Journal of Gene Medicine最新文献_第10页

Identification and validation of non-coding RNA-mediated high expression of IQGAP3 in poor prognosis of lung adenocarcinoma 非编码 RNA 介导的 IQGAP3 高表达在肺腺癌不良预后中的识别和验证

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-16 DOI: 10.1002/jgm.3664

Ziwei Su, Yang Wang, Jialing Cao, Jie Ma, Guangzhao Wang, Huijuan Ren, Yihan Zhang, Kangliang Sheng, Xueying Zhu, Yongzhong Wang

Background

The primary reason for tumor-related deaths worldwide is lung adenocarcinoma (LUAD). The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is crucial for contributing to tumor initiation and progression. However, the precise function and molecular mechanism of IQGAP3 in LUAD remain unknown. The present study aimed to investigate the expression, prognosis, mechanism and tumor immunity associated with IQGAP3 in LUAD.

Methods

The relationship between IQGAP3 and the poor prognosis of LUAD was analyzed using The Cancer Genome Atlas (TCGA) database. This analysis was further validated on lung cancer tissues and cell lines. The function of IQGAP3 was investigated by silencing it in LUAD cell lines. To predict microRNA (miRNA) and long non-coding RNA associated with IQGAP3, the starBase database was utilized, and the predictions were verified by enhancing the function of miRNA. Finally, the relationship between IQGAP3 and tumor immunity was evaluated using Spearman's correlation analysis.

Results

TCGA database revealed that higher levels of IQGAP3 were associated with advanced tumor stage, N stage and poor prognosis in LUAD patients. To confirm that, we conducted experiments on lung cancer tissues and cell lines and found that silencing IQGAP3 significantly inhibited tumor cell proliferation and migration. The expression of IQGAP3 showed a negative correlation with has-miR-101-3p and has-miR-135a-5p, whereas it showed a positive correlation with GSEC, AC005034.3 and TYMSOS. Furthermore, the introduction of miRNA-mimics into lung cancer cell resulted in a significant inhibition of cancer cell growth and migration. Following that, the level of IQGAP3 showed a positive correlation with the infiltration of immune cells in tumors.

Conclusions

These results reveal that IQGAP3 significantly promotes LUAD progression and could serve as a prognostic biomarker for LUAD. Furthermore, IQGAP3 is most likely regulated by the GSEC/TYMSOS-hsa-miR-101-3p axis and the AC005034.3-hsa-miR-135a-5p axis in LUAD.

背景全球肿瘤相关死亡的主要原因是肺腺癌（LUAD）。致癌基因 IQ motif-containing GTPase activating protein 3 (IQGAP3) 是导致肿瘤发生和发展的关键因素。然而，IQGAP3在LUAD中的确切功能和分子机制仍然未知。本研究旨在探讨 IQGAP3 在 LUAD 中的表达、预后、机制及肿瘤免疫相关性。方法利用癌症基因组图谱（TCGA）数据库分析了IQGAP3与LUAD不良预后之间的关系。该分析在肺癌组织和细胞系中得到了进一步验证。通过在 LUAD 细胞系中沉默 IQGAP3，研究了它的功能。为了预测与IQGAP3相关的微RNA（miRNA）和长非编码RNA，研究人员利用了starBase数据库，并通过增强miRNA的功能验证了预测结果。最后，利用斯皮尔曼相关分析评估了 IQGAP3 与肿瘤免疫之间的关系。结果 TCGA 数据库显示，在 LUAD 患者中，较高水平的 IQGAP3 与肿瘤晚期、N 期和预后不良有关。为了证实这一点，我们对肺癌组织和细胞系进行了实验，发现沉默 IQGAP3 能显著抑制肿瘤细胞的增殖和迁移。IQGAP3 的表达与 has-miR-101-3p 和 has-miR-135a-5p 呈负相关，而与 GSEC、AC005034.3 和 TYMSOS 呈正相关。此外，将 miRNA 模拟物引入肺癌细胞可显著抑制癌细胞的生长和迁移。随后，IQGAP3 的水平与肿瘤中免疫细胞的浸润呈正相关。结论这些结果表明，IQGAP3 能明显促进 LUAD 的进展，可作为 LUAD 的预后生物标志物。此外，在 LUAD 中，IQGAP3 很可能受到 GSEC/TYMSOS-hsa-miR-101-3p 轴和 AC005034.3-hsa-miR-135a-5p 轴的调控。

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引用次数: 0

BRIX1 promotes ribosome synthesis and enhances glycolysis by selected translation of GLUT1 in colorectal cancer BRIX1 通过选择 GLUT1 的翻译促进结直肠癌中核糖体的合成并增强糖酵解作用

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-16 DOI: 10.1002/jgm.3632

Chunhui Jiang, Longci Sun, Siyuan Wen, Yuan Tian, Chunjie Xu, Qing Xu, Hanbing Xue

Background

Ribosome biogenesis protein BRX1 homolog (BRIX1) is critically required for the synthesis of the 60S ribosome subunit. However, the role and mechanism of BRIX1 in colorectal cancer (CRC) remain unclear.

Methods

Kyoto Encyclopedia of Gene and Genome pathway and Gene Ontology analyses were used for bioinformatics analysis. The rRNA levels were detected in CRC tissues and cells. Nascent RNA synthesis was detected via cellular immunofluorescence. The correlation was analyzed between patient Positron Emission Tomography-Computed Tomography (PET–CT) values and their BRIX1 expression. The extracellular acidification rate (ECAR) and oxygen consumption rate were determined via live metabolic analyses. Polysome fractions were collected for BRIX1 mRNA used in translation. The orthotopic model and Cell Counting Kit-8 (CCK8) assay were used to assess BRIX1 function in CRC.

Results

BRIX1 is a core protein involved in ribosome-related pathway changes in CRC. Gene Ontology analysis showed that BRIX1 was primarily enriched in ribosome assembly and ribosome biogenesis pathways. In fresh CRC tissue, rRNA levels (5S, 5.8S, 18S and 28S) were higher in the BRIX1 high-expression group than in the BRIX1 low-expression group. Similarly, BRIX1 knockdown significantly decreased rRNA levels for 5S, 5.8S, 18S and 28S in CRC cells, whereas overexpression of BRIX1 significantly increased these levels. In addition, BRIX1 knockdown inhibited nascent RNA synthesis in CRC cells. In clinical data analysis, BRIX1 expression was related to the glucose uptake in PET–CT. BRIX1 knockdown significantly decreased the ECAR value, glucose uptake and lactic acid production in CRC cells, whereas BRIX1 overexpression significantly increased these. Furthermore, BRIX1 knockdown significantly decreased the protein expression of GLUT1, whereas BRIX1 overexpression significantly increased this; however, expression of BRIX1 mRNA was unaffected in either case. Blocking glycolysis by si-GLUT1 or galactose reversed BRIX1 promotion of glycolysis and cell proliferation in CRC cells.

背景核糖体生物发生蛋白 BRX1 同源物（BRIX1）是合成 60S 核糖体亚基的关键所在。然而，BRIX1 在结直肠癌（CRC）中的作用和机制仍不清楚。方法采用京都基因百科全书和基因本体分析进行生物信息学分析。检测 CRC 组织和细胞中的 rRNA 水平。通过细胞免疫荧光检测新生 RNA 的合成。分析了患者正电子发射断层扫描（PET-CT）值与 BRIX1 表达之间的相关性。通过活体代谢分析确定了细胞外酸化率（ECAR）和耗氧量。收集多聚体碎片，以检测用于翻译的 BRIX1 mRNA。采用正位模型和细胞计数试剂盒-8（CCK8）检测法评估 BRIX1 在 CRC 中的功能。结果 BRIX1 是参与 CRC 核糖体相关通路变化的核心蛋白。基因本体分析表明，BRIX1主要富集于核糖体组装和核糖体生物发生通路。在新鲜的 CRC 组织中，BRIX1 高表达组的 rRNA 水平（5S、5.8S、18S 和 28S）高于 BRIX1 低表达组。同样，在 CRC 细胞中，BRIX1 基因敲除会显著降低 5S、5.8S、18S 和 28S 的 rRNA 水平，而过表达 BRIX1 则会显著提高这些水平。此外，BRIX1 基因敲除抑制了 CRC 细胞中新生 RNA 的合成。在临床数据分析中，BRIX1的表达与PET-CT的葡萄糖摄取有关。敲除 BRIX1 会明显降低 CRC 细胞的 ECAR 值、葡萄糖摄取量和乳酸生成量，而过表达 BRIX1 则会明显增加这些指标。此外，BRIX1敲除会明显降低GLUT1的蛋白表达，而BRIX1过表达则会明显提高GLUT1的蛋白表达。通过 si-GLUT1 或半乳糖阻断糖酵解可逆转 BRIX1 对 CRC 细胞糖酵解和细胞增殖的促进作用。

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引用次数: 0

AKT/FOXM1/STMN1 signaling pathway activation by SMC1A promotes tumor growth in breast cancer SMC1A 激活 AKT/FOXM1/STMN1 信号通路可促进乳腺癌肿瘤生长

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-15 DOI: 10.1002/jgm.3661

Kaichun Li, Ping Dai, Jian Li, Long Liu, Shiyu Cheng, Qingliang Fang, Bingxiang Wu

Background

Upregulation of SMC1A (Structural maintenance of chromosomes 1A) is linked with many types of cancer and its oncogenic function, which has been associated with crucial cellular mechanisms (cell division, cell cycle checkpoints regulation and DNA repair). Recent studies have shown that SMC1A was involved in breast cancer, although the exact mechanisms of SMC1A remain to be determined.

Methods

Using The Cancer Genome Atlas (TCGA) database, we examined SMC1A expression and its relation to other genes, including FOXM1 and STMN1. Short hairpin RNA was used to subsequently examine the biological roles of SMC1A in MDA-MB-231 and MDA-MB-468 cell lines. Bioinformatics were performed to identify the SMC1A-related gene FOXM1.

Results

Here, we used the TCGA database to show that SMC1A is overexpressed in breast cancer. Later investigations showed SMC1A's role in breast cancer cell survival, apoptosis and invasion. Using bioinformatics and western blot assays, we confirmed that FOXM1 acted as the downstream of SMC1A, and SMC1A knockdown significantly downregulated the FOXM1 expression via the AKT signal pathway. Interestingly, the inhibition effects induced by SMC1A downregulation could be reversed by FOXM1 overexpression. In the clinic, SMC1A expression is favorably linked with FOXM1 expression in breast cancer tumor tissues.

Conclusions

Collectively, our results not only enhance our knowledge of SMC1A's molecular pathways in breast cancer, but also suggest a potential new therapeutic target.

背景 SMC1A（染色体结构维护 1A）的上调与许多类型的癌症及其致癌功能有关，它与关键的细胞机制（细胞分裂、细胞周期检查点调节和 DNA 修复）相关。最近的研究表明，SMC1A 与乳腺癌有关，但其确切机制仍有待确定。方法我们利用癌症基因组图谱（TCGA）数据库研究了 SMC1A 的表达及其与其他基因（包括 FOXM1 和 STMN1）的关系。随后，我们使用短发夹核糖核酸检测了 SMC1A 在 MDA-MB-231 和 MDA-MB-468 细胞系中的生物学作用。生物信息学研究确定了 SMC1A 相关基因 FOXM1。结果我们利用 TCGA 数据库发现 SMC1A 在乳腺癌中过表达。随后的研究表明，SMC1A 在乳腺癌细胞存活、凋亡和侵袭中发挥作用。通过生物信息学和 Western 印迹分析，我们证实 FOXM1 是 SMC1A 的下游，而 SMC1A 的敲除可通过 AKT 信号通路显著下调 FOXM1 的表达。有趣的是，FOXM1 的过量表达可以逆转 SMC1A 下调引起的抑制作用。在临床上，SMC1A 的表达与乳腺癌肿瘤组织中 FOXM1 的表达密切相关。结论综上所述，我们的研究结果不仅增进了我们对 SMC1A 在乳腺癌中分子通路的了解，还提出了一个潜在的新治疗靶点。

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引用次数: 0

miR-451a suppresses the proliferation and migration of high-grade serous ovarian cancer by targeting RAB5A through the Ras/Raf/MEK/ERK pathway miR-451a 通过 Ras/Raf/MEK/ERK 通路靶向 RAB5A 抑制高级别浆液性卵巢癌的增殖和迁移

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-15 DOI: 10.1002/jgm.3649

Shujie Liu, Kun Wang, Zhendan Zhao, Yu Pang, Fang Liu, Pengling Wang, Zhiling Wang, Xingsheng Yang

Background

Ovarian cancer is one of the most common cancers in women. Profiles changes of microRNAs (miRNAs) are closely linked to malignant tumors. In the present study, we investigated expression of miR-451a in high-grade serous ovarian cancer (HGSOC). We also investigated the potential pathological roles and the likely mechanism of miR-451a in the development of HGSOC using animal models and cell lines.

Methods

Using bioinformatics techniques and a real-time PCR, we analyzed differently expressed miRNAs in HGSOC compared to normal tissue. MTT (i.e. 3-[4, 5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), EDU (i.e. 5-ethynyl-2′-deoxyuridine) and transwell assays were performed to investigate the effect of miR-451a on the proliferation and migration of HGSOC SKOV-3 cells. A dual luciferase reporter assay was performed to verify the targeting relationship of miR-451 and RAB5A (one of the Rab GTPase proteins that regulates endocytosis and vesicle transport). Also, we analyzed levels of the RAB5A mRNA and protein by real-time PCR, western blotting and immunohistochemistry assays in HGSOC cells and tissues. Finally, we performed in vivo experiments using HGSOC mice.

Results

miR-451a was substantially upregulated in HGSOC and associated with favorable clinical characteristics. miR-451a knockdown significantly increased growth and metastasis of HGSOC cell line SKOV-3 through Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. In addition, RAB5A, an early endosome marker, was shown to be a direct target of miR-451a. Moreover, RAB5A is correlated with unfavorable clinical features and shows independent prognostic significance in HGSOC.

Conclusions

We found that the miR-451a/RAB5A axis is associated with tumorigenesis and progression through the Ras/Raf/MEK/ERK pathway, providing prognostic indicators and therapeutic targets for patients with HGSOC.

背景卵巢癌是女性最常见的癌症之一。微小RNA（miRNA）谱的变化与恶性肿瘤密切相关。本研究调查了 miR-451a 在高级别浆液性卵巢癌（HGSOC）中的表达。我们还利用动物模型和细胞系研究了 miR-451a 在 HGSOC 发展过程中的潜在病理作用和可能的机制。方法我们利用生物信息学技术和实时 PCR 分析了 HGSOC 中不同于正常组织表达的 miRNA。采用 MTT（即 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑）、EDU（即 5-乙炔基-2′-脱氧尿苷）和透孔试验研究 miR-451a 对 HGSOC SKOV-3 细胞增殖和迁移的影响。为了验证 miR-451 与 RAB5A（调节内吞和囊泡运输的 Rab GTPase 蛋白之一）的靶向关系，我们进行了双荧光素酶报告实验。此外，我们还通过实时 PCR、Western 印迹和免疫组化等方法分析了 HGSOC 细胞和组织中 RAB5A mRNA 和蛋白的水平。最后，我们利用 HGSOC 小鼠进行了体内实验。通过 Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) 信号转导，miR-451a 被敲除能显著增加 HGSOC 细胞株 SKOV-3 的生长和转移。此外，早期内质体标记物 RAB5A 被证明是 miR-451a 的直接靶标。此外，RAB5A 与不利的临床特征相关，在 HGSOC 中显示出独立的预后意义。结论我们发现，miR-451a/RAB5A 轴通过 Ras/Raf/MEK/ERK 通路与肿瘤发生和进展相关，为 HGSOC 患者提供了预后指标和治疗靶点。

{"title":"miR-451a suppresses the proliferation and migration of high-grade serous ovarian cancer by targeting RAB5A through the Ras/Raf/MEK/ERK pathway","authors":"Shujie Liu, Kun Wang, Zhendan Zhao, Yu Pang, Fang Liu, Pengling Wang, Zhiling Wang, Xingsheng Yang","doi":"10.1002/jgm.3649","DOIUrl":"https://doi.org/10.1002/jgm.3649","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ovarian cancer is one of the most common cancers in women. Profiles changes of microRNAs (miRNAs) are closely linked to malignant tumors. In the present study, we investigated expression of miR-451a in high-grade serous ovarian cancer (HGSOC). We also investigated the potential pathological roles and the likely mechanism of miR-451a in the development of HGSOC using animal models and cell lines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using bioinformatics techniques and a real-time PCR, we analyzed differently expressed miRNAs in HGSOC compared to normal tissue. MTT (i.e. 3-[4, 5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), EDU (i.e. 5-ethynyl-2′-deoxyuridine) and transwell assays were performed to investigate the effect of miR-451a on the proliferation and migration of HGSOC SKOV-3 cells. A dual luciferase reporter assay was performed to verify the targeting relationship of miR-451 and RAB5A (one of the Rab GTPase proteins that regulates endocytosis and vesicle transport). Also, we analyzed levels of the RAB5A mRNA and protein by real-time PCR, western blotting and immunohistochemistry assays in HGSOC cells and tissues. Finally, we performed in vivo experiments using HGSOC mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>miR-451a was substantially upregulated in HGSOC and associated with favorable clinical characteristics. miR-451a knockdown significantly increased growth and metastasis of HGSOC cell line SKOV-3 through Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. In addition, RAB5A, an early endosome marker, was shown to be a direct target of miR-451a. Moreover, RAB5A is correlated with unfavorable clinical features and shows independent prognostic significance in HGSOC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We found that the miR-451a/RAB5A axis is associated with tumorigenesis and progression through the Ras/Raf/MEK/ERK pathway, providing prognostic indicators and therapeutic targets for patients with HGSOC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139473978","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

Unveiling Anoikis-related genes: A breakthrough in the prognosis of bladder cancer 揭示 Anoikis 相关基因：膀胱癌预后的突破性进展

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-11 DOI: 10.1002/jgm.3651

Shen Jiang, Xiping Yang, Yang Lin, Yunfei Liu, Lisa Jia Tran, Jing Zhang, Chengjun Qiu, Fangdie Ye, Zhou Sun

Background

Bladder cancer (BLCA) is a prevalent malignancy worldwide. Anoikis remains a new form of cell death. It is necessary to explore Anoikis-related genes in the prognosis of BLCA.

Methods

We obtained RNA expression profiles from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases for dimensionality reduction analysis and isolated epithelial cells, T cells and fibroblasts for copy number variation analysis, pseudotime analysis and transcription factor analysis based on R package. We integrated machine-learning algorithms to develop the artificial intelligence-derived prognostic signature (AIDPS).

Results

The performance of AIDPS with clinical indicators was stable and robust in predicting BLCA and showed better performance in every validation dataset compared to other models. Mendelian randomization analysis was conducted. Single nucleotide polymorphism (SNP) sites of rs3100578 (HK2) and rs66467677 (HSP90B1) exhibited significant correlation of bladder problem (not cancer) and bladder cancer, whereasSNP sites of rs3100578 (HK2) and rs947939 (BAD) had correlation between bladder stone and bladder cancer. The immune infiltration analysis of the TCGA-BLCA cohort was calculated via the ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) algorithm which contains stromal, immune and estimate scores. We also found significant differences in the IC₅₀ values of Bortezomib_1191, Docetaxel_1007, Staurosporine_1034 and Rapamycin_1084 among the high- and low-risk groups.

Conclusions

In conclusion, these findings indicated Anoikis-related prognostic genes in BLCA and constructed an innovative machine-learning model of AIDPS with high prognostic value for BLCA.

背景膀胱癌（BLCA）是一种全球流行的恶性肿瘤。Anoikis仍然是一种新的细胞死亡形式。有必要研究与 Anoikis 相关的基因对 BLCA 预后的影响。方法我们从癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因表达总库（Gene Expression Omnibus）数据库中获取 RNA 表达谱进行降维分析，并分离上皮细胞、T 细胞和成纤维细胞进行拷贝数变异分析、伪时间分析和基于 R 软件包的转录因子分析。我们整合了机器学习算法，开发了人工智能衍生预后特征（AIDPS）。结果 AIDPS与临床指标相结合，在预测BLCA方面表现稳定、稳健，与其他模型相比，AIDPS在每个验证数据集中都表现出更好的性能。进行了孟德尔随机分析。rs3100578（HK2）和rs66467677（HSP90B1）的单核苷酸多态性（SNP）位点与膀胱问题（非癌症）和膀胱癌有显著相关性，而rs3100578（HK2）和rs947939（BAD）的SNP位点与膀胱结石和膀胱癌有相关性。TCGA-BLCA队列的免疫浸润分析是通过ESTIMATE（即使用表达数据估算恶性肿瘤中的基质和免疫细胞）算法计算得出的，该算法包含基质、免疫和估算分数。我们还发现，硼替佐米_1191、多西他赛_1007、Staurosporine_1034 和雷帕霉素_1084 的 IC50 值在高风险组和低风险组之间存在明显差异。结论总之，这些研究结果表明了 BLCA 中与 Anoikis 相关的预后基因，并构建了一个创新的 AIDPS 机器学习模型，该模型对 BLCA 具有较高的预后价值。

{"title":"Unveiling Anoikis-related genes: A breakthrough in the prognosis of bladder cancer","authors":"Shen Jiang, Xiping Yang, Yang Lin, Yunfei Liu, Lisa Jia Tran, Jing Zhang, Chengjun Qiu, Fangdie Ye, Zhou Sun","doi":"10.1002/jgm.3651","DOIUrl":"https://doi.org/10.1002/jgm.3651","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bladder cancer (BLCA) is a prevalent malignancy worldwide. Anoikis remains a new form of cell death. It is necessary to explore Anoikis-related genes in the prognosis of BLCA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We obtained RNA expression profiles from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases for dimensionality reduction analysis and isolated epithelial cells, T cells and fibroblasts for copy number variation analysis, pseudotime analysis and transcription factor analysis based on R package. We integrated machine-learning algorithms to develop the artificial intelligence-derived prognostic signature (AIDPS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The performance of AIDPS with clinical indicators was stable and robust in predicting BLCA and showed better performance in every validation dataset compared to other models. Mendelian randomization analysis was conducted. Single nucleotide polymorphism (SNP) sites of rs3100578 (HK2) and rs66467677 (HSP90B1) exhibited significant correlation of bladder problem (not cancer) and bladder cancer, whereasSNP sites of rs3100578 (HK2) and rs947939 (BAD) had correlation between bladder stone and bladder cancer. The immune infiltration analysis of the TCGA-BLCA cohort was calculated via the ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) algorithm which contains stromal, immune and estimate scores. We also found significant differences in the IC<sub>50</sub> values of Bortezomib_1191, Docetaxel_1007, Staurosporine_1034 and Rapamycin_1084 among the high- and low-risk groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In conclusion, these findings indicated Anoikis-related prognostic genes in BLCA and constructed an innovative machine-learning model of AIDPS with high prognostic value for BLCA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139434994","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

Prognosis and therapy in thyroid cancer by gene signatures related to natural killer cells 通过与自然杀伤细胞相关的基因特征预测和治疗甲状腺癌

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-09 DOI: 10.1002/jgm.3657

Zhen Jin, Yadong Han, Jiaxin Zhang, Zhao Liu, Ran Li, Zhao Liu

Background

Natural killer (NK) cells are crucial to cancer development and prognosis. However, the role of NK cell-related genes in immunotherapy and the tumor immune microenvironment (TIME) is not well understood. This study aimed to develop reliable risk signatures associated with NK cell-related genes for predicting thyroid cancer (THCA).

Methods

The single-cell RNA sequencing (scRNA-seq) data from seven THCA samples (GSE184362) and bulk-RNA-seq data of 502 THCA patients (TCGA-THCA) were included. The scRNA-seq data was analyzed using the “Seurat” R package to identify differentially expressed genes in NK cells. The clustering analysis was carried out using the R package “ConsensusClusterPlus”. The gene set variation analysis (GSVA) algorithm was applied to assess the variations in biological pathways among subtypes. The ESTIMATE algorithm was utilized to calculate the scores for stromal, immune and estimate variables. In addition, we used the single sample Gene Set Enrichment Analysis and CIBERSORT algorithms to assess the degree to which immune cells and pathways related to immunity were enriched based on the meta-cohort. In the TCGA-THCA cohort, the “glmnet” R package was used for the gene selection, and LASSO Cox analysis was used to construct prognostic features. The “maftools” R package was used to examine the somatic mutation landscape of THCA in both low- and high-risk groups.

Results

One-hundred and eighty-five NK cell marker genes were screened, and nine genes were associated with the THCA prognosis. KLF2, OSTF1 and TAPBP were finally identified and constructed a risk signature with significant prognostic value. KLF2 and OSTF1 were protective genes, and TAPBP was a risk gene. Patients at high risk had a considerably lower overall survival compared with those at low risk. Mutations in the TCGA-THCA cohort were predominantly C > T. Increased tumor mutation burden (TMB) levels were linked to overall survival. The low-risk H-TMB+ group had a better prognosis, while the high-risk L-TMB+ group had the worst prognosis.

Conclusion

Natural killer cell-related genes KLF2, OSTF1 and TAPBP were used to develop a novel prognostic risk signature, offering a new perspective on the prognosis and treatment of THCA.

背景自然杀伤（NK）细胞对癌症的发展和预后至关重要。然而，NK细胞相关基因在免疫疗法和肿瘤免疫微环境（TIME）中的作用还不甚明了。本研究旨在开发与NK细胞相关基因有关的可靠风险特征，用于预测甲状腺癌（THCA）。方法纳入了7个甲状腺癌样本（GSE184362）的单细胞RNA测序（scRNA-seq）数据和502名甲状腺癌患者的批量RNA-seq数据（TCGA-THCA）。使用 "Seurat "R软件包对scRNA-seq数据进行分析，以确定NK细胞中的差异表达基因。聚类分析使用 R 软件包 "ConsensusClusterPlus "进行。基因组变异分析（GSVA）算法用于评估亚型间生物通路的变异。ESTIMATE算法用于计算基质、免疫和估计变量的得分。此外，我们还使用了单样本基因组富集分析（Gene Set Enrichment Analysis）和 CIBERSORT 算法来评估基于元队列的免疫细胞和免疫相关通路的富集程度。在TCGA-THCA队列中，使用 "glmnet "R软件包进行基因选择，并使用LASSO Cox分析构建预后特征。maftools "R软件包用于研究THCA低危组和高危组的体细胞突变情况。结果筛选出 185 个 NK 细胞标记基因，其中 9 个基因与 THCA 预后相关。最终确定了 KLF2、OSTF1 和 TAPBP，并构建了一个具有显著预后价值的风险特征。KLF2和OSTF1是保护基因，TAPBP是风险基因。与低风险患者相比，高风险患者的总生存率要低得多。TCGA-THCA队列中的基因突变主要是C >T。肿瘤突变负荷（TMB）水平的增加与总生存率有关。低风险 H-TMB+ 组预后较好，而高风险 L-TMB+ 组预后最差。结论自然杀伤细胞相关基因 KLF2、OSTF1 和 TAPBP 被用于建立新的预后风险特征，为 THCA 的预后和治疗提供了新的视角。

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引用次数: 0

Genome-wide polygenic risk score for rheumatoid arthritis prediction in postmenopausal women 用于预测绝经后妇女类风湿关节炎的全基因组多基因风险评分

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-08 DOI: 10.1002/jgm.3659

Yingke Xu, Qing Wu

Background

Rheumatoid arthritis (RA), a common autoimmune disease, exhibits a vital genetic component. Polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) offer potential utility in predicting disease susceptibility. The present study aimed to develop and validate a PRS for predicting RA risk in postmenopausal women.

Methods

The study developed a novel PRS using 225,000 genetic variants from a GWAS dataset. The PRS was developed in a cohort of 8967 postmenopausal women and validated in an independent cohort of 6269 postmenopausal women. Among the development cohort, approximately 70% were Hispanic and approximately 30% were African American. The testing cohort comprised approximately 50% Hispanic and 50% Caucasian individuals. Stratification according to PRS quintiles revealed a pronounced gradient in RA prevalence and odds ratios.

Results

High PRS was significantly associated with increased RA risk in individuals aged 60–70 years, ≥ 70 years, and overweight and obese participants. Furthermore, at age 65 years, individuals in the bottom 5% of the PRS distribution have an absolute risk of RA at 30.6% (95% confidence interval = 18.5%–42.6%). The risk increased to 53.8% (95% confidence interval = 42.8%–64.9%) for those in the top 5% of the PRS distribution.

Conclusions

The PRS developed in the present study is significantly associated with RA risk, showing the potential for early screening of RA in postmenopausal women. This work demonstrates the feasibility of personalized medicine in identifying high-risk individuals for RA, indicating the need for further studies to test the utility of PRS in other populations.

背景类风湿性关节炎（RA）是一种常见的自身免疫性疾病，具有重要的遗传因素。从全基因组关联研究（GWAS）中得出的多基因风险评分（PRS）可用于预测疾病的易感性。本研究旨在开发并验证用于预测绝经后女性 RA 风险的 PRS。方法该研究利用 GWAS 数据集中的 225,000 个基因变异开发了一种新型 PRS。该PRS是在8967名绝经后妇女的队列中开发的，并在6269名绝经后妇女的独立队列中进行了验证。在开发队列中，约 70% 为西班牙裔，约 30% 为非裔美国人。测试队列中约有 50%为西班牙裔，50%为白种人。根据 PRS 五分位数进行的分层显示了 RA 患病率和几率的明显梯度。结果在 60-70 岁、≥ 70 岁以及超重和肥胖的参与者中，高 PRS 与 RA 风险的增加明显相关。此外，在 65 岁时，PRS 分布中最低 5%的人患 RA 的绝对风险为 30.6%（95% 置信区间 = 18.5%-42.6%）。而PRS分布前5%的人的风险则增加到53.8%（95%置信区间=42.8%-64.9%）。结论本研究开发的 PRS 与 RA 风险显著相关，显示了对绝经后妇女进行 RA 早期筛查的潜力。这项工作证明了个性化医疗在识别 RA 高危人群方面的可行性，表明有必要开展进一步研究，以测试 PRS 在其他人群中的实用性。

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引用次数: 0

Relevance of pyroptosis-associated genes in nasopharyngeal carcinoma diagnosis and subtype classification 鼻咽癌诊断和亚型分类中的热解相关基因的相关性

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-08 DOI: 10.1002/jgm.3653

Yan Wang, Yuxia Zou, Xianghui Chen, Xiaoyan Wang, Hao Zheng, Qing Ye

Background

Nasopharyngeal carcinoma (NPC) is a highly aggressive and metastatic malignancy originating in the nasopharyngeal tissue. Pyroptosis is a relatively newly discovered, regulated form of necrotic cell death induced by inflammatory caspases that is associated with a variety of diseases. However, the role and mechanism of pyroptosis in NPC are not fully understood.

Methods

We analyzed the differential expression of pyroptosis-related genes (PRGs) between patients with and without NPC from the GSE53819 and GSE64634 datasets of the Gene Expression Omnibus (GEO) database. We mapped receptor operating characteristic profiles for these key PRGs to assess the accuracy of the genes for disease diagnosis and prediction of patient prognosis. In addition, we constructed a nomogram based on these key PRGs and carried out a decision curve analysis. The NPC patients were classified into different pyroptosis gene clusters by the consensus clustering method based on key PRGs, whereas the expression profiles of the key PRGs were analyzed by applying principal component analysis. We also analyzed the differences in key PRGs, immune cell infiltration and NPC-related genes between the clusters. Finally, we performed differential expression analysis for pyroptosis clusters and obtained differentially expressed genes (DEGs) and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.

Results

We obtained 14 differentially expressed PRGs from GEO database. Based on these 14 differentially expressed PRGs, we applied least absolute shrinkage and selection operator analysis and the random forest algorithm to obtain four key PRGs (CHMP7, IL1A, TP63 and GSDMB). We completely distinguished the NPC patients into two pyroptosis gene clusters (pyroptosis clusters A and B) based on four key PRGs. Furthermore, we determined the immune cell abundance of each NPC sample, estimated the association between the four PRGs and immune cells, and determined the difference in immune cell infiltration between the two pyroptosis gene clusters. Finally, we obtained and functional enrichment analyses 259 DEGs by differential expression analysis for both pyroptosis clusters.

Conclusions

PRGs are critical in the development of NPC, and our research on the pyroptosis gene cluster may help direct future NPC therapeutic approaches.

背景鼻咽癌（NPC）是一种起源于鼻咽组织的高度侵袭性和转移性恶性肿瘤。炭疽是一种相对较新发现的、由炎性卡巴酶诱导的细胞坏死调控形式，与多种疾病相关。然而，鼻咽癌中热凋亡的作用和机制尚不完全清楚。方法我们从基因表达总库（Gene Expression Omnibus，GEO）数据库的 GSE53819 和 GSE64634 数据集中分析了鼻咽癌患者和非鼻咽癌患者中热解相关基因（PRGs）的差异表达。我们绘制了这些关键 PRGs 的受体操作特征图谱，以评估这些基因在疾病诊断和预测患者预后方面的准确性。此外，我们还根据这些关键 PRGs 构建了一个提名图，并进行了决策曲线分析。通过基于关键 PRGs 的共识聚类方法，我们将鼻咽癌患者分为不同的热病基因群，并应用主成分分析法对关键 PRGs 的表达谱进行了分析。我们还分析了群组间关键 PRGs、免疫细胞浸润和 NPC 相关基因的差异。最后，我们对热病群进行了差异表达分析，获得了差异表达基因（DEGs），并进行了基因本体和京都基因与基因组百科全书的富集分析。结果我们从 GEO 数据库中获得了 14 个差异表达的 PRGs。在这 14 个差异表达 PRGs 的基础上，我们应用最小绝对收缩和选择算子分析以及随机森林算法得到了四个关键 PRGs（CHMP7、IL1A、TP63 和 GSDMB）。根据四个关键 PRGs，我们将鼻咽癌患者完全区分为两个化脓基因群（化脓群 A 和 B）。此外，我们还测定了每个鼻咽癌样本的免疫细胞丰度，估算了四个 PRGs 与免疫细胞之间的关联，并确定了两个化脓基因簇之间免疫细胞浸润的差异。最后，我们通过差异表达分析获得了 259 个 DEGs，并对两个热蛋白沉积基因簇进行了功能富集分析。结论 PRGs 在鼻咽癌的发展过程中至关重要，我们对热蛋白沉积基因簇的研究可能有助于指导未来的鼻咽癌治疗方法。

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引用次数: 0

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-06 DOI: 10.1002/jgm.3648

Chaomin Yue, Baohua Lin, Xiang Sun, Xindi Xu, Chufan Zhou, Jiaying Fan

Background

Autophagy plays an important role in immunity and inflammation. The present study aimed to explore the prognostic significance of autophagy-related genes (ARGs) in endometrial cancer (EC) using bioinformatics.

Methods

The list of ARGs was obtained from the Human Autophagy Database. The differentially expressed ARGs (DEARGs) between the EC and normal endometrial tissue samples were screened from The Cancer Genome Atlas database. Cox regression analysis was performed on the DEARGs to screen the prognostic ARGs and construct risk signatures for overall survival (OS) and progression-free survival (PFS). The hub ARGs were identified from a protein–protein interaction network, and CDKN2A was obtained from the intersection of prognostic ARGs and hub ARGs. The association of CDKN2A expression with clinical characteristics and immune infiltration were analyzed. Finally, the role of CDKN2A in autophagy was confirmed in EC cell lines.

Results

CDKN2A, PTK6 and DLC1 were used to establish risk signatures for predicting the survival of EC patients. Receiver operating characteristic curve analysis indicated that the risk signatures can accurately predict both OS and PFS. CDKN2A was the only hub prognostic ARG, and showed significant association with the age, survival status, grade, histological type, body mass index and FIGO (i.e. International Federation of Gynecology and Obstetrics) stage (p < 0.05). Furthermore, CDKN2A expression was also correlated with the infiltration of immune cells, indicating that CDKN2A might play a critical role in regulating the immune microenvironment and immune responses in EC. In addition, silencing of CDKN2A gene promoted autophagy in the HEC-1A cell line and upregulated the expression levels of autophagy-related proteins.

Conclusions

CDKN2A is a prognostic factor and therapeutic target in EC, and is likely associated with the tumor immune landscape and autophagy.

背景自噬在免疫和炎症中发挥着重要作用。本研究旨在利用生物信息学方法探讨自噬相关基因（ARGs）在子宫内膜癌（EC）中的预后意义。方法 ARGs 列表来自人类自噬数据库。从癌症基因组图谱（The Cancer Genome Atlas）数据库中筛选出子宫内膜癌组织样本与正常子宫内膜组织样本之间差异表达的ARGs（DEARGs）。对 DEARGs 进行 Cox 回归分析，筛选出预后 ARGs，并构建出总生存期（OS）和无进展生存期（PFS）的风险特征。从蛋白质-蛋白质相互作用网络中确定了中心ARGs，并从预后ARGs和中心ARGs的交叉点中获得了CDKN2A。分析了CDKN2A的表达与临床特征和免疫浸润的关系。最后，在 EC 细胞系中证实了 CDKN2A 在自噬中的作用。结果 CDKN2A、PTK6 和 DLC1 被用于建立预测心肌梗死患者生存率的风险特征。接收操作特征曲线分析表明，风险特征能准确预测OS和PFS。CDKN2A是唯一的枢纽预后ARG，并与年龄、生存状态、分级、组织学类型、体重指数和FIGO（即国际妇产科联盟）分期有显著相关性（p <0.05）。此外，CDKN2A的表达还与免疫细胞的浸润相关，这表明CDKN2A可能在调节EC的免疫微环境和免疫反应中起着关键作用。此外，沉默 CDKN2A 基因可促进 HEC-1A 细胞系的自噬，并上调自噬相关蛋白的表达水平。结论 CDKN2A 是 EC 的预后因子和治疗靶点，可能与肿瘤免疫环境和自噬有关。

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引用次数: 0

MiR-431 promotes cardiomyocyte proliferation by targeting FBXO32 expression MiR-431 通过靶向 FBXO32 的表达促进心肌细胞增殖

IF 3.5 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-01-06 DOI: 10.1002/jgm.3656

Mengsha Li, Chenrui Zhang, Lirong Tan, Tingyan Liu, Tingting Zhu, Xuejiao Wei, Jiacai Liu, Xiaoyun Si, Bing Li

Background

The induction of cardiomyocyte (CM) proliferation is a promising approach for cardiac regeneration following myocardial injury. MicroRNAs (miRNAs) have been reported to regulate CM proliferation. In particular, miR-431 expression decreases during cardiac development, according to Gene Expression Omnibus (GEO) microarray data. However, whether miR-431 regulates CM proliferation has not been thoroughly investigated.

Methods

We used integrated bioinformatics analysis of GEO datasets to identify the most significantly differentially expressed miRNAs. Real-time quantitative PCR and fluorescence in situ hybridization were performed to determine the miRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of miRNA in CM proliferation. Additionally, we detected whether miR-431 affected CM proliferation in a myocardial infarction model. The TargetScan, miRDB and miRWalk online databases were used to predict the potential target genes of miRNAs. Luciferase reporter assays were used to study miRNA interactions with the targeting mRNA.

Results

First, we found a significant reduction in miR-431 levels during cardiac development. Then, by overexpression and inhibition of miR-431, we demonstrated that miR-431 promotes CM proliferation in vitro and in vivo, as determined by immunofluorescence assays of 5-ethynyl-2'-deoxyuridine (EdU), pH3, Aurora B and CM count, whereas miR-431 inhibition suppresses CM proliferation. Then, we found that miR-431 improved cardiac function post-myocardial infarction. In addition, we identified FBXO32 as a direct target gene of miR-431, with FBXO32 mRNA and protein expression being suppressed by miR-431. FBXO32 inhibited CM proliferation. Overexpression of FBXO32 blocks the enhanced effect of miR-431 on CM proliferation, suggesting that FBXO32 is a functional target of miR-431 during CM proliferation.

Conclusion

In summary, miR-431 promotes CM proliferation by targeting FBXO32, providing a potential molecular target for preventing myocardial injury.

背景诱导心肌细胞（CM）增殖是心肌损伤后心脏再生的一种可行方法。据报道，微小核糖核酸（miRNA）可调控心肌细胞的增殖。特别是，根据基因表达总库（GEO）的微阵列数据，miR-431 的表达在心脏发育过程中会减少。然而，miR-431 是否调控 CM 增殖尚未得到深入研究。方法我们对 GEO 数据集进行了综合生物信息学分析，以确定差异表达最显著的 miRNA。通过实时定量 PCR 和荧光原位杂交确定 miRNA 在心脏中的表达模式。我们还进行了功能增益和功能缺失试验，以检测 miRNA 在 CM 增殖中的作用。此外，我们还检测了 miR-431 是否会影响心肌梗死模型中 CM 的增殖。我们使用 TargetScan、miRDB 和 miRWalk 在线数据库预测 miRNA 的潜在靶基因。荧光素酶报告实验用于研究 miRNA 与靶标 mRNA 的相互作用。结果首先，我们发现在心脏发育过程中，miR-431 的水平明显下降。然后，通过过表达和抑制 miR-431，我们证明了 miR-431 在体外和体内促进了 CM 的增殖，这是由 5-乙炔基-2'-脱氧尿苷（EdU）、pH3、极光 B 和 CM 计数的免疫荧光测定确定的，而抑制 miR-431 则抑制了 CM 的增殖。随后，我们发现 miR-431 能改善心肌梗死后的心脏功能。此外，我们还发现 FBXO32 是 miR-431 的直接靶基因，miR-431 可抑制 FBXO32 mRNA 和蛋白的表达。FBXO32 可抑制 CM 增殖。过表达 FBXO32 可阻断 miR-431 对 CM 增殖的增强作用，这表明 FBXO32 是 miR-431 在 CM 增殖过程中的功能靶点。结论综上所述，miR-431 通过靶向 FBXO32 促进 CM 增殖，为预防心肌损伤提供了一个潜在的分子靶点。

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引用次数: 0