Hao Wu, Xinshuang Wang, Jing Yu, Jiao Li, Zhenhua Ma, Xi Sheng, Han Yang, Liping Wei, Xin Qi
The study aimed to analyze differentially expressed lncRNAs in a model of cardiac hypertrophy, specially focusing on the molecular mechanisms of lncRNA NONMMUT023529 (lncRNA N29) in myocardial hypertrophy. Based on gene microarray results, RT-qPCR validation confirmed that lncRNA N29 was significantly upregulated in TAC-induced mice cardiac tissues. Echocardiographic assessments further verified that silencing lncRNA N29 led to a marked improvement in cardiac function, which aligned with the pathological findings revealed by H&E and Masson staining. Meanwhile, immunofluorescence staining results also confirmed that silencing lncRNA N29 effectively inhibited myocardial hypertrophy. Dual luciferase reporter assay and western blot results confirmed that lncRNA can mediate miR-193b-5p/TGFBR2 axis to regulate smad/2/3 expression and mitigate the progression of myocardial hypertrophy. Our findings suggested that the close association between the protective mechanism involving in the silencing lncRNA N29 in myocardial hypertrophy and miR-193b-5p/TGFBR2 axis. We identified that lncRNA N29 might act as a therapeutic target for the treatment of myocardial hypertrophy.
{"title":"Silencing N29 Regulated miR-193b-5p/TGFBR2 Axis to Mitigate the Progression of Cardiac Hypertrophy","authors":"Hao Wu, Xinshuang Wang, Jing Yu, Jiao Li, Zhenhua Ma, Xi Sheng, Han Yang, Liping Wei, Xin Qi","doi":"10.1002/jgm.70002","DOIUrl":"10.1002/jgm.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>The study aimed to analyze differentially expressed lncRNAs in a model of cardiac hypertrophy, specially focusing on the molecular mechanisms of lncRNA NONMMUT023529 (lncRNA N29) in myocardial hypertrophy. Based on gene microarray results, RT-<i>q</i>PCR validation confirmed that lncRNA N29 was significantly upregulated in TAC-induced mice cardiac tissues. Echocardiographic assessments further verified that silencing lncRNA N29 led to a marked improvement in cardiac function, which aligned with the pathological findings revealed by H&E and Masson staining. Meanwhile, immunofluorescence staining results also confirmed that silencing lncRNA N29 effectively inhibited myocardial hypertrophy. Dual luciferase reporter assay and western blot results confirmed that lncRNA can mediate miR-193b-5p/TGFBR2 axis to regulate smad/2/3 expression and mitigate the progression of myocardial hypertrophy. Our findings suggested that the close association between the protective mechanism involving in the silencing lncRNA N29 in myocardial hypertrophy and miR-193b-5p/TGFBR2 axis. We identified that lncRNA N29 might act as a therapeutic target for the treatment of myocardial hypertrophy.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 12","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820220","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}
Pengfei Hu, Ruohan Dou, Zihao Qi, Guanya Liu, Yuantao Su
Background
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and has remarkably high mortality rates. In recent years, altered metabolism has been shown to contribute to the maintenance of pancreatic cancer malignancies. However, the molecular mechanism underlying glucose metabolism reprogramming remains elusive. The aim of this study was to elucidate the role of Yes-associated protein (YAP1), an important effector of the Hippo pathway, in the regulation of aerobic glycolysis in pancreatic cancer. Moreover, the contributions of YAP1 and its associated glycolytic enzymes to prognosis were assessed via The Cancer Genome Atlas (TCGA) dataset.
Methods
YAP1 expression was silenced by short hairpin RNA (shRNA), and its effects on glycolytic activity and mitochondrial respiration were analysed via Agilent Seahorse XF Analysers. The effects of YAP1 on hypoxia-inducible factor-1α (HIF-1α) and its transcriptional activity on glycolytic genes were examined via shRNA-mediated silencing of YAP1. The underlying mechanism by which YAP1 controls the HIF-1α protein level was analysed by exploring the interaction between YAP1 and egg-laying-defective nine family (EGLN) members, which are well-established regulators of the HIF-1α protein level. Finally, the effects of YAP1, EGLN and glycolytic genes on prognosis were analysed via TCGA dataset.
Results
We found that silencing YAP1 expression inhibited anabolic glycolysis in pancreatic cancer cells. YAP1 was demonstrated to regulate the HIF-1α protein level, transcriptional activity and the expression of HIF-1α-targeted glycolytic genes. In-depth analysis demonstrated that EGLN2, a modulator of the HIF-1α protein level, was a direct target of YAP1. Low EGLN2 expression was associated with a poor prognosis. By analysing TCGA dataset and performing immunohistochemical staining, we demonstrated that YAP1 expression was negatively correlated with EGLN2 expression at the mRNA level and protein levels.
Conclusions
The present study demonstrated that YAP1 positively regulates aerobic glycolysis by inhibiting EGLN2 expression, which results in an increased HIF-1α protein level and transcriptional activity. YAP1 was positively regulated and significantly correlated with HIF-1α-targeted glycolytic genes, including glucose transporter type 1(GLUT1), hexokinase2 (HK2) and lactate dehydrogenase A (LDHA). Elevated YAP1 expression and concomitant downregulation of
{"title":"YAP1 Overexpression Enhances the Aerobic Glycolysis Process via Suppression of EGLN2 in Pancreatic Ductal Adenocarcinoma","authors":"Pengfei Hu, Ruohan Dou, Zihao Qi, Guanya Liu, Yuantao Su","doi":"10.1002/jgm.70006","DOIUrl":"10.1002/jgm.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and has remarkably high mortality rates. In recent years, altered metabolism has been shown to contribute to the maintenance of pancreatic cancer malignancies. However, the molecular mechanism underlying glucose metabolism reprogramming remains elusive. The aim of this study was to elucidate the role of Yes-associated protein (YAP1), an important effector of the Hippo pathway, in the regulation of aerobic glycolysis in pancreatic cancer. Moreover, the contributions of YAP1 and its associated glycolytic enzymes to prognosis were assessed via The Cancer Genome Atlas (TCGA) dataset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>YAP1 expression was silenced by short hairpin RNA (shRNA), and its effects on glycolytic activity and mitochondrial respiration were analysed via Agilent Seahorse XF Analysers. The effects of YAP1 on hypoxia-inducible factor-1α (HIF-1α) and its transcriptional activity on glycolytic genes were examined via shRNA-mediated silencing of YAP1. The underlying mechanism by which YAP1 controls the HIF-1α protein level was analysed by exploring the interaction between YAP1 and egg-laying-defective nine family (EGLN) members, which are well-established regulators of the HIF-1α protein level. Finally, the effects of YAP1, EGLN and glycolytic genes on prognosis were analysed via TCGA dataset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that silencing YAP1 expression inhibited anabolic glycolysis in pancreatic cancer cells. YAP1 was demonstrated to regulate the HIF-1α protein level, transcriptional activity and the expression of HIF-1α-targeted glycolytic genes. In-depth analysis demonstrated that EGLN2, a modulator of the HIF-1α protein level, was a direct target of YAP1. Low EGLN2 expression was associated with a poor prognosis. By analysing TCGA dataset and performing immunohistochemical staining, we demonstrated that YAP1 expression was negatively correlated with EGLN2 expression at the mRNA level and protein levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The present study demonstrated that YAP1 positively regulates aerobic glycolysis by inhibiting EGLN2 expression, which results in an increased HIF-1α protein level and transcriptional activity. YAP1 was positively regulated and significantly correlated with HIF-1α-targeted glycolytic genes, including glucose transporter type 1(GLUT1), hexokinase2 (HK2) and lactate dehydrogenase A (LDHA). Elevated YAP1 expression and concomitant downregulation of ","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 12","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuze He, Yunbo Yuan, Linzi Ji, Yuting Shu, Zhihao Wang, Shuxin Zhang, Wanchun Yang, Mina Chen, Yanhui Liu
Background
Glioma, particularly glioblastoma, is the most common and aggressive primary brain tumor, with poor prognosis due to its metabolic heterogeneity. NSUN2, an m5C RNA methyltransferase and direct glucose sensor, has been implicated in various malignancies, but its role in glioma remains unclear.
Methods
Bioinformatic analysis was performed on multiple public databases and our glioma dataset from West China Hospital (WCH). In vitro experiments were conducted to assess the effects of NSUN2 knockdown on glioma cell proliferation, migration, and chemotherapeutic sensitivity. Transcriptomic analysis was employed to obtain mechanistic insights.
Results
NSUN2 expression was significantly upregulated in gliomas and correlated with higher tumor grade and poor prognosis. NSUN2 knockdown reduced glioma cell proliferation, migration, and increased sensitivity to temozolomide. Transcriptomic analysis revealed that NSUN2 knockdown downregulated key genes involved in glioma progression. Mechanistically, NSUN2 positively regulates the activity of mTORC1 signaling, as indicated by phosphorylated S6 ribosomal protein and 4EBP1. Moreover, NSUN2 overexpression reciprocally increased tumor volume compared with controls, indicating NSUN2 promoting glioma cell proliferation in vivo.
Conclusions
Our findings highlight NSUN2 as a critical regulator of glioma malignancy. Targeting NSUN2 disrupts key pathways in glioma progression, suggesting it as a promising therapeutic target. Our work underscores the potential of NSUN2 inhibition to enhance treatment efficacy and improve patient outcomes in glioma.
{"title":"Integrative Analysis Identifies NSUN2 as an Essential Coordinator for Glioma Malignancy and Glucose Metabolism","authors":"Yuze He, Yunbo Yuan, Linzi Ji, Yuting Shu, Zhihao Wang, Shuxin Zhang, Wanchun Yang, Mina Chen, Yanhui Liu","doi":"10.1002/jgm.70004","DOIUrl":"https://doi.org/10.1002/jgm.70004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Glioma, particularly glioblastoma, is the most common and aggressive primary brain tumor, with poor prognosis due to its metabolic heterogeneity. NSUN2, an m5C RNA methyltransferase and direct glucose sensor, has been implicated in various malignancies, but its role in glioma remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatic analysis was performed on multiple public databases and our glioma dataset from West China Hospital (WCH). In vitro experiments were conducted to assess the effects of NSUN2 knockdown on glioma cell proliferation, migration, and chemotherapeutic sensitivity. Transcriptomic analysis was employed to obtain mechanistic insights.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NSUN2 expression was significantly upregulated in gliomas and correlated with higher tumor grade and poor prognosis. NSUN2 knockdown reduced glioma cell proliferation, migration, and increased sensitivity to temozolomide. Transcriptomic analysis revealed that NSUN2 knockdown downregulated key genes involved in glioma progression. Mechanistically, NSUN2 positively regulates the activity of mTORC1 signaling, as indicated by phosphorylated S6 ribosomal protein and 4EBP1. Moreover, NSUN2 overexpression reciprocally increased tumor volume compared with controls, indicating NSUN2 promoting glioma cell proliferation in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlight NSUN2 as a critical regulator of glioma malignancy. Targeting NSUN2 disrupts key pathways in glioma progression, suggesting it as a promising therapeutic target. Our work underscores the potential of NSUN2 inhibition to enhance treatment efficacy and improve patient outcomes in glioma.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 12","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764247","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}
Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically “cold” to “hot.” Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.
{"title":"Augmentation of Solid Tumor Immunotherapy With IL-12","authors":"Christian Geils, Katie L. Kathrein","doi":"10.1002/jgm.70000","DOIUrl":"https://doi.org/10.1002/jgm.70000","url":null,"abstract":"<p><i>Immunotherapy</i> describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically “cold” to “hot.” Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 12","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jgm.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anterior segment dysgenesis (ASD) disorders are phenotypically diverse and have multiple associated genes. This study reports on a Chinese family of three generations with ASD disorders and identifies several associated genes and pathways of the disorders.
Methods
The history of illnesses, clinical observations, and blood samples of all family members were collected. Whole exome sequencing (WES) and polymerase chain reaction (PCR) were conducted to detect the genetic variants between patients and control members in the family. Transcriptomic study and quantitative real-time PCR (qRT-PCR) were subsequently performed to validate the differentially expressed genes (DEGs) and investigate the possible mechanisms of ASD caused by the variations.
Results
The medical examination and illness history identified four members of the family diagnosed with ASD (III:3, II:3, II:2 and I:2). All four patients suffered various degrees of corneal opacity with abnormally thin cornea. Members II:3, II:2, and I:2 also had cataracts and iris hypoplasia and received an intraocular lens implant before the age of 20. We detected a heterozygous missense variation c.6122G > A (p.R2041Q and rs746145647) in fibronectin1 (FN1) in the four patients in this family that was absent in the other healthy members. The transcriptome and RT-PCR analysis revealed that the FN1 mRNA level was significantly upregulated in the blood samples of patients compared to healthy controls. A total of 909 DEGs were identified, including 607 upregulated genes and 302 downregulated genes. GO and KEGG annotation revealed that many DEGs were involved in biological processes closely related to focal adhesion, extracellular matrix-receptor interaction, TGF-β pathway, and the immune system.
Conclusion
This study identified an FN1 mutation associated with ASD patients and probed potential pathways related to it.
{"title":"WES and Transcriptome Analysis Identifies FN1 as a Candidate Gene for Anterior Segment Dysgenesis","authors":"Qinghong Lin, Xuejun Wang, Xiaosong Han, Xiaoliao Peng, Xiaoyu Zhang, Yuwen Ran, Ling Sun, Yan Wang, Tian Han, Xingtao Zhou","doi":"10.1002/jgm.70001","DOIUrl":"10.1002/jgm.70001","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Anterior segment dysgenesis (ASD) disorders are phenotypically diverse and have multiple associated genes. This study reports on a Chinese family of three generations with ASD disorders and identifies several associated genes and pathways of the disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The history of illnesses, clinical observations, and blood samples of all family members were collected. Whole exome sequencing (WES) and polymerase chain reaction (PCR) were conducted to detect the genetic variants between patients and control members in the family. Transcriptomic study and quantitative real-time PCR (qRT-PCR) were subsequently performed to validate the differentially expressed genes (DEGs) and investigate the possible mechanisms of ASD caused by the variations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The medical examination and illness history identified four members of the family diagnosed with ASD (III:3, II:3, II:2 and I:2). All four patients suffered various degrees of corneal opacity with abnormally thin cornea. Members II:3, II:2, and I:2 also had cataracts and iris hypoplasia and received an intraocular lens implant before the age of 20. We detected a heterozygous missense variation c.6122G > A (p.R2041Q and rs746145647) in fibronectin1 (<i>FN1</i>) in the four patients in this family that was absent in the other healthy members. The transcriptome and RT-PCR analysis revealed that the <i>FN1</i> mRNA level was significantly upregulated in the blood samples of patients compared to healthy controls. A total of 909 DEGs were identified, including 607 upregulated genes and 302 downregulated genes. GO and KEGG annotation revealed that many DEGs were involved in biological processes closely related to focal adhesion, extracellular matrix-receptor interaction, TGF-β pathway, and the immune system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study identified an FN1 mutation associated with ASD patients and probed potential pathways related to it.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 12","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142734786","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}
Osteoporosis manifests through adipocyte accrual and osteoblast diminution within bone marrow. However, the precise mechanisms driving the shift from osteogenesis to adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remain largely undefined. In this study, we harnessed the power of bioinformatic tools to analyze gene expression patterns of BMSCs during adipogenic differentiation and osteoporosis using the data from Gene Expression Omnibus (GEO) repositories (GSE113253 and GSE35956), complemented by in vitro and in vivo experiments to validate the findings. Five distinct expression profiles of differentially expressed genes across the adipogenic timeline were identified. The initial phase is marked by ribosome biogenesis and rRNA processing, which is followed by the metabolism of organic acids and processing of inorganic ions. In contrast, the terminal phase is characterized by lipid transport, accumulation, and metabolism, alongside inorganic cation metabolism, thereby underscoring unique transcriptional signatures during the early and late stages of adipogenic differentiation. In BMSCs derived from osteoporotic samples, there is a notable decline in cellular proliferation and a diminished osteogenic capacity. Critically, the genes common to both adipogenesis and osteoporosis in BMSCs are predominantly involved in the negative regulation of Wnt signaling and cellular proliferation. Key genes including SOCS1, MYC, CEBPB, FYN, AXIN2, and RXRA are identified and show downregulation in BMSCs from aged mice. Subsequent in vitro experiments have validated the regulatory influence of RXRA on both adipogenic and osteogenic differentiations of BMSCs, highlighting its crucial role as a central modulator in bone formation and the pathophysiology of osteoporosis.
{"title":"Integrative analyses of genetic mechanisms responsible for bone–fat imbalance in osteoporosis","authors":"Zheng Zhang, Zhengbo Tao, Yuhe Zhang, Zhanrong Zhang, Weijin Zhang, Xuanrui Zhang, Jinzhu Zhao, Chunsheng Tao, Xuhui Zhou","doi":"10.1002/jgm.3739","DOIUrl":"10.1002/jgm.3739","url":null,"abstract":"<p>Osteoporosis manifests through adipocyte accrual and osteoblast diminution within bone marrow. However, the precise mechanisms driving the shift from osteogenesis to adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remain largely undefined. In this study, we harnessed the power of bioinformatic tools to analyze gene expression patterns of BMSCs during adipogenic differentiation and osteoporosis using the data from Gene Expression Omnibus (GEO) repositories (GSE113253 and GSE35956), complemented by in vitro and in vivo experiments to validate the findings. Five distinct expression profiles of differentially expressed genes across the adipogenic timeline were identified. The initial phase is marked by ribosome biogenesis and rRNA processing, which is followed by the metabolism of organic acids and processing of inorganic ions. In contrast, the terminal phase is characterized by lipid transport, accumulation, and metabolism, alongside inorganic cation metabolism, thereby underscoring unique transcriptional signatures during the early and late stages of adipogenic differentiation. In BMSCs derived from osteoporotic samples, there is a notable decline in cellular proliferation and a diminished osteogenic capacity. Critically, the genes common to both adipogenesis and osteoporosis in BMSCs are predominantly involved in the negative regulation of Wnt signaling and cellular proliferation. Key genes including SOCS1, MYC, CEBPB, FYN, AXIN2, and RXRA are identified and show downregulation in BMSCs from aged mice. Subsequent in vitro experiments have validated the regulatory influence of RXRA on both adipogenic and osteogenic differentiations of BMSCs, highlighting its crucial role as a central modulator in bone formation and the pathophysiology of osteoporosis.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585266","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}
Since ANGPTL4 was discovered to be involved in lipid metabolism in 2000 for the first time, Angptl4 has attracted the attention of researchers. With the further research, it was found that angptl4 was also involved in many biological activities (glucose metabolism, angiogenesis, wound healing, tumor growth, etc.) in vivo. In this review, we provide an overview of the fundamental role of ANGPTL4 in metabolic regulation and its impact on tumor growth. These insights may provide a way for exploring ANGPTL4 as a potential therapeutic target for future disease treatments.
{"title":"ANGPTL4—A protein involved in glucose metabolism, lipid metabolism, and tumor development","authors":"Zhilong Xu, Gening Jiang","doi":"10.1002/jgm.3740","DOIUrl":"10.1002/jgm.3740","url":null,"abstract":"<p>Since ANGPTL4 was discovered to be involved in lipid metabolism in 2000 for the first time, Angptl4 has attracted the attention of researchers. With the further research, it was found that angptl4 was also involved in many biological activities (glucose metabolism, angiogenesis, wound healing, tumor growth, etc.) in vivo. In this review, we provide an overview of the fundamental role of ANGPTL4 in metabolic regulation and its impact on tumor growth. These insights may provide a way for exploring ANGPTL4 as a potential therapeutic target for future disease treatments.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523750","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}
Xiaofei Chen, Lijun He, Hai Zhong, Chenxin Yan, Bin Ke, Lin Shi
Background
Non-small cell lung cancer (NSCLC) is the main type of lung cancer with high morbidity and mortality. Vascular mimicry (VM), a distinct microcirculation model in tumors that differs from classical angiogenesis, is strongly associated with poor clinical outcomes in cancer patients. miR-491-5p has been reported to prevent NSCLC progression, including proliferation, metastasis, and angiogenesis. However, the effect and mechanism of miR-491-5p on VM have not been studied in NSCLC.
Methods
The expression of miR-491-5p was detected by quantitative reverse transcription PCR (qPCR) and fluorescence in situ hybridization (FISH). Cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) staining assays were used to examine cell growth. Tube formation assay was used to assess VM in NSCLC cells. Immunohistochemistry (IHC) and western blot were performed to detect protein expression. Immunoprecipitation was used to confirm the interaction between OTU deubiquitinase 7B (OTUD7B) and vascular endothelial growth factor A (VEGFA), and the level of ubiquitinated VEGFA. A nude mouse tumorigenesis model was used to evaluate the carcinogenic capacity of NSCLC cells in vivo. Luciferase reporter assay was used to identify the potential target of miR-491-5p.
Results
MiR-491-5p was found downregulated in NSCLC tissues, and miR-491-5p deficiency was strongly associated with angiogenesis. miR-491-5p mimics suppressed cell viability, migration, and VM. Conversely, an inhibitor of miR-491-5p had the opposite effect. OTUD7B, a deubiquitinase, was identified as a downstream target of miR-491-5p. A luciferase reporter assay indicated that miR-491-5p directly binds to the 3′UTR of OTUD7B. Moreover, mimics of miR-491-5p caused a significant reduction in the OTUD7B protein in NSCLC cells, and an inhibitor of miR-491-5p stabilized the OTUD7B protein. In addition, overexpression of OTUD7B promoted cell proliferation, migration, and VM, similar to the effects of an inhibitor of miR-491-5p. Further exploration revealed that OTUD7B interacts with VEGFA and that the miR-491-5p-OTUD7B axis modulates the ubiquitination of VEGFA. The rescue experiment indicated that OTUD7B compromised the inhibitory effects of miR-491-5p on the cellular function of NSCLC cells.
Conclusions
Overall, our study first proved that miR-491-5p impedes VM by suppressing OUTD7B and promoting the ubiquitination of VEGFA. The miR-491-5p/OTUD7B axis may be a novel target for antiangiogenic therapy in NSCLC.
{"title":"The suppression of OTUD7B by miR-491-5p enhances the ubiquitination of VEGFA to suppress vascular mimicry in non-small cell lung cancer","authors":"Xiaofei Chen, Lijun He, Hai Zhong, Chenxin Yan, Bin Ke, Lin Shi","doi":"10.1002/jgm.3743","DOIUrl":"10.1002/jgm.3743","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Non-small cell lung cancer (NSCLC) is the main type of lung cancer with high morbidity and mortality. Vascular mimicry (VM), a distinct microcirculation model in tumors that differs from classical angiogenesis, is strongly associated with poor clinical outcomes in cancer patients. miR-491-5p has been reported to prevent NSCLC progression, including proliferation, metastasis, and angiogenesis. However, the effect and mechanism of miR-491-5p on VM have not been studied in NSCLC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression of miR-491-5p was detected by quantitative reverse transcription PCR (qPCR) and fluorescence in situ hybridization (FISH). Cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) staining assays were used to examine cell growth. Tube formation assay was used to assess VM in NSCLC cells. Immunohistochemistry (IHC) and western blot were performed to detect protein expression. Immunoprecipitation was used to confirm the interaction between OTU deubiquitinase 7B (OTUD7B) and vascular endothelial growth factor A (VEGFA), and the level of ubiquitinated VEGFA. A nude mouse tumorigenesis model was used to evaluate the carcinogenic capacity of NSCLC cells in vivo. Luciferase reporter assay was used to identify the potential target of miR-491-5p.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MiR-491-5p was found downregulated in NSCLC tissues, and miR-491-5p deficiency was strongly associated with angiogenesis. miR-491-5p mimics suppressed cell viability, migration, and VM. Conversely, an inhibitor of miR-491-5p had the opposite effect. OTUD7B, a deubiquitinase, was identified as a downstream target of miR-491-5p. A luciferase reporter assay indicated that miR-491-5p directly binds to the 3′UTR of OTUD7B. Moreover, mimics of miR-491-5p caused a significant reduction in the OTUD7B protein in NSCLC cells, and an inhibitor of miR-491-5p stabilized the OTUD7B protein. In addition, overexpression of OTUD7B promoted cell proliferation, migration, and VM, similar to the effects of an inhibitor of miR-491-5p. Further exploration revealed that OTUD7B interacts with VEGFA and that the miR-491-5p-OTUD7B axis modulates the ubiquitination of VEGFA. The rescue experiment indicated that OTUD7B compromised the inhibitory effects of miR-491-5p on the cellular function of NSCLC cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Overall, our study first proved that miR-491-5p impedes VM by suppressing OUTD7B and promoting the ubiquitination of VEGFA. The miR-491-5p/OTUD7B axis may be a novel target for antiangiogenic therapy in NSCLC.</p>\u0000 </section>\u0000 </d","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395569","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}
Jing-Jing Lian, Zhao-Xing Li, Hui-ling Lin, Ming-Chuang Sun, Hao Wu, An-Qi Feng, Kang Fang, Xiao-Yuan Wang, Ai-Ping Xu, Yuan Chu, Li Zhang, Tao Chen, Mei-Dong Xu
This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1’s promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1’s regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.
{"title":"The activation of asparagine synthetase by the transcription factor FOXM1 plays a pivotal role in the initiation and progression of ESCC","authors":"Jing-Jing Lian, Zhao-Xing Li, Hui-ling Lin, Ming-Chuang Sun, Hao Wu, An-Qi Feng, Kang Fang, Xiao-Yuan Wang, Ai-Ping Xu, Yuan Chu, Li Zhang, Tao Chen, Mei-Dong Xu","doi":"10.1002/jgm.3741","DOIUrl":"10.1002/jgm.3741","url":null,"abstract":"<p>This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1’s promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1’s regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.</p>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jgm.3741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fuyun Zhu, Dezeng Zou, Ping Shi, Lianhua Tang, Dan Wu, Xiaoxue Hu, Fei Yin, Jianhui Liu
Background
With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied.
Methods
The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package “CancerSubtype” and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe2+ with commercial FerroOrange kits.
Results
Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression.
Conclusions
DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.
{"title":"Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis","authors":"Fuyun Zhu, Dezeng Zou, Ping Shi, Lianhua Tang, Dan Wu, Xiaoxue Hu, Fei Yin, Jianhui Liu","doi":"10.1002/jgm.3742","DOIUrl":"10.1002/jgm.3742","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package “CancerSubtype” and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe<sup>2+</sup> with commercial FerroOrange kits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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