Pub Date : 2024-11-15DOI: 10.1016/j.cellsig.2024.111510
Xuan Shu , Jiahe Yi , Jiangfeng Li , Yufan Ying , Yijie Tang , Ziyan Chen , Jiaming Wang , Fenghao Zhang , Dingheng Lu , Yuqing Wu , Jiazhu Sun , Shen Lin , Zhixiang Qi , Danni Chen , Xiao Wang , Hong Chen , Liping Xie , Xueyou Ma , Jindan Luo
Prostate cancer (PCa) gradually becomes the most common cancer in men in many countries, of which circRNAs and methylated modification exert an essential role in PCa progression. However, the concrete mechanisms of N6-methyladenosine (m6A) modification of circRNAs in PCa remain unclear. In our study, we identified circRPS6KC1, a novel and up-regulated circular RNA in PCa, through circRNA sequencing. We discovered that METTL3 and YTHDF1 were involved in the m6A modification of circRPS6KC1 and the stabilization. Furthermore, we found that suppression of circRPS6KC1 contributed to cellular senescence in prostate cancer. CircRPS6KC1 acted as the miR-761 sponge to regulate the FOXM1 expression. FOXM1 mediated the transcription of PCNA and influenced the p21 degradation, which resulted in up-regulation of p21 protein in a p53-independent manner. In conclusion, our findings showed that N6-methyladenosine modification by METTL3 and YTHDF1 stabilized circRPS6KC1, and circRPS6KC1 played an essential role on cellular senescence via FOXM1/PCNA axis in prostate cancer.
{"title":"N6-methyladenosine-modified circRPS6KC1 regulated cellular senescence in prostate cancer via FOXM1/PCNA axis","authors":"Xuan Shu , Jiahe Yi , Jiangfeng Li , Yufan Ying , Yijie Tang , Ziyan Chen , Jiaming Wang , Fenghao Zhang , Dingheng Lu , Yuqing Wu , Jiazhu Sun , Shen Lin , Zhixiang Qi , Danni Chen , Xiao Wang , Hong Chen , Liping Xie , Xueyou Ma , Jindan Luo","doi":"10.1016/j.cellsig.2024.111510","DOIUrl":"10.1016/j.cellsig.2024.111510","url":null,"abstract":"<div><div>Prostate cancer (PCa) gradually becomes the most common cancer in men in many countries, of which circRNAs and methylated modification exert an essential role in PCa progression. However, the concrete mechanisms of N6-methyladenosine (m6A) modification of circRNAs in PCa remain unclear. In our study, we identified circRPS6KC1, a novel and up-regulated circular RNA in PCa, through circRNA sequencing. We discovered that METTL3 and YTHDF1 were involved in the m6A modification of circRPS6KC1 and the stabilization. Furthermore, we found that suppression of circRPS6KC1 contributed to cellular senescence in prostate cancer. CircRPS6KC1 acted as the miR-761 sponge to regulate the FOXM1 expression. FOXM1 mediated the transcription of PCNA and influenced the p21 degradation, which resulted in up-regulation of p21 protein in a p53-independent manner. In conclusion, our findings showed that N6-methyladenosine modification by METTL3 and YTHDF1 stabilized circRPS6KC1, and circRPS6KC1 played an essential role on cellular senescence via FOXM1/PCNA axis in prostate cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111510"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.cellsig.2024.111507
Parameswar Dalai , Dhruvi Shah , Jigna Shah , Kinal Soni , Aditya Mohanty , Kavya Thanki , Heena Dave , Reena Agrawal-Rajput
Studies have reported that cellular metabolism at the tumor-immune microenvironment (TiME) serves as a critical checkpoint and perturbs/supports anti-cancer immunity. Extra cellular ATP (eATP) may mediate anti-cancer immune response; however, its catabolism by ectonucleotidase generates immunosuppressive adenosine. In the presented work, we have tried to repurpose doxycycline with or without an antagonist of ectonucleotidase for mitigating ATP metabolism and immunosuppression. In this methodology eATP and adenosine levels were quantified. Bone marrow-derived M1 and M2 polarized macrophages were maintained in tumor mimicking condition (TMC). Total/CD4+Tcells were co-cultured with macrophages to understand the impact of doxycycline and/or antagonist of ectonucleotidase on T cell/subset differentiation. Preclinical efficacy of doxycycline and/or ectonucleotidase antagonist and their synergy was scored in 4T1-induced breast carcinoma. We found that Doxycycline manipulated macrophage polarization by decreasing the frequency of CD206+M2 macrophages, which resulted in enhanced CD4+ directed CD8+ T cell response. Doxycycline alleviated the expression of CD39 and CD73, rescuing ATP catabolism. Doxycycline delayed tumor growth by enhancing F4/80+ CD86+ M1 macrophages and subsequently anti-tumor Tbet+ CD4+Tcells, attenuating the frequency of FOXP3+ regulatory T cells, which was cooperatively supported by ARL67156 and AMPCP (CD39 and CD73 antagonist).A synergy was observed with ARL67156 and AMPC Pensuring a possibility of using doxycycline alone or in combination with an antagonist of ectonucleotidase to present adenosine-mediated immunosuppression. Subsequently, our finding indicated that prospective usage of doxycycline as a novel metabolic checkpoint blocker (IMB) against ectonucleotidase and may be modified/delivered appropriately as a monotherapy or in combination with antagonists of ectonucleotidases as an IMB.
{"title":"Antagonists of CD39 and CD73 potentiate doxycycline repositioning to induce a potent antitumor immune response","authors":"Parameswar Dalai , Dhruvi Shah , Jigna Shah , Kinal Soni , Aditya Mohanty , Kavya Thanki , Heena Dave , Reena Agrawal-Rajput","doi":"10.1016/j.cellsig.2024.111507","DOIUrl":"10.1016/j.cellsig.2024.111507","url":null,"abstract":"<div><div>Studies have reported that cellular metabolism at the tumor-immune microenvironment (TiME) serves as a critical checkpoint and perturbs/supports anti-cancer immunity. Extra cellular ATP (eATP) may mediate anti-cancer immune response; however, its catabolism by ectonucleotidase generates immunosuppressive adenosine. In the presented work, we have tried to repurpose doxycycline with or without an antagonist of ectonucleotidase for mitigating ATP metabolism and immunosuppression. In this methodology eATP and adenosine levels were quantified. Bone marrow-derived M1 and M2 polarized macrophages were maintained in tumor mimicking condition (TMC). Total/CD4<sup>+</sup>Tcells were co-cultured with macrophages to understand the impact of doxycycline and/or antagonist of ectonucleotidase on T cell/subset differentiation. Preclinical efficacy of doxycycline and/or ectonucleotidase antagonist and their synergy was scored in 4T1-induced breast carcinoma. We found that Doxycycline manipulated macrophage polarization by decreasing the frequency of CD206<sup>+</sup>M2 macrophages, which resulted in enhanced CD4<sup>+</sup> directed CD8<sup>+</sup> T cell response. Doxycycline alleviated the expression of CD39 and CD73, rescuing ATP catabolism. Doxycycline delayed tumor growth by enhancing F4/80<sup>+</sup> CD86<sup>+</sup> M1 macrophages and subsequently anti-tumor Tbet<sup>+</sup> CD4<sup>+</sup>Tcells, attenuating the frequency of FOXP3<sup>+</sup> regulatory T cells, which was cooperatively supported by ARL67156 and AMPCP (CD39 and CD73 antagonist).A synergy was observed with ARL67156 and AMPC Pensuring a possibility of using doxycycline alone or in combination with an antagonist of ectonucleotidase to present adenosine-mediated immunosuppression. Subsequently, our finding indicated that prospective usage of doxycycline as a novel metabolic checkpoint blocker (IMB) against ectonucleotidase and may be modified/delivered appropriately as a monotherapy or in combination with antagonists of ectonucleotidases as an IMB.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111507"},"PeriodicalIF":4.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.cellsig.2024.111506
Yuanhui Jia, Han Xie, Shengyu Wu, Jiaqi Dong, Hao Ying
Background
Aberrant methylation of genomic DNA has been found in preeclamptic placentas, which is characterized by elevated DNA methylation and hypermethylation of gene body regions, but the underlying mechanism is not yet fully understood.
Methods
Global DNA methylation was assessed through ELISA and HPLC. The methylation sites were detected using the Illumina Human Methylation 450 K Microarray. The methylation level of FAM46C promoter and gene body was detected through the bisulfite sequencing. RNA-seq was utilized to investigate the mechanism by which DNMT3A and FAM46C mediate the migration and invasion of trophoblast cells.
Results
We discovered that DNMT3A knockdown led to elevated levels of gene body methylation and FAM46C transcription. FAM46C downregulation completely rescued the suppressive effects caused by DNMT3A knockdown on the migration and invasion of trophoblast cells. Mechanistically, DNMT3A reduction led to an increase in the enrichment of DNMT3B and DNMT1 in the gene body region of FAM46C. The results of transcriptome sequencing showed that DNMT3A and FAM46C regulate the adhesion of trophoblast cells. Elevated expression of FAM46C and increased methylation levels within its gene body region were observed in extravillous trophoblast cells of early-onset preeclamptic placentas.
Conclusions
DNMT3A-mediated aberrant FAM46C gene body methylation is relevant to the development of early-onset preeclampsia.
背景：在子痫前期胎盘中发现了基因组 DNA 的异常甲基化，其特征是 DNA 甲基化升高和基因体区域的高甲基化，但其潜在机制尚未完全清楚：方法：通过酶联免疫吸附和高效液相色谱法评估全球 DNA 甲基化情况。采用 Illumina 人类甲基化 450 K 芯片检测甲基化位点。通过亚硫酸氢盐测序检测 FAM46C 启动子和基因体的甲基化水平。利用RNA-seq研究了DNMT3A和FAM46C介导滋养层细胞迁移和侵袭的机制：结果：我们发现，DNMT3A敲除会导致基因体甲基化和FAM46C转录水平升高。结果：我们发现，DNMT3A敲除会导致基因体甲基化和FAM46C转录水平升高，而FAM46C的下调可完全缓解DNMT3A敲除对滋养层细胞迁移和侵袭的抑制作用。从机理上讲，DNMT3A的减少导致DNMT3B和DNMT1在FAM46C基因体区域的富集增加。转录组测序结果显示，DNMT3A和FAM46C调控滋养层细胞的粘附。在早发性子痫前期胎盘的滋养层外细胞中观察到了FAM46C的表达升高及其基因体区甲基化水平的升高：结论：DNMT3A介导的FAM46C基因体甲基化异常与早发性子痫前期的发生有关。
{"title":"Induction of FAM46C expression mediated by DNMT3A downregulation is involved in early-onset preeclampsia through gene body methylation","authors":"Yuanhui Jia, Han Xie, Shengyu Wu, Jiaqi Dong, Hao Ying","doi":"10.1016/j.cellsig.2024.111506","DOIUrl":"10.1016/j.cellsig.2024.111506","url":null,"abstract":"<div><h3>Background</h3><div>Aberrant methylation of genomic DNA has been found in preeclamptic placentas, which is characterized by elevated DNA methylation and hypermethylation of gene body regions, but the underlying mechanism is not yet fully understood.</div></div><div><h3>Methods</h3><div>Global DNA methylation was assessed through ELISA and HPLC. The methylation sites were detected using the Illumina Human Methylation 450 K Microarray. The methylation level of FAM46C promoter and gene body was detected through the bisulfite sequencing. RNA-seq was utilized to investigate the mechanism by which DNMT3A and FAM46C mediate the migration and invasion of trophoblast cells.</div></div><div><h3>Results</h3><div>We discovered that DNMT3A knockdown led to elevated levels of gene body methylation and FAM46C transcription. FAM46C downregulation completely rescued the suppressive effects caused by DNMT3A knockdown on the migration and invasion of trophoblast cells. Mechanistically, DNMT3A reduction led to an increase in the enrichment of DNMT3B and DNMT1 in the gene body region of FAM46C. The results of transcriptome sequencing showed that DNMT3A and FAM46C regulate the adhesion of trophoblast cells. Elevated expression of FAM46C and increased methylation levels within its gene body region were observed in extravillous trophoblast cells of early-onset preeclamptic placentas.</div></div><div><h3>Conclusions</h3><div>DNMT3A-mediated aberrant FAM46C gene body methylation is relevant to the development of early-onset preeclampsia.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111506"},"PeriodicalIF":4.4,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.cellsig.2024.111502
Yutong Chen, Ying-Qiang Shen
Reactive oxygen species (ROS) originate from diverse sources and regulate multiple signaling pathways within the cellular environment. Their generation is intricately controlled, and disruptions in their signaling or atypical levels can precipitate pathological conditions. Epigenetics, the examination of heritable alterations in gene expression independent of changes in the genetic code, has been implicated in the pathogenesis of various diseases through aberrant epigenetic modifications. The significant contribution of epigenetic modifications to disease progression underscores their potential as crucial therapeutic targets for a wide array of medical conditions. This study begins by providing an overview of ROS and epigenetics, followed by a discussion on the mechanisms of epigenetic modifications such as DNA methylation, histone modification, and RNA modification-mediated regulation. Subsequently, a detailed examination of the interaction between ROS and epigenetic modifications is presented, offering new perspectives and avenues for exploring the mechanisms underlying specific epigenetic diseases and the development of novel therapeutics.
活性氧（ROS）来源多样，可调节细胞环境中的多种信号通路。它们的生成受到复杂的控制，其信号传导的中断或非典型水平可导致病理状况。表观遗传学是对独立于遗传密码变化的基因表达可遗传改变的研究，它通过异常的表观遗传修饰与各种疾病的发病机制有关。表观遗传修饰对疾病进展的重大影响凸显了其作为各种疾病关键治疗靶点的潜力。本研究首先概述了 ROS 和表观遗传学，然后讨论了 DNA 甲基化、组蛋白修饰和 RNA 修饰介导的调控等表观遗传修饰的机制。随后，详细探讨了 ROS 与表观遗传修饰之间的相互作用，为探索特定表观遗传疾病的机制和开发新型疗法提供了新的视角和途径。
{"title":"Role of reactive oxygen species in regulating epigenetic modifications","authors":"Yutong Chen, Ying-Qiang Shen","doi":"10.1016/j.cellsig.2024.111502","DOIUrl":"10.1016/j.cellsig.2024.111502","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) originate from diverse sources and regulate multiple signaling pathways within the cellular environment. Their generation is intricately controlled, and disruptions in their signaling or atypical levels can precipitate pathological conditions. Epigenetics, the examination of heritable alterations in gene expression independent of changes in the genetic code, has been implicated in the pathogenesis of various diseases through aberrant epigenetic modifications. The significant contribution of epigenetic modifications to disease progression underscores their potential as crucial therapeutic targets for a wide array of medical conditions. This study begins by providing an overview of ROS and epigenetics, followed by a discussion on the mechanisms of epigenetic modifications such as DNA methylation, histone modification, and RNA modification-mediated regulation. Subsequently, a detailed examination of the interaction between ROS and epigenetic modifications is presented, offering new perspectives and avenues for exploring the mechanisms underlying specific epigenetic diseases and the development of novel therapeutics.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111502"},"PeriodicalIF":4.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-05DOI: 10.1016/j.cellsig.2024.111503
Shokufeh Razi , Javad Yaghmoorian Khojini , Hamid Norioun , Mohammad Javad Hayati , Nasim Naseri , Amir Tajbaksh , Seyed Mohammad Gheibihayat
Ferroptosis, a form of iron-dependent regulated cell death, is characterized by the accumulation of lipid peroxides and distinctive morphological features. Moreover, the reduction of intracellular antioxidant enzyme expression or activity, specifically glutathione peroxidase 4 (GPX4) results in activation of the endogenous pathway of ferroptosis. In this review, we aimed to explore the intricate interplay between microRNAs (miRNAs) and ferroptosis, shedding light on its implications in various disease pathologies. This review delves into the role of miRNAs in modulating key regulators of ferroptosis, including genes involved in iron metabolism, lipid peroxidation, and antioxidant defenses. Furthermore, the potential of targeting miRNAs for therapeutic interventions in ferroptosis-related diseases, such as cancer, neurodegenerative disorders, and ischemia/reperfusion injury, is highlighted.
{"title":"MicroRNA-mediated regulation of Ferroptosis: Implications for disease pathogenesis and therapeutic interventions","authors":"Shokufeh Razi , Javad Yaghmoorian Khojini , Hamid Norioun , Mohammad Javad Hayati , Nasim Naseri , Amir Tajbaksh , Seyed Mohammad Gheibihayat","doi":"10.1016/j.cellsig.2024.111503","DOIUrl":"10.1016/j.cellsig.2024.111503","url":null,"abstract":"<div><div>Ferroptosis, a form of iron-dependent regulated cell death, is characterized by the accumulation of lipid peroxides and distinctive morphological features. Moreover, the reduction of intracellular antioxidant enzyme expression or activity, specifically glutathione peroxidase 4 (GPX4) results in activation of the endogenous pathway of ferroptosis. In this review, we aimed to explore the intricate interplay between microRNAs (miRNAs) and ferroptosis, shedding light on its implications in various disease pathologies. This review delves into the role of miRNAs in modulating key regulators of ferroptosis, including genes involved in iron metabolism, lipid peroxidation, and antioxidant defenses. Furthermore, the potential of targeting miRNAs for therapeutic interventions in ferroptosis-related diseases, such as cancer, neurodegenerative disorders, and ischemia/reperfusion injury, is highlighted.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111503"},"PeriodicalIF":4.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.cellsig.2024.111501
Enjie Xu , Zhen Huang , Kunpeng Zhu , Jianping Hu , Xiaolong Ma , Yongjie Wang , Jiazhuang Zhu , Chunlin Zhang
Background
Osteosarcoma (OS) cells commonly suffer from hypoxia and dedifferentiation, resulting in poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated cellular signaling.
Methods
We performed sphere formation assays and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and detected the expression of PDGFRB, p-PDGFRB, focal adhesion kinase (FAK), p-FAK, phosphorylated myosin light chain 2 (p-MLC2), and ras homolog family member A (RhoA) in each group. The effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS cell metastasis both in vitro and in vivo.
Results
Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A upregulated PDGFRB, subsequently activated RhoA, and increased the phosphorylation of MLC2. PDGFRB also enhanced the phosphorylation of FAK. The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB promoted cell dedifferentiation and had a significant impact on the migration and invasion abilities of OS cells in vitro. In addition, PDGFRB increased pulmonary metastasis of OS cells in vivo.
Conclusion
Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton, a process likely linked to the activation of RhoA and the phosphorylation of, thereby promoting OS dedifferentiation and pulmonary metastasis.
{"title":"PDGFRB promotes dedifferentiation and pulmonary metastasis through rearrangement of cytoskeleton under hypoxic microenvironment in osteosarcoma","authors":"Enjie Xu , Zhen Huang , Kunpeng Zhu , Jianping Hu , Xiaolong Ma , Yongjie Wang , Jiazhuang Zhu , Chunlin Zhang","doi":"10.1016/j.cellsig.2024.111501","DOIUrl":"10.1016/j.cellsig.2024.111501","url":null,"abstract":"<div><h3>Background</h3><div>Osteosarcoma (OS) cells commonly suffer from hypoxia and dedifferentiation, resulting in poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated cellular signaling.</div></div><div><h3>Methods</h3><div>We performed sphere formation assays and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and detected the expression of PDGFRB, p-PDGFRB, focal adhesion kinase (FAK), p-FAK, phosphorylated myosin light chain 2 (p-MLC2), and ras homolog family member A (RhoA) in each group. The effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS cell metastasis both in vitro and in vivo.</div></div><div><h3>Results</h3><div>Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A upregulated PDGFRB, subsequently activated RhoA, and increased the phosphorylation of MLC2. PDGFRB also enhanced the phosphorylation of FAK. The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB promoted cell dedifferentiation and had a significant impact on the migration and invasion abilities of OS cells in vitro. In addition, PDGFRB increased pulmonary metastasis of OS cells in vivo.</div></div><div><h3>Conclusion</h3><div>Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton, a process likely linked to the activation of RhoA and the phosphorylation of, thereby promoting OS dedifferentiation and pulmonary metastasis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111501"},"PeriodicalIF":4.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.cellsig.2024.111504
Minhao Qiu , Yining Huang , Xiaoying Zhou , Junyu Yu , Jianmin Li , Wei Wang , Maddalena Zippi , Sirio Fiorino , Wandong Hong
Background
The mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood.
Aims
To investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP.
Methods
In AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2). GeneMANIA has been used for the prediction of potential interaction mechanisms. Validation was carried out using an experimental AP model and a bi-directional Mendelian randomization (MR) analysis.
Results
Compared to mild AP, patients with severe AP had higher gene expression of MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. GeneMANIA revealed 77.6 % physical interactions among MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. Our results indicated that HLAP group had a more severe pancreatic injury, a stronger inflammatory response with higher serum levels of TNF-α, IL-6 and IL-1β in comparison with the AP group, which were significantly mitigated in HLAP-Pi group. Furthermore, SB 203580 inhibited increasing levels of malondialdehyde (MDA) in serum and of inducible nitric oxide synthase (iNOS), P38MAPK, p-P38MAPK and NF-κB p65 in pancreatic tissue as well as decreasing serum values of SOD and GSH-PX in HLAP group. MR analysis suggested that MAPK14 levels were negatively associated with the SOD levels, by using the inverse variance weighted (IVW) method (b = −0.193: se = 0.225; P = 1.03e-17). Reverse MR analysis indicated that SOD was negatively associated with the MAPK14 levels in the IVW analysis (b = −0.163: se = 0.020; P = 1.38e-15).
Conclusion
Interactions between P38MAPK and oxidative stress may play an important role in the pathogenesis of HLAP.
背景：高脂血症相关性急性胰腺炎（HLAP）的发病机制尚未完全明了：目的：研究P38MAPK（丝裂原活化蛋白激酶）和氧化应激在急性胰腺炎发病机制中的作用：在 GEO 数据库中检索了 AP（急性胰腺炎）患者的细胞因子、MAPK14、核因子卡巴 B 亚基 1（NF-κB 1）和超氧化物歧化酶 2（SOD 2）的基因表达谱。GeneMANIA 被用于预测潜在的相互作用机制。利用实验性 AP 模型和双向孟德尔随机化（MR）分析进行了验证：结果：与轻度 AP 相比，重度 AP 患者的 MAPK14、NF-κB1、SOD2、IL-1β 和 IL-6R 基因表达量更高。GeneMANIA发现MAPK14、NF-κB1、SOD2、IL-1β和IL-6R之间存在77.6%的物理相互作用。我们的研究结果表明，与 AP 组相比，HLAP 组的胰腺损伤更严重，炎症反应更强烈，血清中 TNF-α、IL-6 和 IL-1β 水平更高，而 HLAP-Pi 组的炎症反应明显减轻。此外，SB 203580 还抑制了 HLAP 组血清中丙二醛（MDA）水平和胰腺组织中诱导型一氧化氮合酶（iNOS）、P38MAPK、p-P38MAPK 和 NF-κB p65 水平的升高，以及血清中 SOD 和 GSH-PX 值的降低。磁共振分析表明，采用逆方差加权（IVW）法，MAPK14 水平与 SOD 水平呈负相关（b = -0.193: se = 0.225; P = 1.03e-17）。反向 MR 分析表明，在 IVW 分析中，SOD 与 MAPK14 水平呈负相关（b = -0.163: se = 0.020; P = 1.38e-15）：结论：P38MAPK与氧化应激之间的相互作用可能在HLAP的发病机制中发挥重要作用。
{"title":"Hyperlipidemia exacerbates acute pancreatitis via interactions between P38MAPK and oxidative stress","authors":"Minhao Qiu , Yining Huang , Xiaoying Zhou , Junyu Yu , Jianmin Li , Wei Wang , Maddalena Zippi , Sirio Fiorino , Wandong Hong","doi":"10.1016/j.cellsig.2024.111504","DOIUrl":"10.1016/j.cellsig.2024.111504","url":null,"abstract":"<div><h3>Background</h3><div>The mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood.</div></div><div><h3>Aims</h3><div>To investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP.</div></div><div><h3>Methods</h3><div>In AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2). GeneMANIA has been used for the prediction of potential interaction mechanisms. Validation was carried out using an experimental AP model and a bi-directional Mendelian randomization (MR) analysis.</div></div><div><h3>Results</h3><div>Compared to mild AP, patients with severe AP had higher gene expression of MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. GeneMANIA revealed 77.6 % physical interactions among MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. Our results indicated that HLAP group had a more severe pancreatic injury, a stronger inflammatory response with higher serum levels of TNF-α, IL-6 and IL-1β in comparison with the AP group, which were significantly mitigated in HLAP-Pi group. Furthermore, SB 203580 inhibited increasing levels of malondialdehyde (MDA) in serum and of inducible nitric oxide synthase (iNOS), P38MAPK, p-P38MAPK and NF-κB p65 in pancreatic tissue as well as decreasing serum values of SOD and GSH-PX in HLAP group. MR analysis suggested that MAPK14 levels were negatively associated with the SOD levels, by using the inverse variance weighted (IVW) method (b = −0.193: se = 0.225; <em>P</em> = 1.03e-17). Reverse MR analysis indicated that SOD was negatively associated with the MAPK14 levels in the IVW analysis (b = −0.163: se = 0.020; <em>P</em> = 1.38e-15).</div></div><div><h3>Conclusion</h3><div>Interactions between P38MAPK and oxidative stress may play an important role in the pathogenesis of HLAP.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111504"},"PeriodicalIF":4.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.cellsig.2024.111500
Xi Luo , Mengchan Jian , Ping Wu , Yahua Wu , Yulan Ma , Na Feng , Min Lu , Dandan Shi , Rui Liu , Yan Ding , Wenjun Zhang , Li Fan , Xiju He
Background
Autophagy plays an important role in maintaining the stability of intracellular environment, abnormal autophagy is associated with the occurrence and progression of cancer, the role of STIM1 in regulating cancer autophagy remains controversial, and its clinical relevance is unclear. Our study aimed to investigate the effect and mechanism of STIM1 on cervical cancer, thus to provide new molecular therapeutic targets for cervical cancer in clinic.
Methods
We collected CIN III, FIGO IB and IIA fresh Specimens without chemotherapy from patients in Renmin Hospital of Hubei University of Medicine (n = 10). STIM1, TFEB and autophagy related proteins of different stage tissues were detected. In vitro, SKF96365 and AncoA4 were used to inhibit STIM1-administrated Ca2+ entry of SiHa cells, Cyclosporine A (calcineurin inhibitors) were used to inhibit CaN/TFEB pathway, Ad-mCherry-GFPLC3B was used to detect autophagy flux, shSTIM1 was used to knockdown STIM1 expression.
Results
The expression levels of STIM1, TFEB and autophagy related proteins were positively correlated with the progression of cervical cancer. Inhibition of STIM1-mediated SOCE can decrease proliferation and migration, and promoted the apoptosis of cervical cancer cells. Knockdown STIM1 can inhibit autophagy and TFEB nuclear translocation.
Conclusion
STIM1 can promote autophagy and accelerate cervical cancer progression by increasing TFEB nuclear translocation of cervical cancer cells.
{"title":"STIM1 promotes cervical cancer progression through autophagy activation via TFEB nuclear translocation","authors":"Xi Luo , Mengchan Jian , Ping Wu , Yahua Wu , Yulan Ma , Na Feng , Min Lu , Dandan Shi , Rui Liu , Yan Ding , Wenjun Zhang , Li Fan , Xiju He","doi":"10.1016/j.cellsig.2024.111500","DOIUrl":"10.1016/j.cellsig.2024.111500","url":null,"abstract":"<div><h3>Background</h3><div>Autophagy plays an important role in maintaining the stability of intracellular environment, abnormal autophagy is associated with the occurrence and progression of cancer, the role of STIM1 in regulating cancer autophagy remains controversial, and its clinical relevance is unclear. Our study aimed to investigate the effect and mechanism of STIM1 on cervical cancer, thus to provide new molecular therapeutic targets for cervical cancer in clinic.</div></div><div><h3>Methods</h3><div>We collected CIN III, FIGO IB and IIA fresh Specimens without chemotherapy from patients in Renmin Hospital of Hubei University of Medicine (<em>n</em> = 10). STIM1, TFEB and autophagy related proteins of different stage tissues were detected. In vitro, SKF96365 and AncoA4 were used to inhibit STIM1-administrated Ca<sup>2+</sup> entry of SiHa cells, Cyclosporine A (calcineurin inhibitors) were used to inhibit CaN/TFEB pathway, Ad-mCherry-GFPLC3B was used to detect autophagy flux, shSTIM1 was used to knockdown STIM1 expression.</div></div><div><h3>Results</h3><div>The expression levels of STIM1, TFEB and autophagy related proteins were positively correlated with the progression of cervical cancer. Inhibition of STIM1-mediated SOCE can decrease proliferation and migration, and promoted the apoptosis of cervical cancer cells. Knockdown STIM1 can inhibit autophagy and TFEB nuclear translocation.</div></div><div><h3>Conclusion</h3><div>STIM1 can promote autophagy and accelerate cervical cancer progression by increasing TFEB nuclear translocation of cervical cancer cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111500"},"PeriodicalIF":4.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PANoptosis is a distinct inflammatory cell death mechanism that involves interactions between pyroptosis, apoptosis, and necroptosis. It can be regulated by diverse PANoptosome complexes built by integrating components from various cell death modalities. There is a rising interest in PANoptosis' process and functions. Viral infection is an important trigger of PANoptosis. Viruses invade host cells through their unique mechanisms and utilize host cell resources for replication and proliferation. In this process, viruses interfere with the normal physiological functions of host cells, including cell death mechanisms. A variety of viruses, such as influenza A virus (IAV), herpes simplex virus 1 (HSV1) and coronaviruses, have been found to induce PANoptosis in host cells. Given the importance of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and activation, and outlines the multifaceted roles of PANoptosis in viral diseases, including potential therapeutic targets. We also talk about key principles and significant concerns for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is critical for discovering new treatment targets and methods.
{"title":"The emerging role of PANoptosis in viral infections disease","authors":"Xu Cheng , Taoyuan Zeng , Yingshu Xu , Yongai Xiong","doi":"10.1016/j.cellsig.2024.111497","DOIUrl":"10.1016/j.cellsig.2024.111497","url":null,"abstract":"<div><div>PANoptosis is a distinct inflammatory cell death mechanism that involves interactions between pyroptosis, apoptosis, and necroptosis. It can be regulated by diverse PANoptosome complexes built by integrating components from various cell death modalities. There is a rising interest in PANoptosis' process and functions. Viral infection is an important trigger of PANoptosis. Viruses invade host cells through their unique mechanisms and utilize host cell resources for replication and proliferation. In this process, viruses interfere with the normal physiological functions of host cells, including cell death mechanisms. A variety of viruses, such as influenza A virus (IAV), herpes simplex virus 1 (HSV1) and coronaviruses, have been found to induce PANoptosis in host cells. Given the importance of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and activation, and outlines the multifaceted roles of PANoptosis in viral diseases, including potential therapeutic targets. We also talk about key principles and significant concerns for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is critical for discovering new treatment targets and methods.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111497"},"PeriodicalIF":4.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.cellsig.2024.111498
Zhibing Liu , Miaolong He , Zeshun Yu , Longbo Ma , Xiuwen Wang , Fangling Ning
Objective
TRAF interacting protein with forkhead associated domain (TIFA) influence progression of many cancers. However, its role in glioma remains to be explored. This study investigated the function of TIFA in glioma.
Methods
The TIFA expression in glioma and patient outcomes were analyzed using online database. Gene set enrichment analysis (GSEA) revealed related mechanisms of TIFA in glioma. TIFA's effects on glioma glycolysis and growth were assessed using in vitro and in vivo experiments. Moreover, luciferase reporter and ChIP were employed to explore the interactions among E2F1, GLUT1, HK2, and LDHA. The subcutaneous xenograft assay further elaborated the effects of TIFA in glioma.
Results
We found overexpressed TIFA in glioma. Moreover, the high TIFA expression was associated with poor prognosis of glioma. Furthermore, GSEA indicated that overexpressed TIFA promoted E2F1 and glycolysis. Knockdown of TIFA decreased glioma development in cell and mice. TIFA knockdown down-regulated the expression of E2F1, GLUT1, HK2, and LDHA.
Conclusions
The study provides evidence that TIFA regulates E2F1 expression in glioma cells and promotes the proliferation, migration, and glycolysis. TIFA might be an advantageous therapeutic strategy against glioma.
{"title":"TIFA enhances glycolysis through E2F1 and promotes the progression of glioma","authors":"Zhibing Liu , Miaolong He , Zeshun Yu , Longbo Ma , Xiuwen Wang , Fangling Ning","doi":"10.1016/j.cellsig.2024.111498","DOIUrl":"10.1016/j.cellsig.2024.111498","url":null,"abstract":"<div><h3>Objective</h3><div>TRAF interacting protein with forkhead associated domain (TIFA) influence progression of many cancers. However, its role in glioma remains to be explored. This study investigated the function of TIFA in glioma.</div></div><div><h3>Methods</h3><div>The TIFA expression in glioma and patient outcomes were analyzed using online database. Gene set enrichment analysis (GSEA) revealed related mechanisms of TIFA in glioma. TIFA's effects on glioma glycolysis and growth were assessed using in vitro and in vivo experiments. Moreover, luciferase reporter and ChIP were employed to explore the interactions among E2F1, GLUT1, HK2, and LDHA. The subcutaneous xenograft assay further elaborated the effects of TIFA in glioma.</div></div><div><h3>Results</h3><div>We found overexpressed TIFA in glioma. Moreover, the high TIFA expression was associated with poor prognosis of glioma. Furthermore, GSEA indicated that overexpressed TIFA promoted E2F1 and glycolysis. Knockdown of TIFA decreased glioma development in cell and mice. TIFA knockdown down-regulated the expression of E2F1, GLUT1, HK2, and LDHA.</div></div><div><h3>Conclusions</h3><div>The study provides evidence that TIFA regulates E2F1 expression in glioma cells and promotes the proliferation, migration, and glycolysis. TIFA might be an advantageous therapeutic strategy against glioma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"125 ","pages":"Article 111498"},"PeriodicalIF":4.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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