Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, in this review, we investigate the potential of using genetic mouse models to identify genetic markers that can disrupt hearing thresholds in mice and then target the hearing-enriched orthologues and loci in humans. Currently, little is known about the real prevalence of genes that cause hearing impairment (HI) in Africa. Pre-screening mouse cell lines to identify orthologues of interest has the potential to improve the genetic diagnosis for HI in Africa to a significant percentage, for example, 10–20%. Furthermore, the functionality of a candidate gene derived from mouse screening with heterogeneous genetic backgrounds and multi-omic approaches can shed light on the molecular, genetic heterogeneity and plausible mode of inheritance of a gene in hearing-impaired individuals especially in the absence of large families to investigate.
{"title":"Leveraging human–mouse studies to advance the genetics of hearing impairment in Africa","authors":"Kili James, Oluwafemi G. Oluwole","doi":"10.1002/jgm.3714","DOIUrl":"10.1002/jgm.3714","url":null,"abstract":"<p>Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, in this review, we investigate the potential of using genetic mouse models to identify genetic markers that can disrupt hearing thresholds in mice and then target the hearing-enriched orthologues and loci in humans. Currently, little is known about the real prevalence of genes that cause hearing impairment (HI) in Africa. Pre-screening mouse cell lines to identify orthologues of interest has the potential to improve the genetic diagnosis for HI in Africa to a significant percentage, for example, 10–20%. Furthermore, the functionality of a candidate gene derived from mouse screening with heterogeneous genetic backgrounds and multi-omic approaches can shed light on the molecular, genetic heterogeneity and plausible mode of inheritance of a gene in hearing-impaired individuals especially in the absence of large families to investigate.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. Ubiquitin-specific peptidase 18 (USP18) protein has been reported to exert different tumor-related effects in distinct tumor types. Here, we initially investigated the expression and signaling pathways of USP18 in colon adenocarcinoma (COAD).
Methods
A quantitative real-time PCR was conducted to evaluate the mRNA level of USP18 in cultured cells. Immunohistochemical staining was used to explore the protein expression of USP18 in clinical COAD samples. Specific knockdown was achieved by transient transfection of small interfering RNAs into SW480 and HT29 cells using Lipo3000. Cell conting kit-8 assay, transwell assay and matrigel-transwell assays were conducted to evaluate proliferation, migration and invasion capacities, respectively. Western blotting was performed to analyze downstream signaling pathways. A chi-squared test and univariate and multivariate analyses were used to evaluate the clinical data. Xenografts from mice model were assessed to validate the in vitro findings.
Results
Higher USP18 level was identified in COAD tissues and was positively correlated with advanced tumor stage. High USP18 protein expression indicated poorer prognosis of COAD patients. Silencing USP18 suppressed COAD cell proliferation and invasion via destabilizing extracellular signal-regulated kinase (ERK) protein and suppressing ERK downstream pathways. Simultaneously silencing interferon-stimulated gene 15 (ISG15) with USP18 can partially rescue the tumor cell viability, indicating its involvement in USP18 signaling. The oncogenic effects of USP18 were also confirmed in mice models.
Conclusions
USP18 plays oncogenic effects in colon adenocarcinoma via ISG15-ERK pathways. High USP18 expression indicates poor clinical outcomes for colon adenocarcinoma patients.
{"title":"USP18 promotes colon adenocarcinoma progression via targeting the ERK-MNK signaling pathway","authors":"Nan Tang, Xiaojian Liu","doi":"10.1002/jgm.3709","DOIUrl":"10.1002/jgm.3709","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. Ubiquitin-specific peptidase 18 (USP18) protein has been reported to exert different tumor-related effects in distinct tumor types. Here, we initially investigated the expression and signaling pathways of USP18 in colon adenocarcinoma (COAD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A quantitative real-time PCR was conducted to evaluate the mRNA level of <i>USP18</i> in cultured cells. Immunohistochemical staining was used to explore the protein expression of USP18 in clinical COAD samples. Specific knockdown was achieved by transient transfection of small interfering RNAs into SW480 and HT29 cells using Lipo3000. Cell conting kit-8 assay, transwell assay and matrigel-transwell assays were conducted to evaluate proliferation, migration and invasion capacities, respectively. Western blotting was performed to analyze downstream signaling pathways. A chi-squared test and univariate and multivariate analyses were used to evaluate the clinical data. Xenografts from mice model were assessed to validate the in vitro findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Higher USP18 level was identified in COAD tissues and was positively correlated with advanced tumor stage. High USP18 protein expression indicated poorer prognosis of COAD patients. Silencing USP18 suppressed COAD cell proliferation and invasion via destabilizing extracellular signal-regulated kinase (ERK) protein and suppressing ERK downstream pathways. Simultaneously silencing interferon-stimulated gene 15 (ISG15) with USP18 can partially rescue the tumor cell viability, indicating its involvement in USP18 signaling. The oncogenic effects of USP18 were also confirmed in mice models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>USP18 plays oncogenic effects in colon adenocarcinoma via ISG15-ERK pathways. High USP18 expression indicates poor clinical outcomes for colon adenocarcinoma patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aggrephagy, a type of autophagy, degrades the aggregation of misfolded protein in cells. However, the role of aggrephagy in multiple myeloma (MM) has not been fully demonstrated. In this study, we first investigated the correlation between aggrephagy signaling, MM immune microenvironment composition and disease prognosis. Single-cell RNA-seq data, including the expression profiles of 12,187 single cells from seven MM bone marrow (BM) and seven healthy BM samples, were analyzed by non-negative matrix factorization for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from the Gene Expression Omnibus database were used to evaluate the prognostic value of aggrephagy-related immune cell subtypes and predict immune checkpoint blockade immunotherapeutic response in MM. Compared with healthy BM, MM BM exhibited different patterns of aggrephagy-related gene expression. In MM BM, macrophages, CD8+ T cells, B cells and natural killer cells could be grouped into four to nine aggrephagy-related subclusters. The signature of aggrephagy signaling molecule expression in the immune cells correlates with the patient's prognosis. Our investigation provides a novel view of aggrephagy signaling in MM tumor microenvironment cells, which might be a prognostic indicator and potential target for MM treatment.
自噬（Aggrephagy）是自噬的一种，它能降解细胞中错误折叠蛋白的聚集。然而，aggrephagy 在多发性骨髓瘤（MM）中的作用尚未得到充分证实。在这项研究中，我们首先研究了aggrephagy信号传导、MM免疫微环境组成和疾病预后之间的相关性。通过非负矩阵因式分解法分析了单细胞RNA-seq数据，包括来自7个MM骨髓（BM）样本和7个健康BM样本的12187个单细胞的表达谱，其中有44个与aggrephagy相关的基因。基因表达总库（Gene Expression Omnibus）数据库中的大量RNA-seq队列被用来评估侵袭相关免疫细胞亚型的预后价值，并预测MM的免疫检查点阻断免疫治疗反应。与健康血清相比，MM 血清中与吞噬细胞相关的基因表达表现出不同的模式。在 MM BM 中，巨噬细胞、CD8+ T 细胞、B 细胞和自然杀伤细胞可分为四至九个侵袭相关亚群。侵噬信号分子在免疫细胞中的表达特征与患者的预后相关。我们的研究为侵噬信号在 MM 肿瘤微环境细胞中的表达提供了一个新的视角，这可能是一个预后指标和 MM 治疗的潜在靶点。
{"title":"Single-cell sequencing reveals the correlation of aggrephagy signaling and multiple myeloma immune microenvironment composition","authors":"Xin Wang, Yu Feng, Fangfang Wang, Zhimei Lin, Jingcao Huang, Qian Li, Hongmei Luo, Xiang Liu, Xinyu Zhai, Qianwen Gao, Linfeng Li, Yue Zhang, Jingjing Wen, Li Zhang, Ting Niu, Yuhuan Zheng","doi":"10.1002/jgm.3712","DOIUrl":"10.1002/jgm.3712","url":null,"abstract":"<p>Aggrephagy, a type of autophagy, degrades the aggregation of misfolded protein in cells. However, the role of aggrephagy in multiple myeloma (MM) has not been fully demonstrated. In this study, we first investigated the correlation between aggrephagy signaling, MM immune microenvironment composition and disease prognosis. Single-cell RNA-seq data, including the expression profiles of 12,187 single cells from seven MM bone marrow (BM) and seven healthy BM samples, were analyzed by non-negative matrix factorization for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from the Gene Expression Omnibus database were used to evaluate the prognostic value of aggrephagy-related immune cell subtypes and predict immune checkpoint blockade immunotherapeutic response in MM. Compared with healthy BM, MM BM exhibited different patterns of aggrephagy-related gene expression. In MM BM, macrophages, CD8<sup>+</sup> T cells, B cells and natural killer cells could be grouped into four to nine aggrephagy-related subclusters. The signature of aggrephagy signaling molecule expression in the immune cells correlates with the patient's prognosis. Our investigation provides a novel view of aggrephagy signaling in MM tumor microenvironment cells, which might be a prognostic indicator and potential target for MM treatment.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC.
Methods
An HCC model was established in male Sprague–Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses.
Results
The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs.
Conclusions
The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.
{"title":"Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression","authors":"Jun-Sheng Ni, Si-Yuan Fu, Zong-Yan Wang, Wen-Bin Ding, Jian Huang, Xing-Gang Guo, Fang-Ming Gu","doi":"10.1002/jgm.3693","DOIUrl":"10.1002/jgm.3693","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An HCC model was established in male Sprague–Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of <i>Il17a</i> was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing <i>Fap</i> in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinyun Fang, Dianke Li, Shiyue Wan, Junjie Hu, Peng Zhang, Dai Jie, Linsong Chen, Gening Jiang, Nan Song
Background
Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level.
Methods
By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients.
Results
LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC.
Conclusions
These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.
{"title":"Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes","authors":"Xinyun Fang, Dianke Li, Shiyue Wan, Junjie Hu, Peng Zhang, Dai Jie, Linsong Chen, Gening Jiang, Nan Song","doi":"10.1002/jgm.3694","DOIUrl":"10.1002/jgm.3694","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione <i>S</i>-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hui Ma, Xiaoqian Ma, Lingyu Qi, Qian Zhang, Tiange Wang, Qingdong Guo, Peng Li, Shutian Zhang, Si Liu
<div> <section> <h3> Background</h3> <p>Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA<sub>1</sub>–LPA<sub>6</sub>). Our previous study demonstrated that the LPA-producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain.</p> </section> <section> <h3> Methods</h3> <p>MTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA-stimulated esophageal epithelial cells (Het-1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early-stage ESCC. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA-mediated communication between epithelial cells and cancer cells.</p> </section> <section> <h3> Results</h3> <p>Functional experiments showed that exposing ESCC cancer cells to CM from LPA-treated Het-1a results in promoting proliferation, migration, invasion and epithelial–mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro-migration influence of CM derived from LPA-treated Het-1a. Mechanism studies have demonstrated that LPA activated the NF-<i>κ</i>B signaling pathway through LPA<sub>1/3</sub>, ultimately causing an increase in CCL2 expression and secretion in Het-1a.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings, t
{"title":"Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells","authors":"Hui Ma, Xiaoqian Ma, Lingyu Qi, Qian Zhang, Tiange Wang, Qingdong Guo, Peng Li, Shutian Zhang, Si Liu","doi":"10.1002/jgm.3708","DOIUrl":"https://doi.org/10.1002/jgm.3708","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA<sub>1</sub>–LPA<sub>6</sub>). Our previous study demonstrated that the LPA-producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>MTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA-stimulated esophageal epithelial cells (Het-1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early-stage ESCC. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA-mediated communication between epithelial cells and cancer cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Functional experiments showed that exposing ESCC cancer cells to CM from LPA-treated Het-1a results in promoting proliferation, migration, invasion and epithelial–mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro-migration influence of CM derived from LPA-treated Het-1a. Mechanism studies have demonstrated that LPA activated the NF-<i>κ</i>B signaling pathway through LPA<sub>1/3</sub>, ultimately causing an increase in CCL2 expression and secretion in Het-1a.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings, t","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141251350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dental pulp in a confined environment, with little connection to the outside and only a small distribution of immune cells, provides a good research model for investigating how cells respond to bacterial infections through cytokines.
Methods
The data of single-cell transcriptome sequencing of healthy and inflamed pulp tissue were downloaded from the GEO dataset. The expression character of 79 cytokines was analyzed based on the expression matrix.
Results
The cytokine secretion profiles of the two populations of pulp cells in healthy dental pulp were associated with vascularization and nervous system development, as well as immune cell regulation. For the three populations of pulp stem cells with stem cell activity in the dental pulp, the secretion of cytokines related to nervous system development, regulation of endothelial cell proliferation and migration, and regulation of immune cell function comprised the characteristics that we observed. The cytokines secreted by T cells and macrophages were more of an immune reserve against pathogenic microorganisms. In the inflammatory state, the spectrum of cytokines secreted by various types of cells in the dental pulp tended to be identical, such that it mainly resisted pathogenic microorganisms.
Conclusions
The cytokine secretion profiles of various cell types in healthy and inflamed dental pulp at the single-cell level are summarized.
{"title":"The profile of cytokines against bacterial infection in dental pulp","authors":"Zhongcheng Bai, Jun Liu, Hehuizi Bai","doi":"10.1002/jgm.3707","DOIUrl":"10.1002/jgm.3707","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dental pulp in a confined environment, with little connection to the outside and only a small distribution of immune cells, provides a good research model for investigating how cells respond to bacterial infections through cytokines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The data of single-cell transcriptome sequencing of healthy and inflamed pulp tissue were downloaded from the GEO dataset. The expression character of 79 cytokines was analyzed based on the expression matrix.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The cytokine secretion profiles of the two populations of pulp cells in healthy dental pulp were associated with vascularization and nervous system development, as well as immune cell regulation. For the three populations of pulp stem cells with stem cell activity in the dental pulp, the secretion of cytokines related to nervous system development, regulation of endothelial cell proliferation and migration, and regulation of immune cell function comprised the characteristics that we observed. The cytokines secreted by T cells and macrophages were more of an immune reserve against pathogenic microorganisms. In the inflammatory state, the spectrum of cytokines secreted by various types of cells in the dental pulp tended to be identical, such that it mainly resisted pathogenic microorganisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The cytokine secretion profiles of various cell types in healthy and inflamed dental pulp at the single-cell level are summarized.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guo Zhao, Yuanting Cai, Yuning Wang, Yuan Fang, Shuhang Wang, Ning Li
Background
Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators.
Methods
The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used.
Results
MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39+CD8+ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016).
Conclusions
The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39+CD8+ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.
背景胰腺癌的特点是代谢失调和独特的免疫学特征。然而，对胰腺癌的免疫和代谢失调的全面了解仍不清楚。本研究旨在探讨循环免疫细胞与胰腺癌的因果关系，并确定血液代谢物作为潜在的介导因素。 方法 本研究使用的暴露和结局全基因组关联研究（GWAS）数据来自 GWAS 开放存取数据库（https://gwas.mrcieu.ac.uk）。研究使用了 GWAS 中的 731 个循环免疫细胞特征、1400 种血液代谢物和胰腺癌。然后，我们进行了双向孟德尔随机化（MR）分析，以探索循环免疫细胞与胰腺癌之间的因果关系，并进行了两步MR分析，以发现这一过程中潜在的介导血液代谢物。所有统计分析均在 R 软件中进行。同时还使用了STROBE-MR（即利用孟德尔随机化加强流行病学观察性研究的报告）核对表来报告MR研究。 结果 MR 分析确定了七种与胰腺癌有因果关系的循环免疫细胞。此外，没有强有力的证据表明基因预测的胰腺癌会对这七种类型的循环免疫细胞产生影响。进一步的两步磁共振分析发现，有 10 种血液代谢物与胰腺癌存在因果关系，循环 CD39+CD8+ T 细胞与胰腺癌之间的关系由血液乳清酸介导，比例为 5.18%（P = 0.016）。 结论 本研究为各种循环免疫细胞（尤其是 CD39+CD8+ T 细胞）与胰腺癌之间的因果关系提供了证据支持，而血液中的乳清酸可能是其中介效应。需要进一步研究作为潜在介质的其他风险因素，并建立胰腺癌的全面免疫-代谢网络。
{"title":"Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study","authors":"Guo Zhao, Yuanting Cai, Yuning Wang, Yuan Fang, Shuhang Wang, Ning Li","doi":"10.1002/jgm.3691","DOIUrl":"https://doi.org/10.1002/jgm.3691","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39<sup>+</sup>CD8<sup>+</sup> T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (<i>p</i> = 0.016).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39<sup>+</sup>CD8<sup>+</sup> T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ye Li, Weinian Gao, Shuyan Lei, Xiaoning Wu, Tao Yuan, Kai Ma, Kui Chi
Background
Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved.
Methods
The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen–glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection.
Results
Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells.
Conclusions
Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.
背景：七氟烷（Sevo）预处理和后处理对肝缺血再灌注（I/R）引起的损伤具有保护作用。与此同时，巨噬细胞浸润在这一过程中的参与和确切机制尚不清楚。在此，我们设计了这项研究，以阐明赛沃对肝脏 I/R 损伤的保护作用及其参与分子：方法：通过肝功能分析、苏木精和伊红染色、Masson 三色染色、末端脱氧核苷酸转移酶介导的 2'-deoxyuridine 5'-triphosphate nick end 标记、Western 印迹分析和酶联免疫吸附试验分析赛沃对肝损伤的缓解作用。利用α-小鼠肝12（AML12）细胞建立了体外细胞模型，并对该细胞模型进行了氧-葡萄糖剥夺、再氧和Sevo处理。利用多个生物信息学数据库筛选与肝I/R损伤相关的转录调节因子以及Krueppel样因子5（KLF5）的靶标。为了证实KLF5参与了Sevo介导的肝脏保护作用，研究人员单独或在敲除整合素β2（ITGB2）的情况下人为上调了KLF5的表达：结果：Sevo通过减少细胞凋亡和炎症反应保护肝脏免受I/R损伤。KLF5在I/R损伤后的肝组织中上调，而KLF5的过表达会加重巨噬细胞浸润和I/R损伤引起的肝损伤。KLF5与ITGB2的启动子结合，增强了ITGB2的转录。在小鼠和AML12细胞中，敲除ITGB2可逆转KLF5过表达导致的损伤加重：Sevo阻断了KLF5介导的ITGB2转录激活，从而抑制了肝I/R损伤中巨噬细胞的浸润。
{"title":"Sevoflurane blocks KLF5-mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury","authors":"Ye Li, Weinian Gao, Shuyan Lei, Xiaoning Wu, Tao Yuan, Kai Ma, Kui Chi","doi":"10.1002/jgm.3692","DOIUrl":"10.1002/jgm.3692","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen–glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung cancer stands out as a highly perilous malignant tumor with severe implications for human health. There has been a growing interest in neutrophils as a result of their role in promoting cancer in recent years. Thus, the present study aimed to investigate the heterogeneity of neutrophils in non-small cell lung cancer (NSCLC).
Methods
Single-cell RNA sequencing of tumor-associated neutrophils (TANs) and polymorphonuclear neutrophils sourced from the Gene Expression Omnibus database was analyzed. Moreover, cell–cell communication, differentiation trajectories and transcription factor analyses were performed.
Results
Neutrophils were found to be closely associated with macrophages. Four major types of TANs were identified: a transitional subcluster that migrated from blood to tumor microenvironment (TAN-0), an inflammatory subcluster (TAN-1), a subpopulation that displayed a distinctive transcriptional signature (TAN-2) and a final differentiation state that promoted tumor formation (TAN-3). Meanwhile, TAN-3 displayed a marked increase in glycolytic activity. Finally, transcription factors were analyzed to uncover distinct TAN cluster-specific regulons.
Conclusions
The discovery of the dynamic characteristics of TANs in the present study is anticipated to contribute to yielding a better understanding of the tumor microenvironment and advancing the treatment of NSCLC.
背景：肺癌是一种高度危险的恶性肿瘤，对人类健康具有严重影响。近年来，由于中性粒细胞在促进癌症发生中的作用，人们对中性粒细胞的兴趣日益浓厚。因此，本研究旨在探讨非小细胞肺癌（NSCLC）中中性粒细胞的异质性：方法：分析了来自基因表达总库（Gene Expression Omnibus）的肿瘤相关中性粒细胞（TANs）和多形核中性粒细胞的单细胞RNA测序。此外，还进行了细胞间通讯、分化轨迹和转录因子分析：结果：发现中性粒细胞与巨噬细胞密切相关。结果：研究发现中性粒细胞与巨噬细胞密切相关，并确定了四种主要的 TANs 类型：从血液迁移到肿瘤微环境的过渡亚群（TAN-0）、炎症亚群（TAN-1）、显示独特转录特征的亚群（TAN-2）和促进肿瘤形成的最终分化状态（TAN-3）。同时，TAN-3 显示出明显的糖酵解活性增加。最后，通过分析转录因子发现了不同的TAN集群特异性调控子：结论：本研究发现了TANs的动态特征，预计这将有助于更好地了解肿瘤微环境并推进NSCLC的治疗。
{"title":"Single-cell transcriptome analysis reveals heterogeneity of neutrophils in non-small cell lung cancer","authors":"Yunzhen Wang, Ziyi Zhu, Raojun Luo, Wenwen Chen","doi":"10.1002/jgm.3690","DOIUrl":"10.1002/jgm.3690","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lung cancer stands out as a highly perilous malignant tumor with severe implications for human health. There has been a growing interest in neutrophils as a result of their role in promoting cancer in recent years. Thus, the present study aimed to investigate the heterogeneity of neutrophils in non-small cell lung cancer (NSCLC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell RNA sequencing of tumor-associated neutrophils (TANs) and polymorphonuclear neutrophils sourced from the Gene Expression Omnibus database was analyzed. Moreover, cell–cell communication, differentiation trajectories and transcription factor analyses were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neutrophils were found to be closely associated with macrophages. Four major types of TANs were identified: a transitional subcluster that migrated from blood to tumor microenvironment (TAN-0), an inflammatory subcluster (TAN-1), a subpopulation that displayed a distinctive transcriptional signature (TAN-2) and a final differentiation state that promoted tumor formation (TAN-3). Meanwhile, TAN-3 displayed a marked increase in glycolytic activity. Finally, transcription factors were analyzed to uncover distinct TAN cluster-specific regulons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The discovery of the dynamic characteristics of TANs in the present study is anticipated to contribute to yielding a better understanding of the tumor microenvironment and advancing the treatment of NSCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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