A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death ...A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is ...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.展开更多
Introduction:DNA polymerases are crucial for maintaining genome stability and influencing tumorigenesis.However,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy ...Introduction:DNA polymerases are crucial for maintaining genome stability and influencing tumorigenesis.However,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy targets are not well understood.Methods:We conducted a systematic analysis using TCGA Pan-Cancer Atlas data and Gene Set Cancer Analysis results to examine the expression profiles of 15 DNA polymerases(POLYs)and their clinical correlations.We also evaluated the prognostic value of POLYs by analyzing their expression levels in relation to overall survival time(OS)using Kaplan-Meier survival curves.Additionally,we investigated the correlations between POLY expression and immune cells,DNA damage repair(DDR)pathways,and ubiquitination.Drug sensitivity analysis was performed to assess the relationship between POLY expression and drug response.Results:Our analysis revealed that 14 out of 15 POLYs exhibited significantly distinct expression patterns between tumor and normal samples across most cancer types,except for DNA nucleotidylexotransferase(DNTT).Specifically,POLD1 and POLE showed elevated expression in almost all cancers,while POLQ exhibited high expression levels in all cancer types.Some POLYs showed heightened expression in specific cancer subtypes,while others exhibited low expression.Kaplan-Meier survival curves demonstrated significant prognostic value of POLYs in multiple cancers,including PAAD,KIRC,and ACC.Cox analysis further validated these findings.Alteration patterns of POLYs varied significantly among different cancer types and were associated with poorer survival outcomes.Significant correlations were observed between the expression of POLY members and immune cells,DDR pathways,and ubiquitination.Drug sensitivity analysis indicated an inverse relationship between POLY expression and drug response.Conclusion:Our comprehensive study highlights the significant role of POLYs in cancer development and identifies them as promising prognostic and immunological biomarkers for various cancer types.Additionally,targeting POLYs therapeutically holds promise for tumor immunotherapy.展开更多
The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coor...The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.展开更多
A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions. Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following...A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions. Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following the restoration of blood flow and reoxygenation. This is known as ischemia-reperfusion injury(IRI): a complex multifactorial process that causes cell damage. While the oxygen deprivation due to ischemia depletes cell energy, subsequent tissue oxygenation due to reperfusion induces many cascades, from reactive oxygen species production to apoptosis initiation. Autophagy has also been identified in the pathogenesis of IRI, although such alterations and their subsequent functional significance are controversial. Moreover, proteasome activation may be a relevant pathophysiological mechanism. Different strategies have been adopted to limit IRI damage, including the supplementation of commercial preservation media with pharmacological agents or additives. In this review, we focus on novel strategies related to the ubiquitin proteasome system and oxidative stress inhibition, which have been used to minimize damage in liver transplantation.展开更多
Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activa...Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesisrelated pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.展开更多
The ubiquitin proteasome system(UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An in...The ubiquitin proteasome system(UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An increasing body of evidence has linked alterations in the UPS to gastrointestinal malignancies,including esophageal,gastric and colorectal cancers. Here,we summarize the current literature detailing the involvement of the UPS in gastrointestinal cancer,highlighting its role in tumor occurrence and development,providing information for therapeutic targets research and antigastrointestinal tumor drug design.展开更多
DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-bu...DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-butylphthalide action by various means.We used hydrogen peroxide to induce injury to PC12cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of DI-3-n-butylphthalide.We found that DI-3-nbutylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis.Furthermore,DI-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3.DI-3-nbutylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α,the key transcription factor that regulates Bax and Bnip3 genes.These findings suggest that DI-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis.展开更多
Neuroendocrine(NE)differentiation of cancer and deregulation of the ubiquitin-proteasome system(UPS)are two processes that have been independently linked to the development of aggressive and treatment-resistant tumors...Neuroendocrine(NE)differentiation of cancer and deregulation of the ubiquitin-proteasome system(UPS)are two processes that have been independently linked to the development of aggressive and treatment-resistant tumors.Striking data suggest a plausible interconnection between these two mechanisms,based on indirect evidence of neuropeptide-induced effects on UPS,reversed by proteasome inhibition and deubiquitinaselike properties of NE markers.Deciphering the model of their exact interactions is one of the keys to targeting the NE malignant phenotype more effectively.展开更多
Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenes...Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.展开更多
Background:Cholangiocarcinoma(CCA)represents the epithelial cell cancer with high aggressiveness whose five-year survival rate is poor with standard treatment.Calcyclin-binding protein(CACYBP)shows aberrant expression...Background:Cholangiocarcinoma(CCA)represents the epithelial cell cancer with high aggressiveness whose five-year survival rate is poor with standard treatment.Calcyclin-binding protein(CACYBP)shows aberrant expression within several malignant tumors,but the role of CACYBP in CCA remains unknown.Methods:Immunohistochemical(IHC)analysis was used to identify CACYBP overexpression in clinical samples of CCA patients.Moreover,its correlation with clinical outcome was revealed.Furthermore,CACYBP’s effect on CCA cell growth and invasion was investigated in vitro and in vivo using loss-of-function experiments.Results:CACYBP showed up-regulation in CCA,which predicts the dismal prognostic outcome.CACYBP had an important effect on in-vitro and in-vivo cancer cell proliferation and migration.Additionally,knockdown of CACYBP weakened protein stability by promoting ubiquitination of MCM2.Accordingly,MCM2 up-regulation partly reversed CACYBP deficiency’s inhibition against cancer cell viability and invasion.Thus,MCM2 might drive CCA development by Wnt/β-catenin pathway.Conclusions:CACYBP exerted a tumor-promoting role in CCA by suppressing ubiquitination of MCM2 and activating Wnt/β-catenin pathway,hence revealing that it may be the possible therapeutic target for CCA treatment.展开更多
Objective Ubiquitin conjugate enzyme E2O(UBE2O)is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis.This study investigated the role of UBE2O in hepatocellular carcinoma(HCC).Method...Objective Ubiquitin conjugate enzyme E2O(UBE2O)is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis.This study investigated the role of UBE2O in hepatocellular carcinoma(HCC).Methods The expression of UBE2O was detected using qRT-PCR,Western blotting,and immunohistochemical staining.Cell proliferation and Transwell assays were used to detect proliferation,migration,and invasion of HCC cells,respectively.Bioinformatic analysis was performed to analyze the relationship between UBE2O and the clinical features,prognosis,and immune cell infiltration of HCC.Results UBE2O was significantly over-expressed in HCC tissues.High expression of UBE2O was associated with poor tumor grade and poor prognosis.Functional experiments showed that down-regulation of UBE2O inhibited HCC cell proliferation,migration,and invasion.Co-expression gene analysis and gene set enrichment analysis showed that UBE2O was associated with protein hydrolysis,cell cycle,and cancer-related pathways in HCC.The results of immune analysis revealed that the expression of UBE2O was positively correlated with the immune infiltration and expression of immune-related chemokines of HCC.Conclusions UBE2O is significantly correlated with the prognosis of HCC and may be a valuable prognostic biomarker for HCC.展开更多
Glioma is the most common primary brain tumor.Exploration of new tumorigenesis mechanism of glioma is critical to determine more effective treatment targets as well as to develop effective prognosis methods that can e...Glioma is the most common primary brain tumor.Exploration of new tumorigenesis mechanism of glioma is critical to determine more effective treatment targets as well as to develop effective prognosis methods that can enhance the treatment efficacy.We previously demonstrated that the deubiquitinase biquitin carboxyl-terminal hydrolase L5(UCHL5)was downregulated in human glioma.However,the effect and mechanism of UCHL5 on the proliferation of glioma cells remains unknown.Methods:Transfection of siRNA was used to knockdown the expression of UCHL5 in U251 cells.The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay,Edu assay,and colony formation assay were employed to identify the effect of UCHL5 on the proliferation of U251 glioma cells.Western blotting and quantitative real-time PCR were carried out to detect the interaction of UCHL5 and PTEN.The effect of UCHL5 on the growth of glioma in vivo was evaluated in nude mice.Then Immunohistochemistry(IHC)were performed to analysis the expression of UCHL5 and PTEN in human glioma tissues.Results:Here,we have reported that silencing of UCHL5 could promote the proliferation of U251 glioma cells through MTT assay,Edu assay,and colony formation assay.Mechanically,we revealed that UCHL5 stabilizes the phosphatase and tensin homolog(PTEN)expression by deubiquitination,thereby inhibiting cell proliferation in U251 cells.Tumor xenograft experiments further demonstrated that silencing the UCHL5 expression could accelerate U251 cell growth in vivo.Finally,in human glioma tissue microarray,the positive correlation between UCHL5 and PTEN expression was confirmed through IHC assay.Conclusion:UCHL5 restrains the proliferation of U251 glioma cells by stabilizing and deubiquitinating PTEN.Our findings provide ideas for developing enhanced targeted PTEN therapy for patients with glioma.展开更多
β-transducin repeat-containing protein(β-TrCP)is an F-box protein subunit of the E3 Skp1-Cullin-F box(SCF)type ubiquitin-ligase complex,and provides the substrate specificity for the ligase.To find potent ligands of...β-transducin repeat-containing protein(β-TrCP)is an F-box protein subunit of the E3 Skp1-Cullin-F box(SCF)type ubiquitin-ligase complex,and provides the substrate specificity for the ligase.To find potent ligands ofβ-TrCP useful for the proteolysis targeting chimera(PROTAC)system usingβ-TrCP in the future,we developed a high-throughput screening system for small moleculeβ-TrCP ligands.We screened the chemical library utilizing the system and obtained several hit compounds.The effects of the hit compounds on in vitro ubiquitination activity of SCFβ-TrCP1 and on downstream signaling pathways were examined.Hit compounds NPD5943,NPL62020-01,and NPL42040-01 inhibited the TNFα-induced degradation of IκBαand its phosphorylated form.Hence,they inhibited the activation of the transcription activity of NF-κB,indicating the effective inhibition ofβ-TrCP by the hit compounds in cells.Next,we performed an in silico analysis of the hit compounds to determine the important moieties of the hit compounds.Carboxyl groups of NPL62020-01 and NPL42040-01 and hydroxyl groups of NPD5943 created hydrogen bonds withβ-TrCP similar to those created by intrinsic target phosphopeptides ofβ-TrCP.Our findings enhance our knowledge of useful small molecule ligands ofβ-TrCP and the importance of residues that can be ligands ofβ-TrCP.展开更多
BACKGROUND Brain gliomas are malignant tumors with high postoperative recurrence rates.Early prediction of prognosis using specific indicators is of great significance.AIM To assess changes in ubiquitin carboxy-termin...BACKGROUND Brain gliomas are malignant tumors with high postoperative recurrence rates.Early prediction of prognosis using specific indicators is of great significance.AIM To assess changes in ubiquitin carboxy-terminal hydrolase L1(UCH-L1)and glial fibrillary acidic protein(GFAP)levels in patients with glioma pre-and postoperatively.METHODS Between June 2018 and June 2021,91 patients with gliomas who underwent surgery at our hospital were enrolled in the glioma group.Sixty healthy volunteers were included in the control group.Serum UCH-L1 and GFAP levels were measured in peripheral blood collected from patients with glioma before and 3 d after surgery.UCH-L1 and GFAP levels in patients with glioma with different clinicopathological characteristics were compared before and after surgery.The patients were followed-up until February 2022.Postoperative glioma recurrence was recorded to determine the serum UCH-L1 and GFAP levels,which could assist in predicting postoperative glioma recurrence.RESULTS UCH-L1 and GFAP levels in patients with glioma decreased significantly 3 d after surgery compared to those before therapy(P<0.05).However,UCH-L1 and GFAP levels in the glioma group were significantly higher than those in the control group before and after surgery(P<0.05).There were no statistically significant differences in preoperative serum UCH-L1 and GFAP levels among patients with glioma according to sex,age,pathological type,tumor location,or number of lesions(P>0.05).Serum UCH-L1 and GFAP levels were significantly lower in the patients with WHO grade I-II tumors than in those with gradeⅢ-IV tumors(P<0.05).Serum UCH-L1 and GFAP levels were lower in the patients with tumor diameter≤5 cm than in those with diameter>5 cm,in which the differences were statistically significant(P<0.05).Glioma recurred in 22 patients.The preoperative and 3-d postoperative serum UCH-L1 and GFAP levels were significantly higher in the recurrence group than these in the non-recurrence group(P<0.05).Receiver operating characteristic curves were plotted.The areas under the curves of preoperative serum UCH-L1 and GFAP levels for predicting postoperative glioma recurrence were 0.785 and 0.775,respectively.However,the efficacy of serum UCH-L1 and GFAP levels 3 d after surgery in predicting postoperative glioma recurrence was slightly lower compared with their preoperative levels.CONCLUSION UCH-L1 and GFAP efficiently reflected the development and recurrence of gliomas and could be used as potential indicators for the recurrence and prognosis of glioma.展开更多
Objective:Using data mining tools,study the potential pathways of estrogen’s cardiovascular effects.Methods:The GeneExpression Omnibus database was used to download the relevant high-throughput microarray dataset GSE...Objective:Using data mining tools,study the potential pathways of estrogen’s cardiovascular effects.Methods:The GeneExpression Omnibus database was used to download the relevant high-throughput microarray dataset GSE72180,which was then analyzed for differential genes using the GEO2R online analysis tool,gene function and pathway enrichment analysis using DAVID 6.8,protein interaction network analysis using the STRING database,and core network extraction using the MCODE algorithm.Results:A total of 131 differential genes were identified and enriched for gene function and signaling pathway analysis,which indicated that these genes were related with focal adhesion and the HIF-1 signaling pathway.MCODE algorithm analysis extracted 1 core sub-network of these genes to be related to ubiquitin protein transferase activity,protein polyubiquitination,protein ubiquitination involved in ubiquitin-dependent proteolytic metabolic processes,ligase activity,and clustering on ubiquitin-mediated protein hydrolysis signaling pathway.Conclusion:By using data mining tools,it is possible to identify how estrogen may influence the cardiovascular system by controlling the ubiquitination process.This information may be used as a reference for etiology and preventive studies of cardiovascular illnesses.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82122043,81972052,81902213,82201537,and 81730065)the China Postdoctoral Science Foundation(Grant Nos.:2021M693946 and 2019M653967).
文摘A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.
基金Supported by Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-009ATianjin Medical University Cancer Hospital National Natural Science Foundation Cultivation Program,No.220108+3 种基金National Natural Science Foundation of China,No.82373134Science and Technology Development Fund of Tianjin Education Commission for Higher Education,No.2022KJ228Chinese Anti-Cancer Association-Heng Rui Anti-angiogenesis Targeted Tumor Research Fund,No.2021001045and Scientific Research Translational Foundation of Wenzhou Safety(Emergency)Institute of Tianjin University,No.TJUWYY2022025.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.
基金supported by the project of funds by the Consultation of Provincial Department and University for S&T Innovation granted by Hebei Provincial Department of Science and Technology and Hebei Medical University(2020TXZH04).
文摘Introduction:DNA polymerases are crucial for maintaining genome stability and influencing tumorigenesis.However,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy targets are not well understood.Methods:We conducted a systematic analysis using TCGA Pan-Cancer Atlas data and Gene Set Cancer Analysis results to examine the expression profiles of 15 DNA polymerases(POLYs)and their clinical correlations.We also evaluated the prognostic value of POLYs by analyzing their expression levels in relation to overall survival time(OS)using Kaplan-Meier survival curves.Additionally,we investigated the correlations between POLY expression and immune cells,DNA damage repair(DDR)pathways,and ubiquitination.Drug sensitivity analysis was performed to assess the relationship between POLY expression and drug response.Results:Our analysis revealed that 14 out of 15 POLYs exhibited significantly distinct expression patterns between tumor and normal samples across most cancer types,except for DNA nucleotidylexotransferase(DNTT).Specifically,POLD1 and POLE showed elevated expression in almost all cancers,while POLQ exhibited high expression levels in all cancer types.Some POLYs showed heightened expression in specific cancer subtypes,while others exhibited low expression.Kaplan-Meier survival curves demonstrated significant prognostic value of POLYs in multiple cancers,including PAAD,KIRC,and ACC.Cox analysis further validated these findings.Alteration patterns of POLYs varied significantly among different cancer types and were associated with poorer survival outcomes.Significant correlations were observed between the expression of POLY members and immune cells,DDR pathways,and ubiquitination.Drug sensitivity analysis indicated an inverse relationship between POLY expression and drug response.Conclusion:Our comprehensive study highlights the significant role of POLYs in cancer development and identifies them as promising prognostic and immunological biomarkers for various cancer types.Additionally,targeting POLYs therapeutically holds promise for tumor immunotherapy.
文摘The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.
基金Supported by Fondo de Investigaciones Sanitarias,Ministerio de Economia y Competitividad(Madrid,Spain),No.PI15/00110
文摘A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions. Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following the restoration of blood flow and reoxygenation. This is known as ischemia-reperfusion injury(IRI): a complex multifactorial process that causes cell damage. While the oxygen deprivation due to ischemia depletes cell energy, subsequent tissue oxygenation due to reperfusion induces many cascades, from reactive oxygen species production to apoptosis initiation. Autophagy has also been identified in the pathogenesis of IRI, although such alterations and their subsequent functional significance are controversial. Moreover, proteasome activation may be a relevant pathophysiological mechanism. Different strategies have been adopted to limit IRI damage, including the supplementation of commercial preservation media with pharmacological agents or additives. In this review, we focus on novel strategies related to the ubiquitin proteasome system and oxidative stress inhibition, which have been used to minimize damage in liver transplantation.
文摘Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesisrelated pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.
基金Supported by The National Natural Science Foundation of China,No.81472208the Open Projects of State Key Laboratory of Molecular Oncology,No.SKL-KF-2015-12the Doctoral Fund of Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital(2013),No.30305030579
文摘The ubiquitin proteasome system(UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An increasing body of evidence has linked alterations in the UPS to gastrointestinal malignancies,including esophageal,gastric and colorectal cancers. Here,we summarize the current literature detailing the involvement of the UPS in gastrointestinal cancer,highlighting its role in tumor occurrence and development,providing information for therapeutic targets research and antigastrointestinal tumor drug design.
文摘DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-butylphthalide action by various means.We used hydrogen peroxide to induce injury to PC12cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of DI-3-n-butylphthalide.We found that DI-3-nbutylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis.Furthermore,DI-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3.DI-3-nbutylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α,the key transcription factor that regulates Bax and Bnip3 genes.These findings suggest that DI-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis.
文摘Neuroendocrine(NE)differentiation of cancer and deregulation of the ubiquitin-proteasome system(UPS)are two processes that have been independently linked to the development of aggressive and treatment-resistant tumors.Striking data suggest a plausible interconnection between these two mechanisms,based on indirect evidence of neuropeptide-induced effects on UPS,reversed by proteasome inhibition and deubiquitinaselike properties of NE markers.Deciphering the model of their exact interactions is one of the keys to targeting the NE malignant phenotype more effectively.
基金supported by the Natural Science Foundation of Hubei Province(No.2021CFB155)China Postdoctoral Science Foundation(No.2021M701338)Part of the work was supported by Postdoctoral Creative Research Positions of Hubei Province of China(No.2021).
文摘Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.
基金funded by Shenzhen Key Medical Discipline Construction Fund(No.SZXK015)Guangdong Provincial Key Clinical Specialty Construction Project,National Key Clinical Specialty Construction Project and Guangdong Medical Science and Technology Research Fund(No.A2021230).
文摘Background:Cholangiocarcinoma(CCA)represents the epithelial cell cancer with high aggressiveness whose five-year survival rate is poor with standard treatment.Calcyclin-binding protein(CACYBP)shows aberrant expression within several malignant tumors,but the role of CACYBP in CCA remains unknown.Methods:Immunohistochemical(IHC)analysis was used to identify CACYBP overexpression in clinical samples of CCA patients.Moreover,its correlation with clinical outcome was revealed.Furthermore,CACYBP’s effect on CCA cell growth and invasion was investigated in vitro and in vivo using loss-of-function experiments.Results:CACYBP showed up-regulation in CCA,which predicts the dismal prognostic outcome.CACYBP had an important effect on in-vitro and in-vivo cancer cell proliferation and migration.Additionally,knockdown of CACYBP weakened protein stability by promoting ubiquitination of MCM2.Accordingly,MCM2 up-regulation partly reversed CACYBP deficiency’s inhibition against cancer cell viability and invasion.Thus,MCM2 might drive CCA development by Wnt/β-catenin pathway.Conclusions:CACYBP exerted a tumor-promoting role in CCA by suppressing ubiquitination of MCM2 and activating Wnt/β-catenin pathway,hence revealing that it may be the possible therapeutic target for CCA treatment.
基金supported by grants from the National Natural Science Foundation of China(No.81670554 and No.8217113366)the Science and Technology Plan of Wuhan City(No.2020020601012208)+2 种基金the Natural Science Fund for Distinguished Young Scholars of Hubei Province(No.2017CFA068)the National Key R&D Program of China(No.2019YFC0121505)the Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University(No.CXPY2020042).
文摘Objective Ubiquitin conjugate enzyme E2O(UBE2O)is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis.This study investigated the role of UBE2O in hepatocellular carcinoma(HCC).Methods The expression of UBE2O was detected using qRT-PCR,Western blotting,and immunohistochemical staining.Cell proliferation and Transwell assays were used to detect proliferation,migration,and invasion of HCC cells,respectively.Bioinformatic analysis was performed to analyze the relationship between UBE2O and the clinical features,prognosis,and immune cell infiltration of HCC.Results UBE2O was significantly over-expressed in HCC tissues.High expression of UBE2O was associated with poor tumor grade and poor prognosis.Functional experiments showed that down-regulation of UBE2O inhibited HCC cell proliferation,migration,and invasion.Co-expression gene analysis and gene set enrichment analysis showed that UBE2O was associated with protein hydrolysis,cell cycle,and cancer-related pathways in HCC.The results of immune analysis revealed that the expression of UBE2O was positively correlated with the immune infiltration and expression of immune-related chemokines of HCC.Conclusions UBE2O is significantly correlated with the prognosis of HCC and may be a valuable prognostic biomarker for HCC.
基金supported by grants from the Shenzhen Science and Technology Innovation Commission Grant(Nos.JCYJ20180507182253653 and JCYJ20190808172201639)Guangdong Province Basic and Applied Basic Research Fund(No.2022A1515111143).
文摘Glioma is the most common primary brain tumor.Exploration of new tumorigenesis mechanism of glioma is critical to determine more effective treatment targets as well as to develop effective prognosis methods that can enhance the treatment efficacy.We previously demonstrated that the deubiquitinase biquitin carboxyl-terminal hydrolase L5(UCHL5)was downregulated in human glioma.However,the effect and mechanism of UCHL5 on the proliferation of glioma cells remains unknown.Methods:Transfection of siRNA was used to knockdown the expression of UCHL5 in U251 cells.The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay,Edu assay,and colony formation assay were employed to identify the effect of UCHL5 on the proliferation of U251 glioma cells.Western blotting and quantitative real-time PCR were carried out to detect the interaction of UCHL5 and PTEN.The effect of UCHL5 on the growth of glioma in vivo was evaluated in nude mice.Then Immunohistochemistry(IHC)were performed to analysis the expression of UCHL5 and PTEN in human glioma tissues.Results:Here,we have reported that silencing of UCHL5 could promote the proliferation of U251 glioma cells through MTT assay,Edu assay,and colony formation assay.Mechanically,we revealed that UCHL5 stabilizes the phosphatase and tensin homolog(PTEN)expression by deubiquitination,thereby inhibiting cell proliferation in U251 cells.Tumor xenograft experiments further demonstrated that silencing the UCHL5 expression could accelerate U251 cell growth in vivo.Finally,in human glioma tissue microarray,the positive correlation between UCHL5 and PTEN expression was confirmed through IHC assay.Conclusion:UCHL5 restrains the proliferation of U251 glioma cells by stabilizing and deubiquitinating PTEN.Our findings provide ideas for developing enhanced targeted PTEN therapy for patients with glioma.
基金supported by research grants from the JSPS/MEXT KAKENHI(JP19H05302 and JP21H00295 to N.W.)the MOSTRIKEN Collaboration Project(2021YFE0108000 to J.L.and N.W.).
文摘β-transducin repeat-containing protein(β-TrCP)is an F-box protein subunit of the E3 Skp1-Cullin-F box(SCF)type ubiquitin-ligase complex,and provides the substrate specificity for the ligase.To find potent ligands ofβ-TrCP useful for the proteolysis targeting chimera(PROTAC)system usingβ-TrCP in the future,we developed a high-throughput screening system for small moleculeβ-TrCP ligands.We screened the chemical library utilizing the system and obtained several hit compounds.The effects of the hit compounds on in vitro ubiquitination activity of SCFβ-TrCP1 and on downstream signaling pathways were examined.Hit compounds NPD5943,NPL62020-01,and NPL42040-01 inhibited the TNFα-induced degradation of IκBαand its phosphorylated form.Hence,they inhibited the activation of the transcription activity of NF-κB,indicating the effective inhibition ofβ-TrCP by the hit compounds in cells.Next,we performed an in silico analysis of the hit compounds to determine the important moieties of the hit compounds.Carboxyl groups of NPL62020-01 and NPL42040-01 and hydroxyl groups of NPD5943 created hydrogen bonds withβ-TrCP similar to those created by intrinsic target phosphopeptides ofβ-TrCP.Our findings enhance our knowledge of useful small molecule ligands ofβ-TrCP and the importance of residues that can be ligands ofβ-TrCP.
基金Supported by Hebei Medical Science Research Project,No.20220648。
文摘BACKGROUND Brain gliomas are malignant tumors with high postoperative recurrence rates.Early prediction of prognosis using specific indicators is of great significance.AIM To assess changes in ubiquitin carboxy-terminal hydrolase L1(UCH-L1)and glial fibrillary acidic protein(GFAP)levels in patients with glioma pre-and postoperatively.METHODS Between June 2018 and June 2021,91 patients with gliomas who underwent surgery at our hospital were enrolled in the glioma group.Sixty healthy volunteers were included in the control group.Serum UCH-L1 and GFAP levels were measured in peripheral blood collected from patients with glioma before and 3 d after surgery.UCH-L1 and GFAP levels in patients with glioma with different clinicopathological characteristics were compared before and after surgery.The patients were followed-up until February 2022.Postoperative glioma recurrence was recorded to determine the serum UCH-L1 and GFAP levels,which could assist in predicting postoperative glioma recurrence.RESULTS UCH-L1 and GFAP levels in patients with glioma decreased significantly 3 d after surgery compared to those before therapy(P<0.05).However,UCH-L1 and GFAP levels in the glioma group were significantly higher than those in the control group before and after surgery(P<0.05).There were no statistically significant differences in preoperative serum UCH-L1 and GFAP levels among patients with glioma according to sex,age,pathological type,tumor location,or number of lesions(P>0.05).Serum UCH-L1 and GFAP levels were significantly lower in the patients with WHO grade I-II tumors than in those with gradeⅢ-IV tumors(P<0.05).Serum UCH-L1 and GFAP levels were lower in the patients with tumor diameter≤5 cm than in those with diameter>5 cm,in which the differences were statistically significant(P<0.05).Glioma recurred in 22 patients.The preoperative and 3-d postoperative serum UCH-L1 and GFAP levels were significantly higher in the recurrence group than these in the non-recurrence group(P<0.05).Receiver operating characteristic curves were plotted.The areas under the curves of preoperative serum UCH-L1 and GFAP levels for predicting postoperative glioma recurrence were 0.785 and 0.775,respectively.However,the efficacy of serum UCH-L1 and GFAP levels 3 d after surgery in predicting postoperative glioma recurrence was slightly lower compared with their preoperative levels.CONCLUSION UCH-L1 and GFAP efficiently reflected the development and recurrence of gliomas and could be used as potential indicators for the recurrence and prognosis of glioma.
基金supported by Jilin Provincial Department of Education Project(20200201515 JC).
文摘Objective:Using data mining tools,study the potential pathways of estrogen’s cardiovascular effects.Methods:The GeneExpression Omnibus database was used to download the relevant high-throughput microarray dataset GSE72180,which was then analyzed for differential genes using the GEO2R online analysis tool,gene function and pathway enrichment analysis using DAVID 6.8,protein interaction network analysis using the STRING database,and core network extraction using the MCODE algorithm.Results:A total of 131 differential genes were identified and enriched for gene function and signaling pathway analysis,which indicated that these genes were related with focal adhesion and the HIF-1 signaling pathway.MCODE algorithm analysis extracted 1 core sub-network of these genes to be related to ubiquitin protein transferase activity,protein polyubiquitination,protein ubiquitination involved in ubiquitin-dependent proteolytic metabolic processes,ligase activity,and clustering on ubiquitin-mediated protein hydrolysis signaling pathway.Conclusion:By using data mining tools,it is possible to identify how estrogen may influence the cardiovascular system by controlling the ubiquitination process.This information may be used as a reference for etiology and preventive studies of cardiovascular illnesses.