BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role...BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.展开更多
Drought is a common environmental condition that significantly impairs plant growth.In response to drought,plants close their stomata to minimize transpiration and meanwhile activate many stress-responsive genes to mi...Drought is a common environmental condition that significantly impairs plant growth.In response to drought,plants close their stomata to minimize transpiration and meanwhile activate many stress-responsive genes to mitigate damage.These stress-related mRNA transcripts require the assistance of RNA-binding proteins throughout their metabolic process,culminating in protein synthesis in the cytoplasm.In this study,we identified HLN1(Hyaluronan 1),an RNAbinding protein with similarity to the animal hyaluronan-binding protein 4/serpin mRNA binding protein 1(HABP4/SERBP1),as crucial for plant drought tolerance.The hln1 loss-of-function mutant exhibited higher transpiration rates due to impaired stomatal closure,making it highly susceptible to drought.Drought stress increased HLN1 expression,and the protein underwent liquid-liquid phase separation(LLPS)to form mRNA-ribonucleoprotein(mRNP)condensates in the cytoplasm under osmotic stress.We identified GAD2 as a potential mRNA target of HLN1.GAD2 encodes the predominant glutamate decarboxylase synthesizingγ‐aminobutyric acid(GABA),a non-proteinogenic amino acid that modulates stomatal movement.RIP-qPCR and EMSA showed that HLN1 binds GAD2 mRNA,which promotes HLN1 condensate formation.In hln1 mutants,GAD2 transcripts were less stable,reducing steady-state mRNA levels.As a result,hln1 accumulated less GABA and exhibited impaired stomatal closure under drought.Conversely,HLN1 overexpression stabilized GAD2 mRNA,increased GABA levels,and enhanced drought tolerance in transgenic plants.GAD2 overexpression in hln1 mutants also rescued the drought-sensitive phenotypes.Overall,our study reveals a mechanism whereby HLN1 stabilizes GAD2 mRNA to enhance GABA production and drought tolerance.These findings provide novel strategies for engineering drought-resistant crops.展开更多
BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a cr...BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury.The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1(NIPSNAP1)is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.AIM To clarify the protective mechanism of NIPSNAP1 against hepatic I/R,with a focus on mitophagy and mitochondrial dynamics,as well as the potential mechanism by which n6-methyladenosine(m6A)modification regulates NIPSNAP1.METHODS Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R.HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.RESULTS We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2(IGF2BP2)expression in vivo and in vitro.NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics;in contrast,NIPSNAP1 overexpression resulted in the opposite effects.Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1,thereby regulating its mRNA stability.CONCLUSION NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis,serving as a novel target of the m6A reader IGF2BP2.Therefore,targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.展开更多
Angiogenesis is essential for supporting tumor progression and metastasis.However,the potential role of the epitranscriptome in regulating angiogenesis remains unclear.Here,we identify the RNA N6-methyladenosine(m^(6)...Angiogenesis is essential for supporting tumor progression and metastasis.However,the potential role of the epitranscriptome in regulating angiogenesis remains unclear.Here,we identify the RNA N6-methyladenosine(m^(6)A)reader insulin-like growth factor 2(IGF2)messenger RNA(mRNA)-binding protein 2(IGF2BP2)as the top enriched m^(6)A regulator in hypervascular colorectal cancer(CRC),with its expression correlating with poor prognosis.Knockdown of IGF2BP2 in CRC cells suppressed their ability to promote pro-angiogenic phenotypes in endothelial cells in vitro,as well as vascular abnormalization,tumor progression,and metastasis in vivo.Supporting these findings,intestine-specific Igf2bp2 knock-in mice exhibited accelerated azoxymethane(AOM)plus dextran sulfate sodium(DSS)-induced CRC through enhanced angiogenesis and vascular abnormalities,whereas intestine-specific Igf2bp2 knockout inhibited tumor growth by normalizing tumor vasculature.Mechanistically,IGF2BP2 binds to m^(6)A-modified cell migration inducing and hyaluronan binding protein(CEMIP)mRNA and enhanced its stability,leading to increased secretion of CEMIP.Secreted CEMIP interacts with membrane glucose-regulated protein 78(GRP78)on endothelial cells,activating pro-angiogenic signaling.Importantly,targeting IGF2BP2 through genetic ablation,lipid nanoparticle(LNP)-encapsulated small interfering IGF2BP2,or the chemical inhibitor(CWI1-2)synergized with anti-angiogenic drugs to suppress tumor growth in multiple CRC models.Together,these findings suggest that targeting IGF2BP2 is a promising strategy to enhance the efficacy of anti-angiogenic therapy in CRC.展开更多
Insulin-like growth factor 2 m RNA-binding protein 2(IGF2 BP2,also called IMP2)plays an essential role in the development and maturation of germ cells and embryos and is a candidate gene for goat litter size,based on ...Insulin-like growth factor 2 m RNA-binding protein 2(IGF2 BP2,also called IMP2)plays an essential role in the development and maturation of germ cells and embryos and is a candidate gene for goat litter size,based on a previous genomewide selective sweep analysis.In this study,the m RNA expression level of IGF2 BP2 was found to be significantly higher in a single-lamb group than in a multi-lamb group.Insertions/deletions(indels)within the goat IGF2 BP2 gene,including P4-Ins-13 bp and P5-Del-12 bp,were verified in 918 Shaanbei White Cashmere(SBWC)female goats.The minor allelic frequencies(MAFs)of P4-Ins-13 bp and P5-Del-12 bp loci were 0.349 and 0.295,respectively.Analysis using the Chi-square(χ^(2))test showed that the genotype(χ^(2)=14.479,P=0.006)distribution of P4-Ins-13 bp was significantly different between the single-lamb and multi-lamb groups.Correlation analysis demonstrated that P4-Ins-13 bp was significantly associated with goat litter size(P=0.022),and individual goats with the homozygous deletion/deletion(DD)genotype produced more litters than other goats.Therefore,considered as a potential molecular marker significantly related to lambing traits,the P4-Ins-13 bp mutation of the goat IGF2 BP2 gene can be used in goat breeding with practical molecular marker-assisted selection(MAS)to optimize female reproduction and improve economic efficiency in the goat industry.展开更多
The expression of a gene is governed at various levels,from transcriptional to translational level.The translational control is widely used to regulate gene expression,especially when a rapid,local,and selective contr...The expression of a gene is governed at various levels,from transcriptional to translational level.The translational control is widely used to regulate gene expression,especially when a rapid,local,and selective control over protein synthesis is required.The present review describes instructive examples of translational regulation in yeast,together with regulatory elements within mRNAs.The review also outlines the important contributions of mRNA-binding proteins that act in harmony with several translational elements to generate appropriate translational signals and responses.展开更多
Objective Gastric cancer(GC)is one of the most prevalent cancers worldwide and is associated with high morbidity and mortality rates.The IGF2 mRNA-binding protein(IGF2BP)participates in a variety of cancers.The aim of...Objective Gastric cancer(GC)is one of the most prevalent cancers worldwide and is associated with high morbidity and mortality rates.The IGF2 mRNA-binding protein(IGF2BP)participates in a variety of cancers.The aim of this study was to analyze the expression of IGF2BP3 and explore the genes related to IGF2BP3 in GC.Methods Bioinformatics software was used to analyze the expression of IGF2BP1,IGF2BP2,and IGF2BP3 in tumors,and the expression of IGF2BPs in the GSE118897 dataset.Immunohistochemistry was performed to detect the protein level of IGF2BP3 in GC samples.cBioPortal was used to query gene alteration of IGF2BP3.LinkedOmics was used to identify genes related to IGF2BP3.Results Sangerbox analysis showed that the expression of all IGF2BP family members was higher in GC.cBioporta analysis showed that gene alteration of IGF2BP3 in stomach adenocarcinoma included mutation and amplificatio.LinkedOmics analysis showed that many genes were correlated with IGF2BP3,such as PLAGL2,GET4,IGF2BP1,HMGA2,CLDN6,HOXC13,SMARCA2,TMEM66,CIRBP,NFIX,SLC25A12,and CYB5D2.Conclusion In this study,we founded that IGF2BP3 was overexpressed in GC.Furthermore,this study identified potential genes related to IGF2BP3 in GC,which should be studied further.展开更多
基金Supported by the National Natural Science Foundation of China,No.61802350
文摘BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.
基金supported by Hong Kong University Grants Committee(UGC)General Research Fund(GRF)Grant#12103020(to L.X)Collaborative Research Fund(CRF)grant#C2003-22 WF(to Y.X and L.X).
文摘Drought is a common environmental condition that significantly impairs plant growth.In response to drought,plants close their stomata to minimize transpiration and meanwhile activate many stress-responsive genes to mitigate damage.These stress-related mRNA transcripts require the assistance of RNA-binding proteins throughout their metabolic process,culminating in protein synthesis in the cytoplasm.In this study,we identified HLN1(Hyaluronan 1),an RNAbinding protein with similarity to the animal hyaluronan-binding protein 4/serpin mRNA binding protein 1(HABP4/SERBP1),as crucial for plant drought tolerance.The hln1 loss-of-function mutant exhibited higher transpiration rates due to impaired stomatal closure,making it highly susceptible to drought.Drought stress increased HLN1 expression,and the protein underwent liquid-liquid phase separation(LLPS)to form mRNA-ribonucleoprotein(mRNP)condensates in the cytoplasm under osmotic stress.We identified GAD2 as a potential mRNA target of HLN1.GAD2 encodes the predominant glutamate decarboxylase synthesizingγ‐aminobutyric acid(GABA),a non-proteinogenic amino acid that modulates stomatal movement.RIP-qPCR and EMSA showed that HLN1 binds GAD2 mRNA,which promotes HLN1 condensate formation.In hln1 mutants,GAD2 transcripts were less stable,reducing steady-state mRNA levels.As a result,hln1 accumulated less GABA and exhibited impaired stomatal closure under drought.Conversely,HLN1 overexpression stabilized GAD2 mRNA,increased GABA levels,and enhanced drought tolerance in transgenic plants.GAD2 overexpression in hln1 mutants also rescued the drought-sensitive phenotypes.Overall,our study reveals a mechanism whereby HLN1 stabilizes GAD2 mRNA to enhance GABA production and drought tolerance.These findings provide novel strategies for engineering drought-resistant crops.
基金Supported by the National Natural Science Foundation of China,No.82200658.
文摘BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury.The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1(NIPSNAP1)is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.AIM To clarify the protective mechanism of NIPSNAP1 against hepatic I/R,with a focus on mitophagy and mitochondrial dynamics,as well as the potential mechanism by which n6-methyladenosine(m6A)modification regulates NIPSNAP1.METHODS Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R.HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.RESULTS We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2(IGF2BP2)expression in vivo and in vitro.NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics;in contrast,NIPSNAP1 overexpression resulted in the opposite effects.Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1,thereby regulating its mRNA stability.CONCLUSION NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis,serving as a novel target of the m6A reader IGF2BP2.Therefore,targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.
基金supported by the National Natural Science Foundation of China(82372596)the Research Grants Council Collaborative Research Fund(C4008-23W)+2 种基金the Research Grants Council Research Impact Fund Hong Kong(R4032-21F)the China Postdoctoral Science Foundation(2022M723588)the Medical Scientific Research Foundation of Guangdong Province(A2023439).
文摘Angiogenesis is essential for supporting tumor progression and metastasis.However,the potential role of the epitranscriptome in regulating angiogenesis remains unclear.Here,we identify the RNA N6-methyladenosine(m^(6)A)reader insulin-like growth factor 2(IGF2)messenger RNA(mRNA)-binding protein 2(IGF2BP2)as the top enriched m^(6)A regulator in hypervascular colorectal cancer(CRC),with its expression correlating with poor prognosis.Knockdown of IGF2BP2 in CRC cells suppressed their ability to promote pro-angiogenic phenotypes in endothelial cells in vitro,as well as vascular abnormalization,tumor progression,and metastasis in vivo.Supporting these findings,intestine-specific Igf2bp2 knock-in mice exhibited accelerated azoxymethane(AOM)plus dextran sulfate sodium(DSS)-induced CRC through enhanced angiogenesis and vascular abnormalities,whereas intestine-specific Igf2bp2 knockout inhibited tumor growth by normalizing tumor vasculature.Mechanistically,IGF2BP2 binds to m^(6)A-modified cell migration inducing and hyaluronan binding protein(CEMIP)mRNA and enhanced its stability,leading to increased secretion of CEMIP.Secreted CEMIP interacts with membrane glucose-regulated protein 78(GRP78)on endothelial cells,activating pro-angiogenic signaling.Importantly,targeting IGF2BP2 through genetic ablation,lipid nanoparticle(LNP)-encapsulated small interfering IGF2BP2,or the chemical inhibitor(CWI1-2)synergized with anti-angiogenic drugs to suppress tumor growth in multiple CRC models.Together,these findings suggest that targeting IGF2BP2 is a promising strategy to enhance the efficacy of anti-angiogenic therapy in CRC.
基金the National Natural Science Foundation of China(Nos.32060734 and 31760650)。
文摘Insulin-like growth factor 2 m RNA-binding protein 2(IGF2 BP2,also called IMP2)plays an essential role in the development and maturation of germ cells and embryos and is a candidate gene for goat litter size,based on a previous genomewide selective sweep analysis.In this study,the m RNA expression level of IGF2 BP2 was found to be significantly higher in a single-lamb group than in a multi-lamb group.Insertions/deletions(indels)within the goat IGF2 BP2 gene,including P4-Ins-13 bp and P5-Del-12 bp,were verified in 918 Shaanbei White Cashmere(SBWC)female goats.The minor allelic frequencies(MAFs)of P4-Ins-13 bp and P5-Del-12 bp loci were 0.349 and 0.295,respectively.Analysis using the Chi-square(χ^(2))test showed that the genotype(χ^(2)=14.479,P=0.006)distribution of P4-Ins-13 bp was significantly different between the single-lamb and multi-lamb groups.Correlation analysis demonstrated that P4-Ins-13 bp was significantly associated with goat litter size(P=0.022),and individual goats with the homozygous deletion/deletion(DD)genotype produced more litters than other goats.Therefore,considered as a potential molecular marker significantly related to lambing traits,the P4-Ins-13 bp mutation of the goat IGF2 BP2 gene can be used in goat breeding with practical molecular marker-assisted selection(MAS)to optimize female reproduction and improve economic efficiency in the goat industry.
文摘The expression of a gene is governed at various levels,from transcriptional to translational level.The translational control is widely used to regulate gene expression,especially when a rapid,local,and selective control over protein synthesis is required.The present review describes instructive examples of translational regulation in yeast,together with regulatory elements within mRNAs.The review also outlines the important contributions of mRNA-binding proteins that act in harmony with several translational elements to generate appropriate translational signals and responses.
基金Supported by a grant from the National Natural Science Foundation of China(No.81802788)。
文摘Objective Gastric cancer(GC)is one of the most prevalent cancers worldwide and is associated with high morbidity and mortality rates.The IGF2 mRNA-binding protein(IGF2BP)participates in a variety of cancers.The aim of this study was to analyze the expression of IGF2BP3 and explore the genes related to IGF2BP3 in GC.Methods Bioinformatics software was used to analyze the expression of IGF2BP1,IGF2BP2,and IGF2BP3 in tumors,and the expression of IGF2BPs in the GSE118897 dataset.Immunohistochemistry was performed to detect the protein level of IGF2BP3 in GC samples.cBioPortal was used to query gene alteration of IGF2BP3.LinkedOmics was used to identify genes related to IGF2BP3.Results Sangerbox analysis showed that the expression of all IGF2BP family members was higher in GC.cBioporta analysis showed that gene alteration of IGF2BP3 in stomach adenocarcinoma included mutation and amplificatio.LinkedOmics analysis showed that many genes were correlated with IGF2BP3,such as PLAGL2,GET4,IGF2BP1,HMGA2,CLDN6,HOXC13,SMARCA2,TMEM66,CIRBP,NFIX,SLC25A12,and CYB5D2.Conclusion In this study,we founded that IGF2BP3 was overexpressed in GC.Furthermore,this study identified potential genes related to IGF2BP3 in GC,which should be studied further.
