressed in glioma with prognostic value.
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Affiliation(s)
- Hengrui Liu
- Xinkaiyuan Pharmaceuticals, Beijing, China
- Guangzhou Regenerative Medicine Research Center, Future Homo Sapiens Institute of Regenerative Medicine Co., Ltd (FHIR), Guangzhou, China
| | - Tao Tang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Dong P, Gassler N, Taheri M, Baniahmad A, Dilmaghani NA. A review on the role of cyclin dependent kinases in cancers. Cancer Cell Int 2022; 22:325. [PMID: 36266723 PMCID: PMC9583502 DOI: 10.1186/s12935-022-02747-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Nikolaus Gassler
- Section of Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena, Germany
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Nader Akbari Dilmaghani
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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