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Autophagy-related CMTM6 promotes glioblastoma progression by activating Wnt/β-catenin pathway and acts as an onco-immunological biomarker 与自噬相关的 CMTM6 通过激活 Wnt/β-catenin 通路促进胶质母细胞瘤的发展，并成为一种肿瘤免疫生物标记物
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.3685
Lirui Dai, Jingjia Xiao, Xiang Li, Yiran Tao, Peizhi Zhou, Liang Lyu, Zimin Shi, Xianyin Liang, Ziyang Jia, Shu Jiang

Background

Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes and a limited prognosis. CMTM6, a membrane protein, has been found to upregulate the expression of programmed cell death 1 ligand 1 protein (PD-L1) and acts as an immune checkpoint inhibitor by inhibiting the programmed death 1 protein/PD-L1 signaling pathway. Recent research has demonstrated a high expression of CMTM6 in GBM, suggesting its potential role in influencing the pathogenesis and progression of GBM, as well as its association with immune cell infiltration in the tumor microenvironment. However, the underlying mechanism of CMTM6 in GBM requires further investigation.

Methods

Data from cancer patients in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas cohorts were consolidated for the current study. Through multi-omics analysis, the study systematically examined the expression profile of CMTM6, epigenetic modifications, prognostic significance, biological functions, potential mechanisms of action and alterations in the immune microenvironment. Additionally, the study investigated CMTM6 expression in GBM cell lines and normal cells using reverse transcription PCR and western blot analysis. The impact of CMTM6 on GBM cell proliferation, migration and invasion was evaluated using a combination of cell counting kit-8 assay, clone formation assay, 5-ethynyl-2′-deoxyuridine incorporation assay, wound healing assay and Transwell assay. In order to explore the mechanism of CMTM6, the Wnt/β-catenin signaling pathway and autophagy-related genes were further verified through western blot analysis.

Results

CMTM6 is highly expressed in multiple tumors, particularly GBM. CMTM6 has been shown to be a valuable diagnostic and prognostic biomarker by various bioinformatics approaches. Additionally, CMTM6 plays a pivotal role in the pathogenesis of cancer, specifically GBM, by modulating various biological processes such as DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, tumor stemness and DNA methylation. The findings of the experiment indicate a significant correlation between elevated CMTM6 expression and the proliferation, invasion, migration and autophagy of GBM cells, with potential key roles mediated through the Wnt/β-catenin signaling pathway. Furthermore, CMTM6 is implicated in modulating tumor immune cell infiltration and is closely linked to the expression of various immune checkpoint inhibitors and immune modulators, particularly within the context of GBM. Hi

背景多形性胶质母细胞瘤（GBM）被认为是最常见的恶性脑肿瘤之一，其特点是治疗效果差、预后有限。CMTM6是一种膜蛋白，已被发现能上调程序性细胞死亡1配体1蛋白（PD-L1）的表达，并通过抑制程序性死亡1蛋白/PD-L1信号通路而成为一种免疫检查点抑制剂。最近的研究表明，CMTM6 在 GBM 中高表达，提示其在影响 GBM 的发病机制和进展中的潜在作用，以及与肿瘤微环境中免疫细胞浸润的相关性。然而，CMTM6 在 GBM 中的潜在作用机制还需要进一步研究。 方法 本研究整合了癌症基因组图谱（The Cancer Genome Atlas）、基因表达总库（Gene Expression Omnibus）和中国胶质瘤基因组图谱（Chinese Glioma Genome Atlas）队列中的癌症患者数据。通过多组学分析，该研究系统地考察了 CMTM6 的表达谱、表观遗传修饰、预后意义、生物学功能、潜在作用机制以及免疫微环境的改变。此外，该研究还使用反转录 PCR 和 Western 印迹分析法研究了 CMTM6 在 GBM 细胞系和正常细胞中的表达。研究采用细胞计数试剂盒-8测定、克隆形成测定、5-乙炔基-2′-脱氧尿苷掺入测定、伤口愈合测定和Transwell测定相结合的方法，评估了CMTM6对GBM细胞增殖、迁移和侵袭的影响。为了探索 CMTM6 的作用机制，还通过 Western 印迹分析进一步验证了 Wnt/β-catenin 信号通路和自噬相关基因。 结果 CMTM6在多种肿瘤尤其是GBM中高表达。各种生物信息学方法已证明 CMTM6 是一种有价值的诊断和预后生物标志物。此外，CMTM6 通过调节 DNA 甲基转移酶表达、RNA 修饰、拷贝数变异、基因组异质性、肿瘤干性和 DNA 甲基化等各种生物过程，在癌症（尤其是 GBM）的发病机制中发挥着关键作用。实验结果表明，CMTM6 表达的升高与 GBM 细胞的增殖、侵袭、迁移和自噬之间存在显著的相关性，其潜在的关键作用是通过 Wnt/β-catenin 信号通路介导的。此外，CMTM6 还与调节肿瘤免疫细胞浸润有关，并与各种免疫检查点抑制剂和免疫调节剂的表达密切相关，尤其是在 GBM 中。高水平的 CMTM6 表达还能提高 GBM 患者对放疗和化疗的反应性，从而为指导 GBM 的治疗策略提供有价值的见解。 结论 自噬相关的 CMTM6 在各种类型的癌症尤其是 GBM 中高表达，它能通过 Wnt/β-catenin 信号通路调控 GBM 的进展，可作为 GBM 患者诊断、治疗选择和预后判断的基础靶点。
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引用次数: 0
YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/β-catenin axis YBX1通过AKT/β-catenin轴促进肝内胆管癌的干性和顺铂不敏感性
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-04-27 DOI: 10.1002/jgm.3689
Xiaodong Shi, Zhiliang Hu, Shilei Bai, Chen Zong, Hui Xue, Yao Li, Fengwei Li, Liangrui Chen, Jianbing Xuan, Yong Xia, Lixin Wei, Feng Shen, Kui Wang

Background

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear.

Methods

Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/β-catenin pathways.

Results

YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/β-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/β-catenin axis.

Conclusions

YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

背景 肝内胆管癌（ICC）是一种侵袭性极强的恶性肿瘤，其特点是预后不良，并与肿瘤干性密切相关。然而，调控 ICC 干性的关键分子仍然难以捉摸。虽然Y-盒结合蛋白1（YBX1）通过增强干性和化疗耐药性对多种癌症的预后产生负面影响，但它对ICC的干性和顺铂敏感性的影响仍不清楚。 方法 分析了三个大样本和单细胞RNA-seq数据集，以研究YBX1在ICC中的表达及其与干性的关系。临床样本和集落/球形成试验验证了YBX1在干性和顺铂敏感性中的作用。AZD5363和KYA1979K探讨了YBX1与磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（PKB/AKT）和WNT/β-catenin通路的相互作用。 结果 YBX1在ICC中明显上调，与较差的总生存率和较短的术后复发时间相关，在化疗无反应的ICC组织中YBX1含量较高。YBX1高表达组的干性评分明显升高，与YBX1上调相关的基因富集在多个干性相关通路中。此外，YBX1的表达与多个干性相关基因（SOX9、OCT4、CD133、CD44和EPCAM）显著相关。此外，YBX1的过表达能显著增强ICC细胞的集落和球形形成能力，加速体内肿瘤生长，并降低其对顺铂的敏感性。相反，下调YBX1则会产生相反的效果。转录组分析强调了 YBX1 与 PI3K/AKT 和 WNT/β-catenin 通路之间的联系。此外，AZD5363和KYA1979K被用于阐明YBX1通过调节AKT/β-catenin轴促进ICC干性。 结论 YBX1在ICC中上调，并通过AKT/β-catenin轴促进干性和顺铂不敏感性。我们的研究描述了一种改善 ICC 预后的新型潜在治疗靶点。
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引用次数: 0
Constructing and validating a risk model based on neutrophil-related genes for evaluating prognosis and guiding immunotherapy in colon cancer 构建并验证基于中性粒细胞相关基因的风险模型，以评估结肠癌预后并指导免疫疗法
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-04-15 DOI: 10.1002/jgm.3684
Shasha Wang, Lili Wang, Mingxiu Qiu, Zhongkun Lin, Weiwei Qi, Jing Lv, Yan Wang, Yangyang Lu, Xiaoxuan Li, Wenzhi Chen, Wensheng Qiu

Background

Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients.

Methods

We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan–Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues.

Results

We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy.

Conclusions

The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.

背景 结肠癌是最常见的消化道恶性肿瘤之一。尽管免疫疗法为结肠癌患者带来了新希望，但仍有很大一部分患者无法从免疫疗法中获益。研究表明，中性粒细胞可与免疫细胞和免疫因子相互作用，影响患者的预后。 方法 我们首先使用 CIBERSORT 算法确定肿瘤中性粒细胞的浸润水平，并通过 Spearman 相关性分析和随后的 Cox 分析确定最终风险模型中的关键基因。将Cox回归系数与基因表达水平相乘，得出每位患者的风险评分，并根据风险评分的中位数将患者分为两组。总生存期（OS）和无进展生存期（PFS）的差异通过 Kaplan-Meier 生存分析进行评估，并在独立数据集中验证了模型的准确性。免疫测定评估了免疫浸润和免疫治疗的差异。最后，通过免疫组化和免疫印迹技术验证了三个基因在结肠正常组织和肿瘤组织中的表达情况。 结果 我们在癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因表达总库（Gene Expression Omnibus，GEO）这两个独立的数据集中建立并验证了一个基于中性粒细胞相关基因的风险评分模型，其中SLC11A1和SLC2A3为风险因子，MMP3为保护因子。通过结合临床特征和风险评分模型，构建并验证了一个新的提名图，以更好地预测患者的OS和PFS。免疫分析表明，高风险组患者具有免疫细胞浸润水平、免疫检查点水平和肿瘤突变负荷，更有可能从免疫治疗中获益。 结论 在基于中性粒细胞相关基因的风险模型中，低风险组的OS和PFS均优于高风险组。高风险组患者的免疫浸润水平和肿瘤突变负荷较高，因此可能对免疫疗法更敏感。
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引用次数: 0
NLRC4-mediated pyroptosis was involved in coagulation disorders of acute pancreatitis NLRC4 介导的热蛋白沉积参与了急性胰腺炎的凝血障碍
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-04-04 DOI: 10.1002/jgm.3683
Sunkuan Hu, Tiesu Lin, Yufeng Chen, Yimo Guo, Xuecheng Sun, Lingyan Shi, Jingye Pan

Background

Acute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP.

Methods

RNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation-related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme-linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs).

Results

Coagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes—DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC—may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation-related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL-1β, IL-18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs.

Conclusions

NLRC4-mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.

背景 急性胰腺炎（AP）是一种可能致命的急性疾病，与凝血功能障碍有很大关系。有报道称热蛋白沉积会加重凝血功能障碍，但这一影响在急性胰腺炎中尚未得到充分说明。 方法 从基因表达总库（Gene Expression Omnibus）数据库下载 AP 患者外周血的 RNA 序列数据。采用基因组变异分析和单样本基因组富集分析计算凝血相关特征和热病的富集得分。相关性分析采用了 Spearman 和 Pearson 相关性分析。采集了 AP 患者和健康人的外周血样本和相关临床参数。使用茶碱和脂多糖建立了严重 AP（SAP）小鼠模型。采用酶联免疫吸附试验、化学发光免疫测定和免疫组化分析法检测血清和胰腺组织中的凝血指标和热蛋白沉积标志物水平。此外，我们还评估了热蛋白沉积抑制和 NLRC4 沉默对人脐静脉内皮细胞（HUVECs）功能的影响。 结果 凝血功能障碍与 AP 的严重程度呈显著正相关，可预测 AP 的严重程度。进一步的分析表明，有六个基因-DOCK9、GATA3、FCER1G、NLRC4、C1QB 和 C1QC 可能与 AP 的凝血障碍有关。其中，NLRC4 与大多数凝血相关特征呈正相关的脓毒症呈正相关。来自患者的数据显示，NLRC4和其他裂解标志物（包括IL-1β、IL-18、caspase1和GSDMD）与AP的严重程度显著相关。此外，NLRC4 与 AP 患者的凝血指标呈正相关。小鼠数据显示，SAP 小鼠胰腺组织中的 NLRC4 增加。使用热蛋白沉积抑制剂能有效缓解小鼠的 SAP 和凝血功能障碍。最后，抑制化脓过程或沉默 NLRC4 可缓解 HUVECs 内皮功能障碍。 结论 NLRC4 介导的热蛋白沉积会损害内皮细胞的功能，从而加剧 AP 的凝血功能障碍。抑制裂解酶可改善凝血功能并缓解 AP。
{"title":"NLRC4-mediated pyroptosis was involved in coagulation disorders of acute pancreatitis","authors":"Sunkuan Hu,&nbsp;Tiesu Lin,&nbsp;Yufeng Chen,&nbsp;Yimo Guo,&nbsp;Xuecheng Sun,&nbsp;Lingyan Shi,&nbsp;Jingye Pan","doi":"10.1002/jgm.3683","DOIUrl":"https://doi.org/10.1002/jgm.3683","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>RNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation-related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme-linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Coagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes—<i>DOCK9</i>, <i>GATA3</i>, <i>FCER1G</i>, <i>NLRC4</i>, <i>C1QB</i> and <i>C1QC—</i>may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation-related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL-1<i>β</i>, IL-18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>NLRC4-mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140345658","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
Exploration of the prognostic prediction value of the PANoptosis-based risk score and its correlation with tumor immunity in lung adenocarcinoma 探讨基于 PANoptosis 的风险评分的预后预测价值及其与肺腺癌肿瘤免疫的相关性。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-03-20 DOI: 10.1002/jgm.3682
Xiaojian Zhao, Xuefeng Zhang, Feng Li, Caiping Lu

Lung adenocarcinoma (LUAD) is a common cancer with high mortality worldwide. PANoptosis is a novel inflammatory programmed cell death modality with the characteristics of pyroptosis, apoptosis and necroptosis. It is necessary to explore PANoptosis-related genes in LUAD patients and offer evidence for prognosis prediction and therapeutic strategies. Single-cell RNA sequencing data and RNA expression profiles of LUAD patients from The Cancer Genome Atlas and Gene Expression Omnibus databases are used to screen PANoptosis-related differential genes for the construction of a risk model. Fifteen PANoptosis-related markers with prognostic value were identified by Least Absolute Shrinkage and Selection Operator (LASSO)–Cox regression analysis. Kaplan–Meier analysis and receiver operating characteristic curve analysis further demonstrated the significant predictive capability. Immune infiltration, Single Nucleotide Variants (SNV) mutations, and clinical drug susceptibility were analyzed. In conclusion, a risk model of 15 PANoptosis-related genes has significant value in prognostic prediction for LUAD and has potential to direct clinical therapeutic strategies during the treatment.

肺腺癌（LUAD）是世界上死亡率很高的一种常见癌症。PAN凋亡是一种新型的炎症性程序性细胞死亡方式，具有热凋亡、细胞凋亡和坏死的特点。因此，有必要探究LUAD患者中与PAN凋亡相关的基因，为预后预测和治疗策略提供证据。本研究利用癌症基因组图谱和基因表达总库中的单细胞RNA测序数据和LUAD患者的RNA表达谱，筛选与PAN凋亡相关的差异基因，构建风险模型。通过最小绝对缩减和选择操作者（LASSO）-Cox回归分析，确定了15个具有预后价值的PAN凋亡相关标记。Kaplan-Meier分析和接收者操作特征曲线分析进一步证明了其显著的预测能力。此外，还对免疫浸润、单核苷酸变异（SNV）和临床药物敏感性进行了分析。总之，由15个PANoptosis相关基因组成的风险模型对LUAD的预后预测具有重要价值，并有望在治疗过程中指导临床治疗策略。
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引用次数: 0
Comprehensive analysis of histone acetylation-related genes in glioblastoma and lower-grade gliomas: Insights into drug sensitivity, molecular subtypes, immune infiltration, and prognosis 胶质母细胞瘤和低级别胶质瘤中组蛋白乙酰化相关基因的综合分析：对药物敏感性、分子亚型、免疫浸润和预后的见解。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-03-18 DOI: 10.1002/jgm.3678
Jiajun Qin, Jin Fu, Xianzhen Chen

Objectives

The purpose of this research was to study the impact of histone acetylation on glioblastoma multiforme (GBM) and lower-grade gliomas (LGG) and its potential implications for patient prognosis. We aimed to assess the histone acetylation score (HAs) and its relationship with key genes involved in histone acetylation regulation.

Method

The TCGA-GBMLGG dataset, which provides comprehensive genomic and clinical information, was utilized for this study. We calculated the HAs by analyzing the expression levels of histone acetylation-related genes, including histone acetyltransferases and histone deacetylases, in GBM and LGG patients. Kaplan–Meier survival analysis was performed to evaluate the prognostic value of the HAs. Furthermore, correlation analysis and differential expression analysis were conducted to assess the relationship between the HAs and key genes involved in histone acetylation regulation, as well as the expression differences of immune checkpoint genes.

Results

Our analysis revealed a significant association between the HAs and patient prognosis, with higher HAs correlating to poorer outcomes in GBM and LGG patients. We observed a positive correlation between the HAs and key genes involved in histone acetylation regulation, indicating their potential role in modulating histone acetylation levels. Moreover, we found significant expression differences for immune checkpoint genes between high and low HAs groups, suggesting a potential impact of histone acetylation on the immune response in GBM and LGG.

Conclusion

This study highlights the significance of histone acetylation in GBM and LGG. The HAs demonstrated prognostic value, indicating its potential as a clinically relevant biomarker. The correlation between the HAs and key genes involved in histone acetylation regulation provides insights into the underlying mechanisms driving histone acetylation dysregulation in GBM and LGG. Furthermore, the observed expression differences of immune checkpoint genes suggest a potential link between histone acetylation and the immune response. These findings contribute to our understanding of the molecular basis of GBM and LGG and have implications for personalized treatment approaches targeting histone acetylation and the immune microenvironment. Further validation and functional studies are needed to confirm these findings and explore potential therapeutic strategies.

研究目的本研究旨在研究组蛋白乙酰化对多形性胶质母细胞瘤（GBM）和低级别胶质瘤（LGG）的影响及其对患者预后的潜在影响。我们旨在评估组蛋白乙酰化评分（HAs）及其与参与组蛋白乙酰化调控的关键基因之间的关系：本研究使用了提供全面基因组和临床信息的 TCGA-GBMLGG 数据集。我们通过分析组蛋白乙酰化相关基因（包括组蛋白乙酰转移酶和组蛋白去乙酰化酶）在GBM和LGG患者中的表达水平，计算出HAs。为评估组蛋白乙酰化相关基因的预后价值，还进行了 Kaplan-Meier 生存分析。此外，还进行了相关性分析和差异表达分析，以评估HAs与参与组蛋白乙酰化调控的关键基因之间的关系，以及免疫检查点基因的表达差异：我们的分析表明，HAs与患者的预后有明显的关联，HAs越高，GBM和LGG患者的预后越差。我们观察到 HAs 与参与组蛋白乙酰化调控的关键基因之间存在正相关，这表明它们在调节组蛋白乙酰化水平方面具有潜在作用。此外，我们还发现免疫检查点基因在高HAs组和低HAs组之间存在明显的表达差异，这表明组蛋白乙酰化对GBM和LGG患者的免疫反应有潜在影响：本研究强调了组蛋白乙酰化在GBM和LGG中的重要性。组蛋白乙酰化具有预后价值，表明其有可能成为临床相关的生物标记物。HAs与参与组蛋白乙酰化调控的关键基因之间的相关性，让人们深入了解了GBM和LGG中组蛋白乙酰化失调的潜在机制。此外，观察到的免疫检查点基因的表达差异表明组蛋白乙酰化与免疫反应之间存在潜在联系。这些发现有助于我们了解 GBM 和 LGG 的分子基础，并对针对组蛋白乙酰化和免疫微环境的个性化治疗方法具有重要意义。要证实这些发现并探索潜在的治疗策略，还需要进一步的验证和功能研究。
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引用次数: 0
Overexpression of multidrug resistance-associated protein 1 protects against cardiotoxicity by augmenting the doxorubicin efflux from cardiomyocytes 多药耐药性相关蛋白1的过表达可通过增加多柔比星从心肌细胞的外流来防止心脏毒性。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-03-14 DOI: 10.1002/jgm.3681
Cindy Y. Kok, Sindhu Igoor, Renuka Rao, Shinya Tsurusaki, Tracy Titus, Lauren M. MacLean, Megha Kadian, Rhys Skelton, James J. H. Chong, Eddy Kizana

Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.

多柔比星是一种常用的抗癌药物，可用于治疗多种恶性肿瘤。然而，其主要不良反应是心脏毒性，这种毒性与剂量有关，可以是急性的，也可以是慢性的。多柔比星通过 DNA 损伤、自由活性氧自由基的形成和诱导细胞凋亡造成伤害。我们的目的是在人类 iPS 细胞（hiPSC-CM）衍生的心肌细胞中诱导多药耐药性相关蛋白 1（MRP1）的表达，以确定这是否能使细胞有效清除多柔比星并提供心脏保护。我们生成了编码 MRP1 的慢病毒载体（LV.MRP1），并通过定量 PCR 和 Western 印迹分析验证了它在 HEK293T 细胞和干细胞衍生心肌细胞（hiPSC-CM）中的功能。我们还通过量化转运体从细胞中输出的荧光染料量，测试了过表达 MRP1 的活性。我们证明过表达 MRP1 的细胞中染料螯合减少。最后，我们证明了转导了 LV.MRP1 的 hiPSC-CM 可防止多柔比星损伤。总之，我们已经证明，我们可以成功地在 hiPSC-CM 中过表达 MRP1 蛋白，其功能性转运体活性可保护细胞免受多柔比星诱导的毒性损伤。
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引用次数: 0
Exploration of YBX1 role in the prognostic value and immune characteristics by single-cell and bulk sequencing analysis for liver hepatocellular carcinoma 通过单细胞和批量测序分析探讨 YBX1 在肝肝细胞癌预后价值和免疫特征中的作用
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-03-06 DOI: 10.1002/jgm.3680
Qingqing Zhang, Bingye Zhu, Hongyan Yang, Fei Li, Ying Qu, Lungen Lu, Qidi Zhang

Background

Y-box binding protein 1 (YBX1) plays a variety of roles in progression of multiple tumors. However, the role of YBX1 in prognostic value and immune regulation for liver hepatocellular carcinoma (LIHC) remains unclear. The present study aimed to examine the effect of YBX1 on the regulation of tumor immunity and survival prediction in LIHC patients.

Methods

YBX1-related expression profiles and single-cell and bulk sequencing analysis were performed using online databases. YBX1 expression was validated by a quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. Univariate/multivariate Cox regression analysis was performed to determine independent predictors of overall survival (OS). The ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis were used to assess the relationships between YBX1 and LIHC immunity.

Results

YBX1 was over-expressed in LIHC tissues and cell lines. High YBX1 expression was significantly associated with poor OS. Univariate/multivariate Cox regression analysis revealed that YBX1 was an independent prognostic factor for LIHC. Gene set enrichment analysis revealed that YBX1 was associated with multiple signaling pathways correlated to LIHC. Additionally, YBX1 was expressed in multiple immune cells and was significantly correlated with immune cells, immune checkpoint markers and tumor immune microenvironment. The TIDE analysis demonstrated that LIHC patients with high YBX1 expression showed a higher T-cell dysfunction score and a higher exclusion score, as well as poorer immunotherapy response.

Conclusions

YBX1 plays crucial oncogenic roles in LIHC and is closely associated with the immune defense system. YBX1 inhibition may serve as a potential treatment for LIHC.

背景：Y-盒结合蛋白 1（YBX1Y-box 结合蛋白 1（YBX1）在多种肿瘤的进展过程中发挥着多种作用。然而，YBX1在肝肝细胞癌（LIHC）的预后价值和免疫调节中的作用仍不清楚。本研究旨在探讨YBX1对LIHC患者肿瘤免疫调节和生存预测的影响：方法：利用在线数据库进行YBX1相关表达谱分析以及单细胞和批量测序分析。YBX1的表达通过定量实时PCR（qRT-PCR）、免疫印迹和免疫组化进行了验证。进行了单变量/多变量Cox回归分析，以确定总生存期（OS）的独立预测因素。ESTIMATE（即利用表达数据估算恶性肿瘤组织中的STromal和免疫细胞）算法和肿瘤免疫功能障碍与排斥（TIDE）分析用于评估YBX1与LIHC免疫之间的关系：结果：YBX1在LIHC组织和细胞系中过度表达。YBX1的高表达与不良OS显著相关。单变量/多变量 Cox 回归分析显示，YBX1 是 LIHC 的独立预后因素。基因组富集分析显示，YBX1与多种与LIHC相关的信号通路有关。此外，YBX1在多种免疫细胞中表达，并与免疫细胞、免疫检查点标记物和肿瘤免疫微环境显著相关。TIDE分析表明，YBX1高表达的LIHC患者表现出更高的T细胞功能障碍评分和更高的排斥评分，以及更差的免疫治疗反应：结论：YBX1在LIHC中发挥着关键的致癌作用，并与免疫防御系统密切相关。结论：YBX1在LIHC中起着关键的致癌作用，并与免疫防御系统密切相关，抑制YBX1可作为治疗LIHC的一种潜在方法。
{"title":"Exploration of YBX1 role in the prognostic value and immune characteristics by single-cell and bulk sequencing analysis for liver hepatocellular carcinoma","authors":"Qingqing Zhang,&nbsp;Bingye Zhu,&nbsp;Hongyan Yang,&nbsp;Fei Li,&nbsp;Ying Qu,&nbsp;Lungen Lu,&nbsp;Qidi Zhang","doi":"10.1002/jgm.3680","DOIUrl":"10.1002/jgm.3680","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Y-box binding protein 1 (YBX1) plays a variety of roles in progression of multiple tumors. However, the role of YBX1 in prognostic value and immune regulation for liver hepatocellular carcinoma (LIHC) remains unclear. The present study aimed to examine the effect of YBX1 on the regulation of tumor immunity and survival prediction in LIHC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>YBX1-related expression profiles and single-cell and bulk sequencing analysis were performed using online databases. YBX1 expression was validated by a quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. Univariate/multivariate Cox regression analysis was performed to determine independent predictors of overall survival (OS). The ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis were used to assess the relationships between YBX1 and LIHC immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>YBX1 was over-expressed in LIHC tissues and cell lines. High YBX1 expression was significantly associated with poor OS. Univariate/multivariate Cox regression analysis revealed that YBX1 was an independent prognostic factor for LIHC. Gene set enrichment analysis revealed that YBX1 was associated with multiple signaling pathways correlated to LIHC. Additionally, YBX1 was expressed in multiple immune cells and was significantly correlated with immune cells, immune checkpoint markers and tumor immune microenvironment. The TIDE analysis demonstrated that LIHC patients with high YBX1 expression showed a higher T-cell dysfunction score and a higher exclusion score, as well as poorer immunotherapy response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>YBX1 plays crucial oncogenic roles in LIHC and is closely associated with the immune defense system. YBX1 inhibition may serve as a potential treatment for LIHC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140051116","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
SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity SPINK5通过免疫活性抑制食管鳞状细胞癌转移
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-03-05 DOI: 10.1002/jgm.3667
Jie Chen, Juncheng Lu, Zhiqiang Chen, Zihao Liu, Yuejun Sun, Shuyan He, Yedong Mi, Yi Gao, Dong Shen, Qingfeng Lin

Background

Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer with relatively high mortality worldwide. Serine peptidase inhibitor Kazal-type 5 (SPINK5) is reported to be downregulated in ESCC. However, its explicit role in ESCC remains further investigation.

Methods

The tumor tissues and adjacent non-cancerous tissues were obtained from 196 patients with ESCC for the determination of SPINK5 mRNA levels. Additionally, the relationship between SPINK5 mRNA levels and clinicopathological features of ESCC patients was explored. The effects of SPINK5 on the invasion and migration of ESCC cells were assessed using Transwell assays. Furthermore, SPINK5 mRNA and LEKTI protein were measured in ESCC cell lines after treatment with poly (I:C), lipopolysaccharide (LPS) or unmethylated CpG DNA. Moreover, the correlation between expression of SPINK5 and nuclear factor-kappa B (NF-κB) signaling pathway-related genes was analyzed in the TCGA-ESCC cohort, and the effects of SPINK5 on NF-κB transcription was analyzed using a luciferase reporter gene assay. Finally, the correlations between SPINK5 and infiltration of immune cells, immune scores, stromal scores and ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were explored.

Results

SPINK5 mRNA levels were downregulated in tumor tissues, which was significantly correlated with higher lymph node metastases. Overexpressed SPINK5 inhibited cell invasion and migration in ESCC cell lines. Mechanistically, LPS-induced activation of Toll-like receptor 4 (TLR4) decreased SPINK5 mRNA and LEKTI in KYSE150 and KYSE70 cells. Spearman correlation analysis revealed that SPINK5 mRNA was significantly negatively correlated with a total of seven NF-κB signaling pathway-related genes in TCGA-ESCC patients. Moreover, downregulation of SPINK5 increased and upregulation of SPINK5 decreased the activity of the NF-κB promoter in HEK293T cells. Finally, immune cells infiltration analysis revealed that SPINK5 was significantly correlated with the infiltration of various immune cells, stromal scores, immune scores and ESTIMATE scores.

Conclusions

SPINK5 plays critical roles in the TLR4/NF-κB pathway and immune cells infiltration, which might contribute to the ESCC metastasis. The findings of the present study may provide a promising biomarker for the diagnosis and treatment of esop

背景：食管鳞状细胞癌（ESCC）是食管癌的主要亚型，在全球范围内死亡率相对较高。据报道，丝氨酸肽酶抑制剂卡扎尔 5 型（SPINK5）在 ESCC 中被下调。然而，其在 ESCC 中的明确作用仍有待进一步研究：方法：从 196 例 ESCC 患者的肿瘤组织和邻近的非癌组织中获取 SPINK5 mRNA 水平。此外，还探讨了 SPINK5 mRNA 水平与 ESCC 患者临床病理特征之间的关系。使用Transwell试验评估了SPINK5对ESCC细胞侵袭和迁移的影响。此外，还测定了ESCC细胞系经多聚（I：C）、脂多糖（LPS）或未甲基化CpG DNA处理后的SPINK5 mRNA和LEKTI蛋白。此外，在TCGA-ESCC队列中分析了SPINK5与核因子-kappa B（NF-κB）信号通路相关基因表达的相关性，并使用荧光素酶报告基因实验分析了SPINK5对NF-κB转录的影响。最后，还探讨了SPINK5与免疫细胞浸润、免疫评分、基质评分和ESTIMATE（即利用表达数据估算恶性肿瘤组织中的基质和免疫细胞）评分之间的相关性：结果：SPINK5 mRNA水平在肿瘤组织中下调，这与淋巴结转移率的升高显著相关。过表达的 SPINK5 可抑制 ESCC 细胞系的细胞侵袭和迁移。从机理上讲，LPS诱导的Toll样受体4（TLR4）激活降低了KYSE150和KYSE70细胞中的SPINK5 mRNA和LEKTI。斯皮尔曼相关分析表明，在TCGA-ESCC患者中，SPINK5 mRNA与7个NF-κB信号通路相关基因呈显著负相关。此外，在 HEK293T 细胞中，SPINK5 的下调会增加 NF-κB 启动子的活性，而 SPINK5 的上调则会降低 NF-κB 启动子的活性。最后，免疫细胞浸润分析表明，SPINK5与各种免疫细胞的浸润、基质评分、免疫评分和ESTIMATE评分显著相关：结论：SPINK5在TLR4/NF-κB通路和免疫细胞浸润中起着关键作用，可能会导致ESCC转移。本研究的结果可能为食管鳞状细胞癌的诊断和治疗提供了一种有前景的生物标记物。
{"title":"SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity","authors":"Jie Chen,&nbsp;Juncheng Lu,&nbsp;Zhiqiang Chen,&nbsp;Zihao Liu,&nbsp;Yuejun Sun,&nbsp;Shuyan He,&nbsp;Yedong Mi,&nbsp;Yi Gao,&nbsp;Dong Shen,&nbsp;Qingfeng Lin","doi":"10.1002/jgm.3667","DOIUrl":"10.1002/jgm.3667","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer with relatively high mortality worldwide. Serine peptidase inhibitor Kazal-type 5 (SPINK5) is reported to be downregulated in ESCC. However, its explicit role in ESCC remains further investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The tumor tissues and adjacent non-cancerous tissues were obtained from 196 patients with ESCC for the determination of <i>SPINK5</i> mRNA levels. Additionally, the relationship between <i>SPINK5</i> mRNA levels and clinicopathological features of ESCC patients was explored. The effects of <i>SPINK5</i> on the invasion and migration of ESCC cells were assessed using Transwell assays. Furthermore, <i>SPINK5</i> mRNA and LEKTI protein were measured in ESCC cell lines after treatment with poly (I:C), lipopolysaccharide (LPS) or unmethylated CpG DNA. Moreover, the correlation between expression of <i>SPINK5</i> and nuclear factor-kappa B (NF-κB) signaling pathway-related genes was analyzed in the TCGA-ESCC cohort, and the effects of <i>SPINK5</i> on NF-κB transcription was analyzed using a luciferase reporter gene assay. Finally, the correlations between <i>SPINK5</i> and infiltration of immune cells, immune scores, stromal scores and ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>SPINK5</i> mRNA levels were downregulated in tumor tissues, which was significantly correlated with higher lymph node metastases. Overexpressed <i>SPINK5</i> inhibited cell invasion and migration in ESCC cell lines. Mechanistically, LPS-induced activation of Toll-like receptor 4 (TLR4) decreased <i>SPINK5</i> mRNA and LEKTI in KYSE150 and KYSE70 cells. Spearman correlation analysis revealed that <i>SPINK5</i> mRNA was significantly negatively correlated with a total of seven NF-κB signaling pathway-related genes in TCGA-ESCC patients. Moreover, downregulation of <i>SPINK5</i> increased and upregulation of <i>SPINK5</i> decreased the activity of the NF-κB promoter in HEK293T cells. Finally, immune cells infiltration analysis revealed that <i>SPINK5</i> was significantly correlated with the infiltration of various immune cells, stromal scores, immune scores and ESTIMATE scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>SPINK5</i> plays critical roles in the TLR4/NF-κB pathway and immune cells infiltration, which might contribute to the ESCC metastasis. The findings of the present study may provide a promising biomarker for the diagnosis and treatment of esop","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041041","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
Development of a novel prognostic signature based on single-cell combined bulk RNA analysis in breast cancer 基于乳腺癌单细胞联合大体 RNA 分析的新型预后特征的开发。
IF 3.5 4区 医学 Q2 Biochemistry, Genetics and Molecular Biology
Journal of Gene Medicine
Pub Date : 2024-02-25 DOI: 10.1002/jgm.3673
Ying Xiao, Ge Hu, Ning Xie, Liang Yin, Yaqiang Pan, Cong Liu, Shihan Lou, Cunzhi Zhu

Background

Breast cancer (BC), a malignant tumor, is a significant cause of death and disability among women globally. Recent research indicates that copy number variation plays a crucial role in tumor development. In this study, we employed the Single-Cell Variational Aneuploidy Analysis (SCEVAN) algorithm to differentiate between malignant and non-malignant cells, aiming to identify genetic signatures with prognostic relevance for predicting patient survival.

Methods

We analyzed gene expression profiles and associated clinical data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Using the SCEVAN algorithm, we distinguished malignant from non-malignant cells and investigated cellular interactions within the tumor microenvironment (TME). We categorized TCGA samples based on differentially expressed genes (DEGs) between these cell types. Subsequent Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted. Additionally, we developed polygenic models for the DEGs using least absolute shrinkage and selection operator-penalized Cox regression analysis. To assess the prognostic accuracy of these characteristics, we generated Kaplan–Meier and receiver operating characteristic curves from training and validation datasets. We also monitored the expression variations of prognostic genes across the pseudotime of malignant cells. Patients were divided into high-risk and low-risk groups based on median risk scores to compare their TME and identify potential therapeutic agents. Lastly, polymerase chain reaction was used to validate seven pivotal genes.

Results

The SCEVAN algorithm identified distinct malignant and non-malignant cells in GSE180286. Cellchat analysis revealed significantly increased cellular communication, particularly between fibroblasts, endothelial cells and malignant cells. The DEGs were predominantly involved in immune-related pathways. TCGA samples were classified into clusters A and B based on these genes. Cluster A, enriched in immune pathways, was associated with poorer prognosis, whereas cluster B, predominantly involved in circadian rhythm pathways, showed better outcomes. We constructed a 14-gene prognostic signature, validated in a 1:1 internal TCGA cohort and external GEO datasets (GSE42568 and GSE146558). Kaplan–Meier analysis confirmed the prognostic signature's accuracy (p < 0.001). Receiver operating characteristic curve analysis demonstrated the predictive reliability of these prognostic features. Single-cell pseudotime analysis with monocle2 highlighted the distinct expression trends of these genes in malignant cells, undersco

背景：乳腺癌（BC）是一种恶性肿瘤，是导致全球妇女死亡和残疾的重要原因。最新研究表明，拷贝数变异在肿瘤发生发展中起着至关重要的作用。在这项研究中，我们采用了单细胞变异非整倍体分析（SCEVAN）算法来区分恶性细胞和非恶性细胞，旨在找出与预测患者生存率预后相关的基因特征：我们分析了基因表达总库（GEO）和癌症基因组图谱（TCGA）数据库中的基因表达谱和相关临床数据。利用 SCEVAN 算法，我们区分了恶性和非恶性细胞，并研究了肿瘤微环境（TME）中的细胞相互作用。我们根据这些细胞类型之间的差异表达基因（DEGs）对 TCGA 样本进行了分类。随后进行了京都基因和基因组百科全书通路分析。此外，我们还利用最小绝对缩减和选择算子惩罚性 Cox 回归分析为 DEGs 建立了多基因模型。为了评估这些特征的预后准确性，我们从训练数据集和验证数据集生成了 Kaplan-Meier 和接收者操作特征曲线。我们还监测了预后基因在恶性细胞假时空的表达变化。根据中位风险评分将患者分为高风险组和低风险组，以比较他们的 TME 并确定潜在的治疗药物。最后，利用聚合酶链反应验证了七个关键基因：结果：SCEVAN 算法在 GSE180286 中识别出了不同的恶性和非恶性细胞。Cellchat分析显示，细胞间的交流明显增加，尤其是成纤维细胞、内皮细胞和恶性细胞之间的交流。DEGs主要涉及免疫相关通路。根据这些基因，TCGA样本被分为A组和B组。A组富含免疫通路，预后较差，而B组主要涉及昼夜节律通路，预后较好。我们构建了14个基因的预后特征，并在1:1内部TCGA队列和外部GEO数据集（GSE42568和GSE146558）中进行了验证。Kaplan-Meier分析证实了预后特征的准确性（p 结论：我们的研究结果表明，14个基因的预后特征是准确的：我们的研究结果表明，14 个基因的预后特征可作为预测 BC 患者预后的新型生物标志物。此外，不同风险组的免疫细胞和免疫途径表明，免疫疗法可能是 BC 患者治疗策略的重要组成部分。
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