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Saadh MJ, Ghnim ZS, Mahdi MS, Chandra M, Ballal S, Bareja L, Chaudhary K, Sharma RSK, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. Decoding the Role of Kinesin Superfamily Proteins in Glioma Progression. J Mol Neurosci 2025; 75:10. [PMID: 39847238 DOI: 10.1007/s12031-025-02308-9] [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] [Received: 12/05/2024] [Accepted: 01/04/2025] [Indexed: 01/24/2025]
Abstract
Glioma is a highly aggressive and invasive brain tumor with limited treatment options, highlighting the need for novel therapeutic approaches. Kinesin superfamily proteins (KIFs) are a diverse group of motor proteins that play essential roles in cellular processes such as mitosis, intracellular transport, and signal transduction, all of which are crucial for tumorigenesis. This review focuses on the multifaceted role of KIFs in glioma, examining their clinical relevance, contribution to tumor progression, and potential as therapeutic targets. We discuss how KIFs influence key aspects of glioma biology, including cell proliferation, invasion, migration, and metastasis. Furthermore, we explore the regulation of the cell cycle and critical signaling pathways associated with glioma, such as PI3K-Akt, Wnt/β-catenin, and Hedgehog signaling by KIFs. The review also addresses the emerging interplay between KIFs and non-coding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), in glioma progression. Finally, we examine current therapeutic strategies targeting KIFs, including immunotherapy, chemotherapy, and small-molecule inhibitors, and their potential to improve treatment outcomes for glioma patients. By synthesizing these insights, this review underscores the significance of KIFs in glioma pathogenesis and their promise as novel therapeutic targets in the fight against glioma.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Muktesh Chandra
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - R S K Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Lai L, Miao Q. TFDP1 transcriptionally activates KIF22 to enhance aggressiveness and stemness in endometrial cancer: implications for prognosis and targeted therapy. J Mol Histol 2024; 56:40. [PMID: 39672972 DOI: 10.1007/s10735-024-10293-3] [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: 07/21/2024] [Accepted: 10/24/2024] [Indexed: 12/15/2024]
Abstract
This study aims to elucidate the role of Kinesin Family Member 22 (KIF22) as a critical regulator of aggressive behavior in endometrial cancer (uterine corpus endometrial carcinoma, UCEC) and to uncover its underlying mechanisms, thereby providing a molecular rationale for future targeted treatment. Bioinformatics analyses were employed to assess KIF22 and TFDP1 expression in UCEC, examining their prognostic value and associations with disease progression. Expression levels were validated in UCEC tissues using qRT-PCR and western blotting. Potential TFDP1 binding sites on the KIF22 promoter were predicted using the JASPAR database and confirmed via dual-luciferase reporter assays. Functional assays, including CCK-8, transwell, and spheroid formation assays, were conducted to evaluate the effects of KIF22 knockdown on UCEC cell behavior. A mouse xenograft model was utilized to investigate the in vivo impact of KIF22 suppression on tumor growth and stemness. KIF22 expression was significantly elevated in UCEC tissues, correlating with reduced overall survival in patients with high KIF22 levels. Overexpression of KIF22 enhanced the proliferation, migration, and sphere formation of UCEC cells. Similarly, high TFDP1 expression was associated with poorer patient outcomes. KIF22 was found to be positively regulated by the TFDP1 transcription factor, which bound to the KIF22 promoter and activated its expression in UCEC cells. In vivo, KIF22 knockdown markedly impeded the tumor formation of cells and reduced stemness marker expression. KIF22, upregulated by TFDP1, enhances UCEC cell aggressiveness and is linked to poor prognosis, highlighting its potential as a target for therapeutic intervention in endometrial cancer.
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Affiliation(s)
- Limei Lai
- Department of Gynaecological Oncology, Jinhua Guangfu Oncology Hospital, Surgical Building, Wucheng District, Jinhua, Zhejiang Province, China
| | - Qian Miao
- Department of Medical Oncology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, 100 Minjiang Avenue, Kecheng District, Quzhou City, 324000, Zhejiang Province, China.
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Li C, Jing J, Wang Y, Jiang H. CENPA facilitates glioma stem cell stemness and suppress ferroptosis to accelerate glioblastoma multiforme progression by promoting GBP2 transcription. Pathol Res Pract 2024; 260:155438. [PMID: 38964117 DOI: 10.1016/j.prp.2024.155438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/06/2024]
Abstract
The function of glioma stem cells (GSCs) is closely related to the progression of glioblastoma multiforme (GBM). Centromere protein A (CENPA) has been confirmed to be related to the poor prognosis of GBM patients. However, whether CENPA regulates GSCs function to mediate GBM progression is still unclear. GSCs were isolated from GBM cells. The expression of CENPA and guanylate-binding protein 2 (GBP2) was examined by quantitative real-time PCR and western blot. GSCs proliferation and stemness were assessed using EdU assay and sphere formation assay. Cell ferroptosis was evaluated by detecting related factors. The interaction between CENPA and GBP2 was analyzed by ChIP assay and dual-luciferase reporter assay. Animal experiments were conducted to measure the effect of CENPA knockdown on the tumorigenicity of GSCs in vivo. CENPA was upregulated in GBM tissues and GSCs. CENPA knockdown inhibited GSCs proliferation, stemnness, and promoted ferroptosis. GBP2 was overexpressed in GBM tissues and GSCs, and CENPA enhanced GBP2 transcription by binding to its promoter region. CENPA overexpression accelerated GSCs proliferation and stemnness and suppressed ferroptosis, while GBP2 knockdown reversed these effects. Downregulation of CENPA reduced the tumorigenicity of GSCs by decreasing GBP2 expression in vivo. In conclusion, CENPA enhanced GBP2 transcription to increase its expression, thus accelerating GSCs proliferation and stemnness and repressing ferroptosis. Our findings promote a new idea for GBM treatment.
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Affiliation(s)
- Chuankun Li
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jiangpeng Jing
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yuan Wang
- Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Haitao Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
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Guadagnin AR, Peñagaricano F, Dahl GE, Laporta J. Programming effects of intrauterine hyperthermia on adrenal gland development. J Dairy Sci 2024; 107:6308-6321. [PMID: 38580145 DOI: 10.3168/jds.2023-24606] [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: 12/22/2023] [Accepted: 02/27/2024] [Indexed: 04/07/2024]
Abstract
Maternal heat stress during late pregnancy can lead to intrauterine hyperthermia and affect fetal hypothalamic-pituitary-adrenal axis development and function. Herein, we investigated the effects of chronic environmental heat stress exposure of Holstein cows in the last 2 mo of gestation on their offspring's adrenal gland histomorphology and transcriptome. Cows in their last 54 ± 5 d of gestation were either heat stressed (housed under the shade of a freestall barn) or provided heat stress abatement via active cooling (via water soakers and fans) during a subtropical summer (temperature-humidity index >68). Respiration rate (RR) and skin temperature (ST) were elevated in heat-stressed dams relative to the cows with access to heat abatement (23 breaths/min and 2°C higher for RR and ST, respectively). Heifers born to heat-stressed cows experienced heat stress in utero (HS), whereas heifers born to actively cooled cows did not (CL). The adrenal gland was harvested from 6 heifers per group that were euthanized at birth (d 0; n = 12) or 1 wk after weaning (d 63; n = 12). Circulating cortisol was measured from blood samples collected weekly throughout the preweaning period. At d 63, heifers that experienced HS while developing in utero had heavier adrenal glands, with a greater total tissue surface area and thickness of the zona glomerulosa (ZG), fasciculata (ZF), and reticularis (ZR), compared with CL heifers. In addition, the adrenal gland of HS heifers had fewer cells in the ZG, more and larger cells in the ZF, and larger cells in the ZR, relative to CL heifers. Although no changes in circulating cortisol were observed through the preweaning period, the transcriptomic profile of the adrenal tissue was altered by fetal exposure to hyperthermia. Both at birth and on d 63, approximately 30 pathways were differentially expressed in the adrenal glands of HS heifers relative to CL. These pathways were associated with immune function, inflammation, prolactin signaling, cell function, and calcium transport. Upstream regulators significantly activated or inhibited in the adrenal glands of heifers exposed to intrauterine hyperthermia were identified. Maternal exposure to heat stress during late gestation caused an enlargement of their offspring's adrenal glands by inducing ZG and ZF cell hypertrophy, and caused gene expression changes. These phenotypic, histological, and molecular changes in the adrenal gland might lead to alterations in stress, immune, and metabolic responses later in life.
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Affiliation(s)
- Anne R Guadagnin
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706
| | - Francisco Peñagaricano
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706
| | - Geoffrey E Dahl
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608
| | - Jimena Laporta
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706.
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Pei J, Zhang J, Yu C, Luo J, Wen S, Hua Y, Wei G. Transcriptomics-based exploration of shared M1-type macrophage-related biomarker in acute kidney injury after kidney transplantation and acute rejection after kidney transplantation. Transpl Immunol 2024; 85:102066. [PMID: 38815767 DOI: 10.1016/j.trim.2024.102066] [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: 12/23/2023] [Revised: 05/12/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Macrophage type 1 (M1) cells are associated with both acute kidney injury (AKI) during kidney transplantation and acute rejection (AR) after kidney transplantation. Our study explored M1-related biomarkers involved in both AKI and AR and their potential biological functions. METHODS Based on the Gene Expression Omnibus (GEO) database, the immune cell infiltration levels and differentially expressed genes were examined in AKI and AR in the kidney transplantation; M1-related genes shared in AKI and AR were identified using weighted gene co-expression analysis (WGCNA) system. Subsequently, protein-protein interaction (PPI) networks and machine learning methods to identify Hub genes and construct diagnostic models. Both AKI model and AR rat models were built to validate the expressions of Hub genes and test the injury phenotype, oxidative stress markers, and inflammatory factors. Finally, the transcription factor (TF)-Hub gene and micro-RNA (miRNA)-Hub gene regulatory networks were constructed based on identified Hub genes. RESULTS Out of 2167 differential expression genes (DEGs) in AKI and 2100 DEGs in AR, four M1-related Hub genes were obtained by PPI networks and machine learning methods, namely GBP2, TYROBP, CCR5, and TLR8. The calibration curves in the nomogram diagnostic model for these four Hub genes suggested the same predictive probability as an ideal model for AKI and AR after kidney transplantation (AUC values of the area under the ROC curve were all >0.7). The same observations were confirmed in ischemia reperfusion injury (IRI) and AR rat models by identifying common four Hub genes (GBP2, TYROBP, TLR8, and CCR5). Western blots showed that these four Hub genes were significantly different in rat models of IRI and AR (all p<0.05). Compared with the control group, IRI and AR groups showed aggravated histopathological damage and increased secretion of oxidative stress markers and inflammatory factors in rat kidneys (all p<0.05). Finally, TF-Hub and miRNA-Hub gene regulatory networks were constructed to provide a theoretical basis for the regulation of Hub genes. CONCLUSION We identified four macrophage M1-related Hub genes shared among AKI and AR after kidney transplantation. These genes may be considered for diagnosis of AKI and AR after kidney transplantation.
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Affiliation(s)
- Jun Pei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Jie Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Chengjun Yu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Jin Luo
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Sheng Wen
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Yi Hua
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China.
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China.
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Huang L, Liu Z, Lv X, Sun Y. Investigation of shared genetic features and related mechanisms between diabetes and tuberculosis. Int Urol Nephrol 2024; 56:2743-2753. [PMID: 38512440 DOI: 10.1007/s11255-024-04024-6] [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: 01/18/2024] [Accepted: 03/05/2024] [Indexed: 03/23/2024]
Abstract
OBJECTIVE This study aimed to integrate bioinformatics technology to explore shared hub genes and related mechanisms between diabetes and tuberculosis and to provide a theoretical basis for revealing the disease mechanisms in patients with both diabetes and tuberculosis. METHODS Differentially expressed genes and Venn analysis were used to identify shared genes between diabetes and tuberculosis. PPI network analysis was used to screen key hub genes. GO and KEGG analyses were used to analyze the potential biological functions of these key hub genes. Immune infiltration analysis was performed using the ssGSEA algorithm. EnrichR online analysis website was used to explore potential therapeutic drugs. RESULTS The dataset analysis showed that PSMB9, ISG15, RTP4, CXCL10, GBP2, and GBP3 were six hub genes shared by diabetes and tuberculosis, which not only could distinguish between the two disease samples but also had a high diagnostic rate. GO and KEGG analyses showed that these six genes mainly mediate immune-related biological processes such as interferon, interleukin, and chemokine receptor binding, as well as signaling pathways such as RIG-I-like receptor, NOD-like receptor, and proteasome. Immune infiltration analysis showed that high expression of TIL may mediate the development of both diabetes and tuberculosis. In addition, suloctidil HL60 UP, thioridazine HL60 UP, mefloquine HL60 UP, 1-NITROPYRENE CTD 00001569, and chlorophyllin CTD 00000324 were the candidate drugs predicted by this study that were most likely to target hub genes. CONCLUSION Six differentially expressed genes shared by both diseases (PSMB9, ISG15, RTP4, CXCL10, GBP2, and GBP3) may play a key role in the disease progression of patients with both diabetes and tuberculosis. Candidate drugs targeting these hub genes have therapeutic potential and are worthy of further research. In summary, this study reveals potential shared pathogenic mechanisms between tuberculosis and diabetes.
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Affiliation(s)
- Lifei Huang
- Department of Respiratory and Critical Care Medicine, Haining People's Hospital, Haining, 314400, China
| | - Zhihao Liu
- Department of Respiratory and Critical Care Medicine, Haining People's Hospital, Haining, 314400, China
| | - Xiaodong Lv
- Department of Respiratory, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, 314000, China
| | - Yahong Sun
- Department of Respiratory and Critical Care Medicine, Haining People's Hospital, Haining, 314400, China.
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Bouchenafa R, Johnson de Sousa Brito FM, Piróg KA. Involvement of kinesins in skeletal dysplasia: a review. Am J Physiol Cell Physiol 2024; 327:C278-C290. [PMID: 38646780 PMCID: PMC11293425 DOI: 10.1152/ajpcell.00613.2023] [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: 11/12/2023] [Revised: 04/06/2024] [Accepted: 04/08/2024] [Indexed: 04/23/2024]
Abstract
Skeletal dysplasias are group of rare genetic diseases resulting from mutations in genes encoding structural proteins of the cartilage extracellular matrix (ECM), signaling molecules, transcription factors, epigenetic modifiers, and several intracellular proteins. Cell division, organelle maintenance, and intracellular transport are all orchestrated by the cytoskeleton-associated proteins, and intracellular processes affected through microtubule-associated movement are important for the function of skeletal cells. Among microtubule-associated motor proteins, kinesins in particular have been shown to play a key role in cell cycle dynamics, including chromosome segregation, mitotic spindle formation, and ciliogenesis, in addition to cargo trafficking, receptor recycling, and endocytosis. Recent studies highlight the fundamental role of kinesins in embryonic development and morphogenesis and have shown that mutations in kinesin genes lead to several skeletal dysplasias. However, many questions concerning the specific functions of kinesins and their adaptor molecules as well as specific molecular mechanisms in which the kinesin proteins are involved during skeletal development remain unanswered. Here we present a review of the skeletal dysplasias resulting from defects in kinesins and discuss the involvement of kinesin proteins in the molecular mechanisms that are active during skeletal development.
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Affiliation(s)
- Roufaida Bouchenafa
- Skeletal Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Katarzyna Anna Piróg
- Skeletal Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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Chen Y, Li R, Li Z, Yang B, He J, Li J, Li P, Zhou Z, Wu Y, Zhao Y, Guo G. Bulk and single cells transcriptomes with experimental validation identify USP18 as a novel glioma prognosis and proliferation indicator. Exp Ther Med 2024; 27:229. [PMID: 38596661 PMCID: PMC11002833 DOI: 10.3892/etm.2024.12517] [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: 09/10/2023] [Accepted: 02/21/2024] [Indexed: 04/11/2024] Open
Abstract
The mechanism by which ubiquitin-specific protease 18 (USP18) (enzyme commission: 3.4.19.12) inhibition in cancer promotes cell pyroptosis via the induction of interferon (IFN)-stimulated genes has been recently demonstrated. It is also known that USP18 influences the epithelial-mesenchymal transition of glioma cells. In the present study, the upregulation of USP18 in glioma was revealed through bulk transcriptome analysis, which was associated with poor prognosis in patients with glioma. Furthermore, USP18 levels affected the response to immunotherapy in patients with glioma. Single-cell transcriptome and enrichment analyses demonstrated that USP18 was associated with type 1 IFN responses in glioma T cells. To demonstrate the effect of USP18 expression levels on glioma cells, USP18 expression was knocked down in U251 and U87MG ATCC cell lines. A subsequent Cell Counting Kit-8 assay revealed that glioma cell viability was significantly decreased 4 days after USP18 knockdown. In addition, the knockdown of USP18 expression significantly inhibited the clonogenicity of U251 and U87MG ATCC cells. In conclusion, the present study demonstrated that knockdown of USP18 expression inhibited the proliferation of glioma cells, which may be mediated by the effect of USP18 on the IFN-I response.
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Affiliation(s)
- Yang Chen
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Ren Li
- School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Ziao Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Biao Yang
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jianhang He
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Jiayu Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Peize Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Zihan Zhou
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yongqiang Wu
- Department of Emergency, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Yuanli Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China
| | - Geng Guo
- Department of Emergency, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
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Zheng P, Li XY, Yang XY, Wang H, Ding L, He C, Wan JH, Ke HJ, Lu NH, Li NS, Zhu Y. Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models. World J Gastroenterol 2024; 30:2038-2058. [PMID: 38681131 PMCID: PMC11045495 DOI: 10.3748/wjg.v30.i14.2038] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/19/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models. AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels. METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using Ptf1α to drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J- hM3/Ptf1α(cre) mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database. RESULTS Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway, TLR signaling pathway, and NF-κB signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, P53 pathway, and phagosome pathway. The significantly elevated genes in the TLR and NOD-like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood, while TLR1, TLR7, RIPK3, and OAS2 genes exhibited marked elevation in human AP. The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP. The transgenic mouse model hM3/Ptf1α(cre) successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models. CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the MYD88 gene. Apoptosis holds a central position in the necrotic processes of AP, with TUBA1A and GADD45A genes exhibiting prominence in human AP.
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Affiliation(s)
- Pan Zheng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xue-Yang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Yu Yang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Huan Wang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ling Ding
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Cong He
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Hua Wan
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Jing Ke
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nian-Shuang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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10
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Li R, Chen Y, Yang B, Li Z, Wang S, He J, Zhou Z, Li X, Li J, Sun Y, Guo X, Wang X, Wu Y, Zhang W, Guo G. Integrated bioinformatics analysis and experimental validation identified CDCA families as prognostic biomarkers and sensitive indicators for rapamycin treatment of glioma. PLoS One 2024; 19:e0295346. [PMID: 38181024 PMCID: PMC10769025 DOI: 10.1371/journal.pone.0295346] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/21/2023] [Indexed: 01/07/2024] Open
Abstract
The cell division cycle associated (CDCA) genes regulate the cell cycle; however, their relationship with prognosis in glioma has been poorly reported in the literature. The Cancer Genome Atlas (TCGA) was utilized to probe the CDCA family in relation to the adverse clinical features of glioma. Glioma single-cell atlas reveals specific expression of CDCA3, 4, 5, 8 in malignant cells and CDCA7 in neural progenitor cells (NPC)-like malignant cells. Glioma data from TCGA, the China Glioma Genome Atlas Project (CGGA) and the gene expression omnibus (GEO) database all demonstrated that CDCA2, 3, 4, 5, 7 and 8 are prognostic markers for glioma. Further analysis identified CDCA2, 5 and 8 as independent prognostic factors for glioma. Lasso regression-based risk models for CDCA families demonstrated that high-risk patients were characterized by high tumor mutational burden (TMB), low levels of microsatellite instability (MSI), and low tumor immune dysfunction and rejection (TIDE) scores. These pointed to immunotherapy for glioma as a potentially viable treatment option Further CDCA clustering suggested that the high CDCA subtype exhibited a high macrophage phenotype and was associated with a higher antigen presentation capacity and high levels of immune escape. In addition, hsa-mir-15b-5p was predicted to be common regulator of CDCA3 and CDCA4, which was validated in U87 and U251 cells. Importantly, we found that CDCAs may indicate response to drug treatment, especially rapamycin, in glioma. In summary, our results suggest that CDCAs have potential applications in clinical diagnosis and as drug sensitivity markers in glioma.
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Affiliation(s)
- Ren Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yang Chen
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Biao Yang
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ziao Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Shule Wang
- Department of General and Vascular Surgery, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianhang He
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zihan Zhou
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xuepeng Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jiayu Li
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yanqi Sun
- Department of Emergency, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaolong Guo
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaogang Wang
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yongqiang Wu
- Department of Emergency, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wenju Zhang
- Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Geng Guo
- Department of Emergency, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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11
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Zhong Z, Zhong H. KIF22 promotes the proliferation and glycolysis of melanoma by activating EGFR/STAT3 signaling. Clinics (Sao Paulo) 2023; 78:100307. [PMID: 37944197 PMCID: PMC10661841 DOI: 10.1016/j.clinsp.2023.100307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVES Melanoma is one of the leading causes of cancer death. Kinesin Family member 22 (KIF22) is essential for the invasion of melanoma cells, but the role and mechanism of KIF22 in the proliferation and glycolysis in melanoma remains unknown. METHODS KIF22 expression in melanoma tissues and the relationship between KIF22 high expression and overall survival rate in patients with melanoma were analyzed using the Tnmplot database. KIF22 expression in melanoma cells was examined by western blot. Then, KIF22 was silenced and CCK-8 assay, EDU staining and flow cytometry analysis were adopted for assessing cell proliferation and apoptosis. In addition, the glycolysis metabolism of melanoma cells was reflected by detecting Extracellular Acidification Rates (ECAR) and Oxygen Consumption Rates (OCR). The expression of proteins related to apoptosis, glycolysis and EGFR/STAT3 signaling was tested by western blot. Subsequently, melanoma cells were treated with EGF or Colivelin to further elucidate the regulatory effect of KIF22 on EGFR/STAT3 signaling. RESULTS KIF22 expression was notably upregulated in melanoma tissues and cells, and KIF22 high expression was associated with a poor prognosis. Moreover, KIF22 insufficiency suppressed proliferation and accelerated apoptosis of melanoma cells. Additionally, glycolysis was reduced by KIF22 depletion, evidenced by the decreased ECAR and increased OCR, accompanied by the downregulated expression of HK2, PKM2 and LDHA. Importantly, the impacts of KIF22 depletion on the progression of melanoma were partially attenuated after EGF or Colivelin treatment. CONCLUSION Collectively, KIF22 knockdown suppressed the proliferation and glycolysis and facilitated the apoptosis of melanoma cells by inactivating EGFR/STAT3 signaling.
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Affiliation(s)
- Zhi Zhong
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Hua Zhong
- Department of Clean Operation, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
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12
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Li X, Liu J, Zeng M, Yang K, Zhang S, Liu Y, Yin X, Zhao C, Wang W, Xiao L. GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy. Front Immunol 2023; 14:1127612. [PMID: 37622120 PMCID: PMC10445759 DOI: 10.3389/fimmu.2023.1127612] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
Background Diabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage infiltration has been proven vital in the occurrence and development of DN. This study was designed to investigate the hub genes involved in macrophage-mediated inflammation of DN via bioinformatics analysis and experimental validation. Methods Gene microarray datasets were obtained from the Gene Expression Omnibus (GEO) public website. Integrating the CIBERSORT, weighted gene co-expression network analysis (WGCNA) and DEGs, we screened macrophage M1-associated key genes with the highest intramodular connectivity. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression was utilized to further mine hub genes. GSE104954 acted as an external validation to predict the expression levels and diagnostic performance of these hub genes. The Nephroseq online platform was employed to evaluate the clinical implications of these hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to elucidate the dominant biological functions and signal pathways. Finally, we conducted experiments to verify the role of GBP2 in M1 macrophage-mediated inflammatory response and the underlying mechanism of this role. Results Sixteen DEGs with the highest connectivity in M1 macrophages-associated module (paleturquoise module) were determined. Subsequently, we identified four hub genes through LASSO regression analysis, including CASP1, MS4A4A, CD53, and GBP2. Consistent with the training set, expression levels of these four hub genes manifested memorably elevated and the ROC curves indicated a good diagnostic accuracy with an area under the curve of greater than 0.8. Clinically, enhanced expression of these four hub genes predicted worse outcomes of DN patients. Given the known correlation between the first three hub genes and macrophage-mediated inflammation, experiments were performed to demonstrate the effect of GBP2, which proved that GBP2 contributed to M1 polarization of macrophages by activating the notch1 signaling pathway. Conclusion Our findings detected four hub genes, namely CASP1, MS4A4A, CD53, and GBP2, may involve in the progression of DN via pro-inflammatory M1 macrophage phenotype. GBP2 could be a promising prognostic biomarker and intervention target for DN by regulating M1 polarization.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Li Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, China
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13
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Meng K, Li YY, Liu DY, Hu LL, Pan YL, Zhang CZ, He QY. A five-protein prognostic signature with GBP2 functioning in immune cell infiltration of clear cell renal cell carcinoma. Comput Struct Biotechnol J 2023; 21:2621-2630. [PMID: 38213893 PMCID: PMC10781714 DOI: 10.1016/j.csbj.2023.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/16/2023] [Accepted: 04/16/2023] [Indexed: 01/13/2024] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is of poor clinical outcomes, and currently lacks reliable prognostic biomarkers. By analyzing the datasets of the Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we established a five-protein prognostic signature containing GBP2, HLA-DRA, ISG15, ISG20 and ITGAX. Our data indicate that this signature was closely correlated with advanced stage, higher pathological grade, and unfavorable survivals in patients with ccRCC. We further functionally characterized GBP2. Overexpression of GBP2 enhanced the phosphorylation of STAT2 and STAT3 to trigger JAK-STAT signaling and promote cell migration and invasion in ccRCC. Treatment of Ruxolitinib, a specific inhibitor of JAK/STAT, attenuated the GBP2-mediated phenotypes. Patients with high GBP2 expression were accompanied with more infiltration of immune cells positively stained with CD3, CD8, CD68, and immune checkpoint markers PD-1 and CTLA4, which was validated by Opal multiplex immunohistochemistry in ccRCC tissues. More CD8 + T cells and CD68 + macrophages were observed in patients expressing high GBP2. Taken together, a five-protein prognostic signature was constructed in our study. GBP2 has an oncogenic role via modulating JAK-STAT signaling and tumor immune infiltration, and thus may serve as a potential therapeutic target in ccRCC.
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Affiliation(s)
- Kun Meng
- The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yu-Ying Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Dan-Ya Liu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Li-Ling Hu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yun-Long Pan
- The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China
| | - Chris Zhiyi Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Qing-Yu He
- The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
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Guanine nucleotide-binding protein 2, GNBP2, accelerates the progression of clear cell renal cell carcinoma via regulation of STAT3 signaling transduction pathway. Genes Genomics 2023; 45:1-11. [PMID: 36346541 DOI: 10.1007/s13258-022-01334-w] [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: 06/01/2022] [Accepted: 10/18/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Guanine nucleotide-binding protein 2 (GNBP2) is a GTPase that has critical roles in host immunity and some types of cancer, but its function in clear cell renal cell carcinoma (ccRCC) is not fully understood. OBJECTIVE This work explored the role of GNBP2 in ccRCC progression and the underlying molecular mechanism. METHODS Two public human cancer databases TNMplot and TISIDB were employed to analyze the expression pattern of GNBP2 during ccRCC progression and the correlation between GNBP2 expression and clinical features of ccRCC patients. GNBP2 functions in ccRCC cells were determined by EdU staining, flow cytometry, scratch wound assay, transwell assay, and xenograft model. Gene expression was evaluated using qPCR, Western blot, immunofluorescence staining, and immunohistochemical staining. RESULTS GNBP2 expression was significantly elevated in ccRCC tissues and increased gradually with the increasing tumor grades. Patients with higher GNBP2 expression had shorter overall survival times. Knockdown of GNBP2 suppressed tumor cell proliferation and cell cycle progression and reduced the capability of migration and invasion, while GNBP2 overexpression exhibited protumor effects. GNBP2 silencing by RNA interference significantly inhibited the tumor growth of tumor-bearing nude mice and decreased the proliferation marker Ki67. Mechanistically, GNBP2 downregulation suppressed the STAT3 signaling transduction, as it reduced the phosphorylation of STAT3 and modulated the expression of the target genes, including c-Myc, MMP2, N-cadherin, and E-cadherin. CONCLUSION These findings reveal that GNBP2 promotes ccRCC progression by regulating STAT3 signaling transduction, indicating that GNBP2 might be a promising molecular target for ccRCC therapy.
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Li R, Wang YY, Wang SL, Li XP, Chen Y, Li ZA, He JH, Zhou ZH, Li JY, Guo XL, Wang XG, Wu YQ, Ren YQ, Zhang WJ, Wang XM, Guo G. GBP2 as a potential prognostic predictor with immune-related characteristics in glioma. Front Genet 2022; 13:956632. [PMID: 36186425 PMCID: PMC9523311 DOI: 10.3389/fgene.2022.956632] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/05/2022] [Indexed: 11/20/2022] Open
Abstract
Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.
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Affiliation(s)
- Ren Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yuan-Yuan Wang
- Department of Radiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shu-Le Wang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xue-Peng Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yang Chen
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zi-Ao Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jian-Hang He
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zi-Han Zhou
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jia-Yu Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiao-Long Guo
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiao-Gang Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yong-Qiang Wu
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ye-Qing Ren
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wen-Ju Zhang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiao-Man Wang
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Geng Guo
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- *Correspondence: Geng Guo,
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16
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Wang W, Dong D, Chen L, Wang H, Bi B, Liu T. Identification of Crucial Gene Modules Related to the Efficiency of Anti-PD-1/PD-L1 Therapy and Comprehensive Analyses of a Novel Signature Based on These Modules. Front Genet 2022; 13:893380. [PMID: 35937997 PMCID: PMC9354784 DOI: 10.3389/fgene.2022.893380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Biomarker development for clinical checkpoint inhibition is still in its early stages. It is critical to determine the cause of the lack of a long-term response in patients after immune checkpoint blockade (ICB) treatment and to develop composite biomarkers or signatures to improve personalized approaches. Three modules that were significantly correlated with the immunotherapeutic response were identified. Stimulatory pathways of cellular immunity, extracellular matrix formation-related pathways, and ATP metabolism-related pathways were enriched. Two distinct transcriptional subtypes were determined. Tumor microenvironment (TME) characteristics were highly correlated with “hot” and “cold” tumors. The ICB score was significantly correlated with clinical characteristics including age, Breslow depth, Clerk level, AJCC stage, and T stage. Meanwhile, a low ICB score is characterized by increased activation of immunity, a higher level of immune infiltration, and immune molecule expression. The ICB score showed a robust ability to predict melanoma prognosis in the discovery, internal validation, and external validation cohorts. In addition, a low ICB score was linked to a higher CR/PR rate in the immunotherapeutic cohort. The ICB score could reflect the pre-existing immune features and the expression pattern of “Cold” versus “Hot” tumors in melanoma patients. Thus, it has the potential to serve as a reliable predictor of melanoma prognosis and response to ICB therapy.
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Affiliation(s)
- Wei Wang
- Department of Plastic and Aesthetic Surgery, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Dong Dong
- Department of Plastic and Aesthetic Surgery, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Liang Chen
- Department of Plastic and Aesthetic Surgery, Huadong Hospital, Fudan University, Shanghai, China
| | - Heng Wang
- Department of Plastic and Aesthetic Surgery, Huadong Hospital, Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Bo Bi
- Department of Cosmetic Surgery, Shanghai Changning Maternity and Infant Health Hospital, Shanghai, China
- *Correspondence: Tianyi Liu, ; Bo Bi,
| | - Tianyi Liu
- Department of Plastic and Aesthetic Surgery, Huadong Hospital, Fudan University, Shanghai, China
- *Correspondence: Tianyi Liu, ; Bo Bi,
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Hunt EN, Kopacz JP, Vestal DJ. Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes. Cancers (Basel) 2022; 14:cancers14112794. [PMID: 35681772 PMCID: PMC9179834 DOI: 10.3390/cancers14112794] [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: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 11/19/2022] Open
Abstract
At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not just be tumor cell type–specific but dependent on the growth factor and/or cytokine environment in which the tumor cells reside. To clarify what we do and do not know about GBPs in breast cancer, the current literature on GBP-1, GBP-2, and GBP-5 in breast cancer has been assembled. In addition, we have analyzed the role of each of these GBPs in predicting recurrence-free survival (RFS), overall survival (OS), and distance metastasis-free survival (DMFS) as single gene products in different subtypes of breast cancers. When a large cohort of breast cancers of all types and stages were examined, GBP-1 correlated with poor RFS. However, it was the only GBP to do so. When smaller cohorts of breast cancer subtypes grouped into ER+, ER+/Her2-, and HER2+ tumors were analyzed, none of the GBPs influenced RFS, OS, or DMSF as single agents. The exception is GBP-5, which correlated with improved RFS in Her2+ breast cancers. All three GBPs individually predicted improved RFS, OS, and DMSF in ER- breast cancers, regardless of the PR or HER2 status, and TNBCs.
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