Breast and prostate cancer are the leading causes of death in females and males, respectively. Triple negative breast cancer (TNBC) does not express the estrogen receptor, progesterone receptor, or human epidermal gro...Breast and prostate cancer are the leading causes of death in females and males, respectively. Triple negative breast cancer (TNBC) does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2, resulting in limited treatment options. Androgen deprivation therapy is the standard care for prostate cancer patients;however, metastasis and recurrence are seen in androgen-independent prostate cancer. Both prostate and breast cancer show higher resistance after recurrence and metastasis, which increases the difficulty of treatment. Natural killer (NK) cells play a critical role during innate immunity and tumor recognition and elimination. NK cell function is determined by a delicate balance of inhibitory signals and activation signals received through cell surface receptors. Lectin-like transcript 1 (LLT1, CLEC2D, OCIL) is a ligand of NK cell inhibitory receptor NKRP1A (CD161). Several studies have that reported higher expression of LLT1 is associated with the development of various tumors. Our studies revealed that TNBC and prostate cancer cells express higher levels of LLT1. In the presence of a monoclonal antibody against LLT1, NK cell-mediated killing of TNBC and prostate cancer cells were greatly enhanced. This review highlights the potential that using monoclonal antibodies to block LLT1 - NKRP1A interactions could be an effective immunotherapeutic approach to treat triple negative breast cancer and prostate cancer.展开更多
BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essenti...BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.展开更多
Anthocyanins are important pigments and nutrients in fruits.Red grape is popular because of the high anthocyanin content.Previous studies have identified VvMYBA1 and its homologs as key regulators of fruit color;howev...Anthocyanins are important pigments and nutrients in fruits.Red grape is popular because of the high anthocyanin content.Previous studies have identified VvMYBA1 and its homologs as key regulators of fruit color;however,other transcription factors(TFs)that contribute to fruit color remain poorly understood.The present study identified the R2R3-MYB TF VvMYB24,whose gene expression levels were significantly higher in red berries(L51,Vitis vinifera×Vitis labrusca L.)than in green berries(L20,V.vinifera×V.labrusca L.).Overexpression of VvMYB24 in grape calli increased anthocyanin biosynthesis by upregulating the expression of specific structural genes(VvDFR and VvUFGT).Furthermore,VvMYB24 interacted with VvMYBA1 to form a protein complex that additionally increased the expression of VvDFR and VvUFGT.In addition,light-responsive TF VvHY5 could bind to the VvMYB24 promoters to activate its transcription.Taken together,the results reveal a regulatory module,VvHY5-VvMYB24-VvMYBA1,that influences anthocyanin biosynthesis in grape.展开更多
Phosphorus(Pi)plays a crucial role in the growth and development of plants.Membrane lipid regulation is one of the main mechanisms underlying plant adaptation to Pi deficiency.Previously,the high tolerance to low-Pi s...Phosphorus(Pi)plays a crucial role in the growth and development of plants.Membrane lipid regulation is one of the main mechanisms underlying plant adaptation to Pi deficiency.Previously,the high tolerance to low-Pi stress was justified in an elite line,MSDZ 109,which was obtained from Malus mandshurica.To better understand the mechanism underlying high adaptation to low-Pi stress,currently,lipidomic and transcriptomic analysis,as well as CRISPR/Cas9 and MmGDPD1-overexpressing methodologies were comprehensively integrated into a strategy for elucidating the high tolerance to low-Pi stress.Totally,770 differential metabolites were identified from the roots between the low-Pi and stress-free,belonging to 21 sub-classes of lipid compounds.Fatty acids(FA)constituted the predominant lipid component,accounting for approximately 50%-60%of the total lipids,and triglycerides(TAG)ranked the second,comprising around 12%of the total,consecutively followed by phosphatidylcholine(PC)and diacylglycerol(DAG)with approximately 10%and 8%of the total,respectively.The synchronous transcriptomic analysis revealed a significant up-regulation of genes related to glycerophospholipid and glycerolipid metabolism,specifically those(e.g.,MmGDPD1,MmDGDG1,MmMGDG1,MmSQDG,etc.)involved in phospholipid and galactosyl synthesis in response to low-Pi stress.GUS fusing reporter assay showed that MmGDPD1 promoter induced GUS gene expression and demonstrated initiation activity.Based on expression analysis,a dual-luciferase reporter assay,as well as yeast one-hybrid(Y1H)identification,MmPHR1 was justified to bind with the MmGDPD1 promoter and positively regulate plant tolerance to low-Pi stress.To further elucidate the role of MmGDPD1,CRISPR/Cas9 and MmGDPD1-overexpressing vectors were successfully introduced into apple(‘Royal Gala')calli.Interestingly,the MmGDPD1-KO line calli exhibited the remarkable decreases in the contents of phosphodiesterase(PDE),activity,as well as the contents of total Pi,and Pi in comparison with those of the wild type.Conversely,MmGDPD1-OE ones demonstrated the significant elevation in Pi accumulations,further justifying its potential role in Pi remobilization in apple.Therefore,MmGDPD1 substantially involves elevating low-Pi tolerance via promoting Pi release in M.mandshurica.展开更多
BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identify...BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.展开更多
In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)pro...In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.展开更多
The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
Drought stress significantly impedes apple growth,development,and yield,leading to substantial economic losses within the global apple industry.Malus prunifolia(Mp),a commonly utilized apple rootstock,has shown promis...Drought stress significantly impedes apple growth,development,and yield,leading to substantial economic losses within the global apple industry.Malus prunifolia(Mp),a commonly utilized apple rootstock,has shown promise in augmenting cultivated apple resistance to abiotic stress.Although Alfin-like(ALs)proteins have demonstrated pivotal roles in dicotyledonous plants'response to abiotic stresses,knowledge about AL genes in apple rootstocks is limited,and their functions remain largely elusive.In this study,we identified and characterized 10 MpAL gene members in the apple rootstock genome,confirming their localization within the nucleus.Our investigation revealed the significant regulation of MpALs'expression under drought and abscisic acid(ABA)stresses in M.prunifolia.In this study,one of the members,MpAL1,was selected for further exploration in Arabidopsis and apple to explore its potential function in response to drought and ABA stresses.The results showed that overexpression-MpAL1 transgenic apple calli grew significantly better than WT and MpAL1-RNAi lines,which regulates the accumulation of H_(2)O_(2)and O_(2).-levels.Additionally,transgenic Arabidopsis plants overexpressing MpAL1 exhibited positively regulating antioxidant enzymes activities under stress treatments.Further study showed that silencing MpAL1 in apple plants showed obvious chlorosis in leaves,and accumulation of reactive oxygen species under drought stress.Moreover,our detailed analysis established that MpAL1 regulates several drought and ABA-responsive genes,exerting an influence on their expression in transgenic apple.Collectively,our findings identify MpAL1 as a positive regulator that increases drought stress in apple,shedding light on its potential significance in bolstering drought resistance in this fruit crop.展开更多
Human X-box binding protein 1 （XBP1）, an important transcription factor, participates in many signal transduction processes. To further investigate the biological function of XBP1, sequences of XBP1 promoter and its...Human X-box binding protein 1 （XBP1）, an important transcription factor, participates in many signal transduction processes. To further investigate the biological function of XBP1, sequences of XBP1 promoter and its two deletion mutants were first determined using bioinformatic analysis. The report vectors containing XBP1 promoter and its deletion mutants were then constructed, namely, p1-XBPlp, p2-XBPlp, and p3-XBPlp. Each reporter vector was separately transfected into HepG2, L02, K562, SMMC-7721, HSF, and Lipocyte lto Cell line using FuGENE 6 transfection reagents. The activity of chloramphenicol acetyltransferase （CAT） in each group of transfected cells was detected by ELISA assay, which in turn reflects the transcription activity of the XBP1 gene promoter. The activity involving p3-XBPlp was the highest in HepG2, which was 12.4-fold of that of pCAT3-Basic. The activities of p3-XBPlp in K562 and SMMC-7721 were the second and the third highest, which were 10.9-fold and 10.0-fold of that of the pCAT3-Basic, respectively. The CAT activity in L02 was lower than that in the above-mentioned abnormal cell, and no reporter activity was detected in HSF and Ito Cell. The XBP1 transcription and expression in K562, HepG2 and SMMC-7721 were found to be higher than that in L02, HSF and Ito cells, based on the results of real-time RT-PCR and Western blot. The XBP1 transcription and expression in L02, HSF was lower, whereas that in Ito cells was totally lacking. The result was similar to that of CAT-ELISA. Therefore, the XBP1 gene promoter can drive its downstream gene expression and its activity is cell line-dependent. The core sequence of XBP1 promoter was found between -227bp and 66bp sequence. This sequence was closely associated with the transcriptional activity of XBP1 promoter.展开更多
文摘Breast and prostate cancer are the leading causes of death in females and males, respectively. Triple negative breast cancer (TNBC) does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2, resulting in limited treatment options. Androgen deprivation therapy is the standard care for prostate cancer patients;however, metastasis and recurrence are seen in androgen-independent prostate cancer. Both prostate and breast cancer show higher resistance after recurrence and metastasis, which increases the difficulty of treatment. Natural killer (NK) cells play a critical role during innate immunity and tumor recognition and elimination. NK cell function is determined by a delicate balance of inhibitory signals and activation signals received through cell surface receptors. Lectin-like transcript 1 (LLT1, CLEC2D, OCIL) is a ligand of NK cell inhibitory receptor NKRP1A (CD161). Several studies have that reported higher expression of LLT1 is associated with the development of various tumors. Our studies revealed that TNBC and prostate cancer cells express higher levels of LLT1. In the presence of a monoclonal antibody against LLT1, NK cell-mediated killing of TNBC and prostate cancer cells were greatly enhanced. This review highlights the potential that using monoclonal antibodies to block LLT1 - NKRP1A interactions could be an effective immunotherapeutic approach to treat triple negative breast cancer and prostate cancer.
文摘BACKGROUND Diabetic retinopathy(DR)is a major microvascular complication of diabetes mellitus,leading to significant visual impairment and blindness among adults.Current treatment options are limited,making it essential to explore novel therapeutic strategies.Curcumol,a sesquiterpenoid derived from traditional Chinese medicine,has shown anti-inflammatory and anti-cancer properties,but its potential role in DR remains unclear.AIM To investigate the therapeutic effects of curcumol on the progression of DR and to elucidate the underlying molecular mechanisms,particularly its impact on the fat mass and obesity-associated(FTO)protein and the long non-coding RNA(lncRNA)MAF transcription factor G antisense RNA 1(MAFG-AS1).METHODS A streptozotocin-induced mouse model of DR was established,followed by treatment with curcumol.Retinal damage and inflammation were evaluated through histological analysis and molecular assays.Human retinal vascular endothelial cells were exposed to high glucose conditions to simulate diabetic environments in vitro.Cell proliferation,migration,and inflammation markers were assessed in curcumoltreated cells.LncRNA microarray analysis identified key molecules regulated by curcumol,and further experiments were conducted to confirm the involvement of FTO and MAFG-AS1 in the progression of DR.RESULTS Curcumol treatment significantly reduced blood glucose levels and alleviated retinal damage in streptozotocininduced DR mouse models.In high-glucose-treated human retinal vascular endothelial cells,curcumol inhibited cell proliferation,migration,and inflammatory responses.LncRNA microarray analysis identified MAFG-AS1 as the most upregulated lncRNA following curcumol treatment.Mechanistically,FTO demethylated MAFG-AS1,stabilizing its expression.Rescue experiments demonstrated that the protective effects of curcumol against DR were mediated through the FTO/MAFG-AS1 signaling pathway.CONCLUSION Curcumol ameliorates the progression of DR by modulating the FTO/MAFG-AS1 axis,providing a novel therapeutic pathway for the treatment of DR.These findings suggest that curcumol-based therapies could offer a promising alternative for managing this debilitating complication of diabetes.
基金supported by the National Natural Science Foundation of China(Grant No.31972368)the China Agriculture Research System(Grant No.CARS-29-yc-6)+1 种基金the Major Agricultural Science Projects of Liaoning Province(Grant No.2023JH1/10200004)the Science and Technology Program of Shenyang(Grant No.23-410-2-03).
文摘Anthocyanins are important pigments and nutrients in fruits.Red grape is popular because of the high anthocyanin content.Previous studies have identified VvMYBA1 and its homologs as key regulators of fruit color;however,other transcription factors(TFs)that contribute to fruit color remain poorly understood.The present study identified the R2R3-MYB TF VvMYB24,whose gene expression levels were significantly higher in red berries(L51,Vitis vinifera×Vitis labrusca L.)than in green berries(L20,V.vinifera×V.labrusca L.).Overexpression of VvMYB24 in grape calli increased anthocyanin biosynthesis by upregulating the expression of specific structural genes(VvDFR and VvUFGT).Furthermore,VvMYB24 interacted with VvMYBA1 to form a protein complex that additionally increased the expression of VvDFR and VvUFGT.In addition,light-responsive TF VvHY5 could bind to the VvMYB24 promoters to activate its transcription.Taken together,the results reveal a regulatory module,VvHY5-VvMYB24-VvMYBA1,that influences anthocyanin biosynthesis in grape.
基金supported by grants from the National Guidance Foundation for Local Science and Technology Development of China(Grant No.2023-009)the Department of Science and Technology of Guizhou Province(Grant No.qiankehezhicheng-[2020]1Y025)。
文摘Phosphorus(Pi)plays a crucial role in the growth and development of plants.Membrane lipid regulation is one of the main mechanisms underlying plant adaptation to Pi deficiency.Previously,the high tolerance to low-Pi stress was justified in an elite line,MSDZ 109,which was obtained from Malus mandshurica.To better understand the mechanism underlying high adaptation to low-Pi stress,currently,lipidomic and transcriptomic analysis,as well as CRISPR/Cas9 and MmGDPD1-overexpressing methodologies were comprehensively integrated into a strategy for elucidating the high tolerance to low-Pi stress.Totally,770 differential metabolites were identified from the roots between the low-Pi and stress-free,belonging to 21 sub-classes of lipid compounds.Fatty acids(FA)constituted the predominant lipid component,accounting for approximately 50%-60%of the total lipids,and triglycerides(TAG)ranked the second,comprising around 12%of the total,consecutively followed by phosphatidylcholine(PC)and diacylglycerol(DAG)with approximately 10%and 8%of the total,respectively.The synchronous transcriptomic analysis revealed a significant up-regulation of genes related to glycerophospholipid and glycerolipid metabolism,specifically those(e.g.,MmGDPD1,MmDGDG1,MmMGDG1,MmSQDG,etc.)involved in phospholipid and galactosyl synthesis in response to low-Pi stress.GUS fusing reporter assay showed that MmGDPD1 promoter induced GUS gene expression and demonstrated initiation activity.Based on expression analysis,a dual-luciferase reporter assay,as well as yeast one-hybrid(Y1H)identification,MmPHR1 was justified to bind with the MmGDPD1 promoter and positively regulate plant tolerance to low-Pi stress.To further elucidate the role of MmGDPD1,CRISPR/Cas9 and MmGDPD1-overexpressing vectors were successfully introduced into apple(‘Royal Gala')calli.Interestingly,the MmGDPD1-KO line calli exhibited the remarkable decreases in the contents of phosphodiesterase(PDE),activity,as well as the contents of total Pi,and Pi in comparison with those of the wild type.Conversely,MmGDPD1-OE ones demonstrated the significant elevation in Pi accumulations,further justifying its potential role in Pi remobilization in apple.Therefore,MmGDPD1 substantially involves elevating low-Pi tolerance via promoting Pi release in M.mandshurica.
基金Supported by the National Key R&D Program of China,No.2022YFC2503700 and No.2022YFC2503703the National Health Commission Key Laboratory of Nuclear Technology Medical Transformation(Mianyang Central Hospital),No.2023HYX005.
文摘BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.
基金Supported by Italian Association for Cancer Research(AIRC),No.21956Italian Ministry of Health-5×1000 funds 2023.
文摘In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by the National Natural Science Foundation of China(Grant Nos.32102311 and 32102338)the China Postdoctoral Science Foundation(Grant No.2021M690129).
文摘Drought stress significantly impedes apple growth,development,and yield,leading to substantial economic losses within the global apple industry.Malus prunifolia(Mp),a commonly utilized apple rootstock,has shown promise in augmenting cultivated apple resistance to abiotic stress.Although Alfin-like(ALs)proteins have demonstrated pivotal roles in dicotyledonous plants'response to abiotic stresses,knowledge about AL genes in apple rootstocks is limited,and their functions remain largely elusive.In this study,we identified and characterized 10 MpAL gene members in the apple rootstock genome,confirming their localization within the nucleus.Our investigation revealed the significant regulation of MpALs'expression under drought and abscisic acid(ABA)stresses in M.prunifolia.In this study,one of the members,MpAL1,was selected for further exploration in Arabidopsis and apple to explore its potential function in response to drought and ABA stresses.The results showed that overexpression-MpAL1 transgenic apple calli grew significantly better than WT and MpAL1-RNAi lines,which regulates the accumulation of H_(2)O_(2)and O_(2).-levels.Additionally,transgenic Arabidopsis plants overexpressing MpAL1 exhibited positively regulating antioxidant enzymes activities under stress treatments.Further study showed that silencing MpAL1 in apple plants showed obvious chlorosis in leaves,and accumulation of reactive oxygen species under drought stress.Moreover,our detailed analysis established that MpAL1 regulates several drought and ABA-responsive genes,exerting an influence on their expression in transgenic apple.Collectively,our findings identify MpAL1 as a positive regulator that increases drought stress in apple,shedding light on its potential significance in bolstering drought resistance in this fruit crop.
基金This work was supported by the Research Foundation of Chongqing Education Committee (No. KJ070314)Innovation Foundation of Chongqing Medical University (No. CX200526)Research Foundation for Advanced Talents of Chongqing Medical Univer-sity (No. QD200316).
文摘Human X-box binding protein 1 （XBP1）, an important transcription factor, participates in many signal transduction processes. To further investigate the biological function of XBP1, sequences of XBP1 promoter and its two deletion mutants were first determined using bioinformatic analysis. The report vectors containing XBP1 promoter and its deletion mutants were then constructed, namely, p1-XBPlp, p2-XBPlp, and p3-XBPlp. Each reporter vector was separately transfected into HepG2, L02, K562, SMMC-7721, HSF, and Lipocyte lto Cell line using FuGENE 6 transfection reagents. The activity of chloramphenicol acetyltransferase （CAT） in each group of transfected cells was detected by ELISA assay, which in turn reflects the transcription activity of the XBP1 gene promoter. The activity involving p3-XBPlp was the highest in HepG2, which was 12.4-fold of that of pCAT3-Basic. The activities of p3-XBPlp in K562 and SMMC-7721 were the second and the third highest, which were 10.9-fold and 10.0-fold of that of the pCAT3-Basic, respectively. The CAT activity in L02 was lower than that in the above-mentioned abnormal cell, and no reporter activity was detected in HSF and Ito Cell. The XBP1 transcription and expression in K562, HepG2 and SMMC-7721 were found to be higher than that in L02, HSF and Ito cells, based on the results of real-time RT-PCR and Western blot. The XBP1 transcription and expression in L02, HSF was lower, whereas that in Ito cells was totally lacking. The result was similar to that of CAT-ELISA. Therefore, the XBP1 gene promoter can drive its downstream gene expression and its activity is cell line-dependent. The core sequence of XBP1 promoter was found between -227bp and 66bp sequence. This sequence was closely associated with the transcriptional activity of XBP1 promoter.
