In this study,we investigated the functional role of eukaryotic initiation factor 5B(EIF5B)in hepatocellular carcinoma(HCC)and the underlying mechanisms.Bioinformatics analysis demonstrated that the EIF5B transcript a...In this study,we investigated the functional role of eukaryotic initiation factor 5B(EIF5B)in hepatocellular carcinoma(HCC)and the underlying mechanisms.Bioinformatics analysis demonstrated that the EIF5B transcript and protein levels as well as the EIF5Bcopy number were significantly higher in the HCC tissues compared with the non-cancerous liver tissues.Down-regulation of EIF5B significantly decreased proliferation and invasiveness of the HCC cells.Furthermore,EIF5B knockdown suppressed epithelial-mesenchymal transition(EMT)and the cancer stem cell(CSC)phenotype.Down-regulation of EIF5B also increased the sensitivity of HCC cells to 5-fluorouracil(5-FU).In the HCC cells,activation of the NF-kappa B signaling pathway and IkB phosphorylation was significantly reduced by EIF5B silencing.IGF2BP3 increased the stability of the EIF5B mRNA in an m6A-dependent manner.Our data suggested that EIF5B is a promising prognostic biomarker and therapeutic target in HCC.展开更多
Vanishing white matter disease （VWM）, a human atitosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B （elF2B）. elF2B is responsible for tile initiation of protein...Vanishing white matter disease （VWM）, a human atitosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B （elF2B）. elF2B is responsible for tile initiation of protein synthesis by its guanine nucleotide exchange lhctor （GEF） activity. Mutations ofelF2B impair GEF activity at different degree. Previous studies implied improperly activated unlblded protein response （UPR） and endoplasmic reticulum stress （ERS） participated in the pathogenesis ofVWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. Methods： ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Argl 13 His, p. Arg269＊ or p. Ser610-Asp613del in el F2 Be. A representative U PR-PERK component of activating transcription lhctor 4 （ATF4） was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. Results： The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity ofp. Arg269＊ group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-1 and LC3-11 in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants alter ERS induction. Conclusions： GEF activities in dilt;erent genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion inutants showed less tolerable to ERS.展开更多
基金supported by National Natural Science Foundation of China(No.81773167)Project of Traditional Chinese Medicine of Guangdong Administration(No.20132155)Medical and Health Science and Technology Project of Guangzhou Baiyun District(No.2020-YL-002).
文摘In this study,we investigated the functional role of eukaryotic initiation factor 5B(EIF5B)in hepatocellular carcinoma(HCC)and the underlying mechanisms.Bioinformatics analysis demonstrated that the EIF5B transcript and protein levels as well as the EIF5Bcopy number were significantly higher in the HCC tissues compared with the non-cancerous liver tissues.Down-regulation of EIF5B significantly decreased proliferation and invasiveness of the HCC cells.Furthermore,EIF5B knockdown suppressed epithelial-mesenchymal transition(EMT)and the cancer stem cell(CSC)phenotype.Down-regulation of EIF5B also increased the sensitivity of HCC cells to 5-fluorouracil(5-FU).In the HCC cells,activation of the NF-kappa B signaling pathway and IkB phosphorylation was significantly reduced by EIF5B silencing.IGF2BP3 increased the stability of the EIF5B mRNA in an m6A-dependent manner.Our data suggested that EIF5B is a promising prognostic biomarker and therapeutic target in HCC.
基金grants from the Natural Science Foundation of China，National Key Technology R and D Program，Key Laboratory Program of Ministry of Education
文摘Vanishing white matter disease （VWM）, a human atitosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B （elF2B）. elF2B is responsible for tile initiation of protein synthesis by its guanine nucleotide exchange lhctor （GEF） activity. Mutations ofelF2B impair GEF activity at different degree. Previous studies implied improperly activated unlblded protein response （UPR） and endoplasmic reticulum stress （ERS） participated in the pathogenesis ofVWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. Methods： ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Argl 13 His, p. Arg269＊ or p. Ser610-Asp613del in el F2 Be. A representative U PR-PERK component of activating transcription lhctor 4 （ATF4） was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. Results： The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity ofp. Arg269＊ group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-1 and LC3-11 in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants alter ERS induction. Conclusions： GEF activities in dilt;erent genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion inutants showed less tolerable to ERS.
