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Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression 白细胞介素-17A教育的肝星状细胞通过成纤维细胞活化蛋白的表达促进肝细胞癌的发生。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-06-11 DOI: 10.1002/jgm.3693
Jun-Sheng Ni, Si-Yuan Fu, Zong-Yan Wang, Wen-Bin Ding, Jian Huang, Xing-Gang Guo, Fang-Ming Gu

Background

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.

背景：肝癌的典型特征是具有复杂的炎症性肿瘤微环境，在这种环境中，一系列细胞因子和基质细胞组成了一个环境，对肿瘤发生产生了重大影响。白细胞介素-17A（IL-17A）是一种主要由 Th17 细胞分泌的关键性促炎细胞因子，在肝癌的病因和进展中发挥着重要作用。然而，IL-17A 与肝星状细胞（HSCs）相互作用促进肝细胞癌（HCC）发展的确切机制仍有待全面阐明。本研究试图揭示IL-17A与造血干细胞在HCC中的相互作用：方法：用二乙基亚硝胺在雄性 Sprague-Dawley 大鼠体内建立了一个 HCC 模型，以探讨 IL-17A 和造血干细胞在 HCC 发病机制中的作用。利用腺相关病毒实现了Il17a的体内过表达。体外分析采用了一系列分子技术，包括 RT-qPCR、酶联免疫吸附试验、Western 印迹、细胞计数试剂盒-8 试验和集落形成试验：研究结果表明，IL-17A 是促进 HCC 的关键介质，主要是通过激活肝祖细胞（HPCs）。这种促肿瘤作用似乎是由造血干细胞介导的，而不是通过直接作用于 HPCs。值得注意的是，IL-17A 诱导的成纤维细胞活化蛋白（FAP）在造血干细胞中的表达成为 HCC 进展的关键因素。据观察，抑制 IL-17A 刺激的造血干细胞中的 FAP 可逆转造血干细胞对 HCC 的促进作用：本研究的综合证据表明，造血干细胞中的 IL-17A/FAP 信号轴通过增强造血干细胞的活化作用而促进了 HCC 的发展。这些发现增强了 IL-17A 作为 HCC 诊断和预防靶点的潜力，为治疗干预提供了新途径。
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引用次数: 0
Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes 通过单细胞转录组分析了解肺腺癌和鳞癌肿瘤微环境的异质性：对不同免疫疗法结果的影响
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-06-07 DOI: 10.1002/jgm.3694
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.

背景：免疫检查点阻断已成为治疗非小细胞肺癌（NSCLC）的关键策略。然而，肺腺癌（LUAD）和肺鳞癌（LUSC）这两种主要的非小细胞肺癌亚型之间的免疫治疗结果存在显著差异。这种差异可能源于肿瘤免疫微环境在转录组水平上的异质性：本研究通过单细胞RNA测序对38例NSCLC患者的转录组特征进行综合分析，发现LUAD和LUSC之间存在不同的肿瘤微环境（TME），相关结果在新辅助免疫疗法患者的批量转录组和多重免疫荧光（mIF）验证队列中得到进一步证实：结果：与LUSC相比，LUAD表现出更活跃的免疫微环境。这包括癌细胞中 HLA I/II 的高表达、树突状细胞抗原呈递潜能的增强以及 T/NK 细胞细胞毒性活性的增强。在 LUSC 中，癌细胞高表达属于醛酮还原酶、谷胱甘肽 S 转移酶和醛脱氢酶家族的基因，这与本中心验证队列中的免疫疗法结果呈负相关。进一步分析发现，LUSC 中浸润的癌相关成纤维细胞（CAFs）增加，这在癌症基因组图谱队列中得到了证实。多重 mIF 显示，在主要病理反应（MPR）患者中，ADH1B+ CAFs 的浸润相应增加，而在非主要病理反应患者中，FAP+ CAFs 的存在率较高。此外，在 LUSC 中还发现了免疫抑制性细胞外基质重塑的上调：这些综合分析加深了人们对 LUAD 和 LUSC TME 差异的理解，为选择患者和制定亚型特异性治疗策略提供了启示。
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引用次数: 0
Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells 溶血磷脂酸通过提高食管上皮细胞分泌的 CCL2 水平促进 ESCC 的进展
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-06-05 DOI: 10.1002/jgm.3708
Hui Ma, Xiaoqian Ma, Lingyu Qi, Qian Zhang, Tiange Wang, Qingdong Guo, Peng Li, Shutian Zhang, Si Liu

Background

Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA1–LPA6). 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.

Methods

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.

Results

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-κB signaling pathway through LPA1/3, ultimately causing an increase in CCL2 expression and secretion in Het-1a.

Conclusions

Our findings, t

背景溶血磷脂酸（LPA）是一种小型生物活性脂质，它通过六种G蛋白偶联受体（LPA1-LPA6）在各种肿瘤进展过程中发挥着强有力的调节作用。我们之前的研究表明，食管鳞状细胞癌（ESCC）中的LPA生成酶自旋共振素（ATX）上调，ATX的高表达水平预示着不良预后。食管鳞状细胞癌是一种起源于上皮细胞的恶性肿瘤。癌细胞与正常细胞之间的相互作用会影响其发展。然而，在 ESCC 的发展过程中，LPA 对食管上皮细胞和癌细胞之间相互作用的影响仍不确定。 方法 采用 MTS 和 Edu 试验测定 ESCC 细胞在 LPA 刺激的食管上皮细胞（Het-1a）培养基（CM）中的增殖情况。为了评估 ESCC 细胞的转移能力，还进行了伤口愈合试验、跨孔迁移试验和侵袭试验。细胞因子阵列分析用于检测 CM 中不同分泌的细胞因子。癌症基因组图谱（TCGA）和基因表达总库（GEO）数据库被用来揭示ESCC中受LPA影响的通路和细胞因子。免疫组化染色法用于测量早期 ESCC 中 ATX 和 CCL2 的表达。采用定量实时 PCR、Western 印迹、酶联免疫吸附试验和抗体中和试验来测定 LPA 介导的上皮细胞与癌细胞之间的通讯机制。 结果 功能实验表明，将 ESCC 癌细胞暴露于经 LPA 处理的 Het-1a 的 CM 中，可促进其增殖、迁移、侵袭和上皮-间质转化过程。通过细胞因子阵列分析，我们发现 LPA 会触发上皮细胞释放多种细胞因子。在对 TCGA 和 GEO 数据库进行筛选后，我们发现 CCL2 与 ESCC 中 ATX 的表达相关。此外，还观察到上皮细胞在受到 LPA 刺激时，CCL2 的 mRNA 表达和分泌水平都会上调。阻断 CCL2 能有效降低经 LPA 处理的 Het-1a 细胞 CM 的促迁移影响。机制研究表明，LPA 通过 LPA1/3 激活 NF-κB 信号通路，最终导致 Het-1a 中 CCL2 表达和分泌增加。 结论 我们的研究结果综合证明，来自 LPA 处理过的食管上皮细胞的 CM 在促进 ESCC 的进展中起着重要作用，而 CCL2 是主要的调节因子。
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引用次数: 0
The profile of cytokines against bacterial infection in dental pulp 细胞因子对牙髓细菌感染的影响。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-05-29 DOI: 10.1002/jgm.3707
Zhongcheng Bai, Jun Liu, Hehuizi Bai

Background

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.

背景：牙髓处于一个封闭的环境中，与外界几乎没有联系，只有少量的免疫细胞分布，这为研究细胞如何通过细胞因子对细菌感染做出反应提供了一个很好的研究模型：方法：从 GEO 数据集中下载了健康牙髓组织和发炎牙髓组织的单细胞转录组测序数据。方法：从 GEO 数据集中下载了健康和发炎牙髓组织的单细胞转录组测序数据，并根据表达矩阵分析了 79 种细胞因子的表达特征：结果：健康牙髓中两组牙髓细胞的细胞因子分泌特征与血管形成、神经系统发育以及免疫细胞调节有关。对于牙髓中具有干细胞活性的三组牙髓干细胞，我们观察到的细胞因子分泌特征包括与神经系统发育有关的细胞因子、调节内皮细胞增殖和迁移的细胞因子以及调节免疫细胞功能的细胞因子。T 细胞和巨噬细胞分泌的细胞因子更多的是针对病原微生物的免疫储备。在炎症状态下，牙髓中各类细胞分泌的细胞因子谱趋于一致，因此主要是抵抗病原微生物：总结了健康牙髓和炎症牙髓中各类细胞在单细胞水平上的细胞因子分泌谱。
{"title":"The profile of cytokines against bacterial infection in dental pulp","authors":"Zhongcheng Bai,&nbsp;Jun Liu,&nbsp;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":null,"pages":null},"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}
引用次数: 0
Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study 基因预测的血液代谢物介导了循环免疫细胞与胰腺癌之间的关联：孟德尔随机化研究
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-05-16 DOI: 10.1002/jgm.3691
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。
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引用次数: 0
Sevoflurane blocks KLF5-mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury 七氟烷可阻断KLF5介导的ITGB2转录激活，从而抑制肝缺血再灌注损伤中巨噬细胞的浸润。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-05-14 DOI: 10.1002/jgm.3692
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。
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引用次数: 0
Single-cell transcriptome analysis reveals heterogeneity of neutrophils in non-small cell lung cancer 单细胞转录组分析揭示了非小细胞肺癌中性粒细胞的异质性。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-05-12 DOI: 10.1002/jgm.3690
Yunzhen Wang, Ziyi Zhu, Raojun Luo, Wenwen Chen

Background

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。
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引用次数: 0
mmu-miR-185 regulates osteoclasts differentiation and migration by targeting Btk mmu-miR-185 通过靶向 Btk 调节破骨细胞的分化和迁移
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-05-01 DOI: 10.1002/jgm.3687
Dan He, Yueying Jiao, Jian Xu, Junjie Luo, Yaqi Cui, Xiabing Han, Hongshan Zhao

Background

Bones undergo a constant remodeling, a process involving osteoclast-mediated bone resorption and osteoblast-mediated bone formation, crucial for maintaining healthy bone mass. We previously observed that miR-185 depletion may promote bone formation by regulating Bgn expression and the BMP/Smad signaling pathway. However, the effects of miR-185-5p on the osteoclasts and bone remodeling have not been elucidated, warranting further exploration.

Methods

Tartrate-resistant acid phosphatase staining was utilized to assess the differentiation ability of bone marrow mononuclear macrophages (BMMs) from mmu-miR-185 gene knockout (KO) mice and wild-type (WT) mice. A reverse transcriptase-quantitative PCR was conducted to compare differences in miR-185-5p and osteoclast marker molecules, including Trap, Dcstamp, Ctsk and Nfatc1, between the KO group and WT group BMMs. Western blot analysis was employed to observe the expression of osteoclast marker molecules. A cell-counting kit-8 was used to analyze cell proliferation ability. Transwell experiments were conducted to detect cell migration. Dual-luciferase reporter assays were employed to confirm whether Btk is a downstream target gene of miR-185-5p.

Results

miR-185 depletion promoted osteoclast differentiation in bone marrow-derived monocytes/macrophages. Overexpression of miR-185-5p in RAW264.7 cells inhibited differentiation and migration of osteoclasts. Furthermore, Btk was identified as a downstream target gene of miR-185-5p, suggesting that miR-185-5p may inhibit osteoclast differentiation and migration by targeting Btk.

Conclusions

miR-185 regulates osteoclasts differentiation, with overexpression of miR-185-5p inhibiting osteoclast differentiation and migration in vitro. Additionally, miR-185-5p may modulate osteoclastic differentiation and migration by regulating Btk expression.

背景骨骼不断重塑，这一过程涉及破骨细胞介导的骨吸收和成骨细胞介导的骨形成，对维持健康的骨量至关重要。我们以前曾观察到，miR-185 的消耗可通过调节 Bgn 的表达和 BMP/Smad 信号通路来促进骨形成。然而，miR-185-5p 对破骨细胞和骨重塑的影响尚未阐明，值得进一步探讨。 方法 利用耐酒石酸磷酸酶染色法评估 mmu-miR-185 基因敲除（KO）小鼠和野生型（WT）小鼠骨髓单核巨噬细胞（BMMs）的分化能力。反转录酶定量 PCR 比较了 KO 组和 WT 组骨髓单核巨噬细胞中 miR-185-5p 和破骨细胞标记分子（包括 Trap、Dcstamp、Ctsk 和 Nfatc1）的差异。采用 Western 印迹分析观察破骨细胞标记分子的表达。使用细胞计数试剂盒-8分析细胞增殖能力。透孔实验用于检测细胞迁移。采用双荧光素酶报告实验证实 Btk 是否是 miR-185-5p 的下游靶基因。 结果 miR-185 的缺失促进了骨髓单核细胞/巨噬细胞的破骨细胞分化。在 RAW264.7 细胞中过表达 miR-185-5p 可抑制破骨细胞的分化和迁移。此外，Btk 被确定为 miR-185-5p 的下游靶基因，这表明 miR-185-5p 可能通过靶向 Btk 来抑制破骨细胞的分化和迁移。 结论 miR-185 可调控破骨细胞的分化，过表达 miR-185-5p 可抑制体外破骨细胞的分化和迁移。此外，miR-185-5p 可能通过调节 Btk 的表达来调节破骨细胞的分化和迁移。
{"title":"mmu-miR-185 regulates osteoclasts differentiation and migration by targeting Btk","authors":"Dan He,&nbsp;Yueying Jiao,&nbsp;Jian Xu,&nbsp;Junjie Luo,&nbsp;Yaqi Cui,&nbsp;Xiabing Han,&nbsp;Hongshan Zhao","doi":"10.1002/jgm.3687","DOIUrl":"https://doi.org/10.1002/jgm.3687","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bones undergo a constant remodeling, a process involving osteoclast-mediated bone resorption and osteoblast-mediated bone formation, crucial for maintaining healthy bone mass. We previously observed that <i>miR-185</i> depletion may promote bone formation by regulating <i>Bgn</i> expression and the BMP/Smad signaling pathway. However, the effects of <i>miR-185-5p</i> on the osteoclasts and bone remodeling have not been elucidated, warranting further exploration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Tartrate-resistant acid phosphatase staining was utilized to assess the differentiation ability of bone marrow mononuclear macrophages (BMMs) from <i>mmu-miR-185</i> gene knockout (KO) mice and wild-type (WT) mice. A reverse transcriptase-quantitative PCR was conducted to compare differences in <i>miR-185-5p</i> and osteoclast marker molecules, including <i>Trap</i>, <i>Dcstamp</i>, <i>Ctsk</i> and <i>Nfatc1</i>, between the KO group and WT group BMMs. Western blot analysis was employed to observe the expression of osteoclast marker molecules. A cell-counting kit-8 was used to analyze cell proliferation ability. Transwell experiments were conducted to detect cell migration. Dual-luciferase reporter assays were employed to confirm whether <i>Btk</i> is a downstream target gene of <i>miR-185-5p</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>miR-185</i> depletion promoted osteoclast differentiation in bone marrow-derived monocytes/macrophages. Overexpression of <i>miR-185-5p</i> in RAW264.7 cells inhibited differentiation and migration of osteoclasts. Furthermore, <i>Btk</i> was identified as a downstream target gene of <i>miR-185-5p</i>, suggesting that <i>miR-185-5p</i> may inhibit osteoclast differentiation and migration by targeting <i>Btk</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>miR-185</i> regulates osteoclasts differentiation, with overexpression of <i>miR-185-5p</i> inhibiting osteoclast differentiation and migration in vitro. Additionally, <i>miR-185-5p</i> may modulate osteoclastic differentiation and migration by regulating <i>Btk</i> expression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817270","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}
引用次数: 0
Comprehensive profiling of endocrine metabolism identifies a novel signature with robust predictive value in ovarian cancer 内分泌代谢综合分析确定了对卵巢癌具有强大预测价值的新特征
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-04-30 DOI: 10.1002/jgm.3686
Dan Yu, Yan Luo, Rong Guo, Fang Ma, Yunyun Chang, Jianhong Dang

Background

The cell endocrine pathway is a critical physiological process composed of the endoplasmic reticulum, Golgi apparatus and associated vesicles. Loss of enzymes or proteins can cause dysfunction of endoplasmic reticulum and Golgi apparatus and affect secretion pathways leading to a variety of human diseases, including cancer.

Methods

The single-cell RNA sequencing and single nucleotide variant principal component analysis data of ovarian cancer were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Eighty-four genes from SECRETORY_PATHWAYs were obtained from the gene set enrichment analysis (GSEA) website. Univariate cox regression analyses and ConsensusClusterPlus were used to identify prognostic genes and molecular subtypes, which were validated using the tumor immune dysfunction and exclusion (i.e. TIDE) analysis and gene mutation analysis. A prognosis model was established by randomForestSRC. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ssGSEA, ESTIMATE, MCP-counter and GSEA. The drug sensitive analysis was performed using pRRophetic package. Immunotherapy datasets and pan-carcinoma analysis were used to examine the performance of prognostic model.

Results

Eighteen prognostic genes from SECRETORY_PATHWAYs were found in both TCGA and GEO datasets. Next, two clusters (C1 and C2) were determined, for which C1 with a poor prognosis had higher immune infiltration. Tumor-related pathways, such as PATHWAYS_IN_CANCER and B_CELL_RECEPTOR_SIGNALING_PATHWAY, were enriched in C1. Moreover, C2 was suitable for immunotherapy. A four-gene (DNAJA1, NDRG3, LUZP1 and ZCCHC24) signature was developed and successfully validated. RiskScore of higher levels were significantly associated with worse prognoses. An enhanced immune infiltration, increased pathways score and inappropriate immunotherapy were observed in the high RiskScore group. The high- and low-RiskScore groups had different drug sensitivities. Immunotherapy datasets and pan-carcinoma analysis indicated that the low RiskScore group may benefit from immunotherapy.

Conclusions

Based on the perspective of the secretory signaling pathway, a robust prognostic signature with great performances was determined, which may provide clues for clinical precision treatment of ovarian cancer.

背景 细胞内分泌途径是一个关键的生理过程，由内质网、高尔基体和相关囊泡组成。酶或蛋白质的缺失会导致内质网和高尔基体功能失调，影响分泌途径，从而引发包括癌症在内的多种人类疾病。 方法 从癌症基因组图谱（The Cancer Genome Atlas）和基因表达总集（Gene Expression Omnibus，GEO）数据集中检索卵巢癌的单细胞 RNA 测序和单核苷酸变异主成分分析数据。从基因组富集分析（GSEA）网站获取了 SECRETORY_PATHWAYs 中的 84 个基因。利用单变量Cox回归分析和ConsensusClusterPlus确定预后基因和分子亚型，并通过肿瘤免疫功能障碍和排斥（即TIDE）分析和基因突变分析进行验证。随机森林SRC建立了预后模型。通过ssGSEA、ESTIMATE、MCP-counter和GSEA分别进行了大量浸润免疫细胞和通路富集分析。药物敏感性分析使用 pRRophetic 软件包进行。免疫治疗数据集和泛癌分析用于检验预后模型的性能。 结果 在TCGA和GEO数据集中发现了18个来自SECRETORY_PATHWAYs的预后基因。然后，确定了两个集群（C1 和 C2），其中预后较差的 C1 具有较高的免疫浸润。C1中富集了与肿瘤相关的通路，如PATHWAYS_IN_CANCER和B_CELL_RECEPTOR_SIGNALING_PATHWAY。此外，C2 适合免疫疗法。四基因（DNAJA1、NDRG3、LUZP1 和 ZCCHC24）特征被开发出来并成功验证。风险分数越高，预后越差。在高风险分数组中，可以观察到免疫浸润增强、路径评分增加和不适当的免疫疗法。高风险分数组和低风险分数组对药物的敏感性不同。免疫治疗数据集和泛癌分析表明，低风险分数组可能会从免疫治疗中获益。 结论 基于分泌信号通路的视角，确定了一个性能卓越的稳健预后特征，可为卵巢癌的临床精准治疗提供线索。
{"title":"Comprehensive profiling of endocrine metabolism identifies a novel signature with robust predictive value in ovarian cancer","authors":"Dan Yu,&nbsp;Yan Luo,&nbsp;Rong Guo,&nbsp;Fang Ma,&nbsp;Yunyun Chang,&nbsp;Jianhong Dang","doi":"10.1002/jgm.3686","DOIUrl":"https://doi.org/10.1002/jgm.3686","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The cell endocrine pathway is a critical physiological process composed of the endoplasmic reticulum, Golgi apparatus and associated vesicles. Loss of enzymes or proteins can cause dysfunction of endoplasmic reticulum and Golgi apparatus and affect secretion pathways leading to a variety of human diseases, including cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The single-cell RNA sequencing and single nucleotide variant principal component analysis data of ovarian cancer were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Eighty-four genes from SECRETORY_PATHWAYs were obtained from the gene set enrichment analysis (GSEA) website. Univariate cox regression analyses and ConsensusClusterPlus were used to identify prognostic genes and molecular subtypes, which were validated using the tumor immune dysfunction and exclusion (i.e. TIDE) analysis and gene mutation analysis. A prognosis model was established by randomForestSRC. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ssGSEA, ESTIMATE, MCP-counter and GSEA. The drug sensitive analysis was performed using pRRophetic package. Immunotherapy datasets and pan-carcinoma analysis were used to examine the performance of prognostic model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eighteen prognostic genes from SECRETORY_PATHWAYs were found in both TCGA and GEO datasets. Next, two clusters (C1 and C2) were determined, for which C1 with a poor prognosis had higher immune infiltration. Tumor-related pathways, such as PATHWAYS_IN_CANCER and B_CELL_RECEPTOR_SIGNALING_PATHWAY, were enriched in C1. Moreover, C2 was suitable for immunotherapy. A four-gene (DNAJA1, NDRG3, LUZP1 and ZCCHC24) signature was developed and successfully validated. RiskScore of higher levels were significantly associated with worse prognoses. An enhanced immune infiltration, increased pathways score and inappropriate immunotherapy were observed in the high RiskScore group. The high- and low-RiskScore groups had different drug sensitivities. Immunotherapy datasets and pan-carcinoma analysis indicated that the low RiskScore group may benefit from immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Based on the perspective of the secretory signaling pathway, a robust prognostic signature with great performances was determined, which may provide clues for clinical precision treatment of ovarian cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817254","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}
引用次数: 0
MEG3 shuttled by exosomes released from human bone marrow mesenchymal stem cells promotes TP53 stability to regulate MCM5 transcription in keloid fibroblasts 人骨髓间充质干细胞释放的外泌体穿梭的 MEG3 可促进 TP53 的稳定性，从而调节瘢痕疙瘩成纤维细胞中 MCM5 的转录
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-04-30 DOI: 10.1002/jgm.3688
Feibin Zhu, Yuanjian Ye, Ying Shao, Chunli Xue

Background

Despite the interest in mesenchymal stem cells (MSC), their potential to treat abnormal scarring, especially keloids, is yet to be described. The present study aimed to investigate the therapeutic potential of exosomes derived from human bone marrow MSCs (hBMSC-Exos) in alleviating keloid formation.

Methods

Exosomes were isolated from hBMSC, and keloid fibroblasts (KFs) were treated with hBMSC-Exos. Cell counting kit-8, wound healing, transwell invasion, immunofluorescence, and western blot assays were conducted to study the malignant phenotype of KFs. Mice were induced with keloids and treated with hBMSC-Exos. The effect of hBMSC-Exos on keloid formation in vivo was evaluated by hematoxylin and eosin staining, Masson staining, immunohistochemistry, and western blotting. The GSE182192 dataset was screened for differentially expressed long non-coding RNA during keloid formation. Next, maternally expressed gene 3 (MEG3) was knocked down in hBMSC to obtain hBMSC-Exossh-MEG3. The molecular mechanism of MEG3 was investigated by bioinformatic screening, and the relationship between MEG3 and TP53 or MCM5 was verified.

Results

hBMSC-Exos inhibited the malignant proliferation, migration, and invasion of KFs at same time as promoting their apoptosis, Moreover, hBMSC-Exos reduced the expression of fibrosis- and collagen-related proteins in the cells and the formation of keloids caused by KFs. The reduction in MEG3 enrichment in hBMSC-Exos weakened the inhibitory effect of hBMSC-Exos on KF activity. hBMSC-Exos delivered MEG3 to promote MCM5 transcription by TP53 in KFs. Overexpression of MCM5 in KFs reversed the effects of hBMSC-Exossh-MEG3, leading to reduced KF activity.

Conclusions

hBMSC-Exos delivered MEG3 to promote the protein stability of TP53, thereby activating MCM5 and promoting KF activity.

背景 尽管间充质干细胞（MSC）备受关注，但其治疗异常瘢痕，尤其是瘢痕疙瘩的潜力尚未得到描述。本研究旨在探讨从人类骨髓间充质干细胞中提取的外泌体（hBMSC-Exos）在缓解瘢痕疙瘩形成方面的治疗潜力。 方法 从 hBMSC 中分离出外泌体，用 hBMSC-Exos 处理瘢痕疙瘩成纤维细胞（KFs）。通过细胞计数试剂盒-8、伤口愈合、Transwell侵袭、免疫荧光和Western印迹检测来研究KFs的恶性表型。诱导小鼠患瘢痕疙瘩，并用 hBMSC-Exos 治疗。通过苏木精和伊红染色、Masson 染色、免疫组织化学和 Western 印迹法评估了 hBMSC-Exos 对体内瘢痕疙瘩形成的影响。在 GSE182192 数据集中筛选了瘢痕疙瘩形成过程中差异表达的长非编码 RNA。然后，在 hBMSC 中敲除母源表达基因 3（MEG3），得到 hBMSC-Exossh-MEG3。通过生物信息学筛选研究了 MEG3 的分子机制，并验证了 MEG3 与 TP53 或 MCM5 的关系。 结果 hBMSC-Exos 可抑制 KFs 的恶性增殖、迁移和侵袭，同时促进其凋亡。hBMSC-Exos 中 MEG3 富集的减少削弱了 hBMSC-Exos 对 KF 活性的抑制作用。在 KFs 中过表达 MCM5 可逆转 hBMSC-Exossh-MEG3 的作用，从而降低 KF 的活性。 结论 hBMSC-Exos 传递 MEG3 促进 TP53 蛋白的稳定性，从而激活 MCM5 并促进 KF 的活性。
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