Background:Alterations in splicing factors contribute to aberrant alternative splicing(AS),which subsequently promotes tumor progression.The splicing factor polypyrimidine tract binding protein 1(PTBP1)has been shown ...Background:Alterations in splicing factors contribute to aberrant alternative splicing(AS),which subsequently promotes tumor progression.The splicing factor polypyrimidine tract binding protein 1(PTBP1)has been shown to facilitate cancer progression by modulating oncogenic variants.However,its specific role and underlying mechanisms in hepatocellular carcinoma(HCC)remain to be elucidated.Methods:PTBP1 expression was evaluated in HCC tissues and cell lines.Subsequently,cells were transfected with vectors designed for PTBP1 overexpression or downregulation.The biological function of PTBP1 was assessed in vitro and in vivo using MTS assays,colony formation assays,transwell assays,xenograft formation,tail vein injection,and orthotopic models.Transcriptome analysis was conducted to elucidate the underlying molecular mechanisms.Results:Our findings demonstrated that PTBP1 exhibited elevated expression in HCC cell lines and tissues.Furthermore,its expression positively correlated with overall and disease-free survival rates,as well as tumor grade and stage.PTBP1 knockdown reduced HCC cell proliferation,migration,and invasion in vitro and suppressed hepatocarcinoma xenograft growth and infiltration in vivo.RNA sequencing(RNA-Seq)analysis identified the AS events associated with PTBP1.PTBP1 functionally enhanced cell proliferation,invasion,and migration by modulating the AS of the microtubule-associated protein tau(MAPT)gene and promoting oncogene expression.Notably,the dysregulation of MAPT splicing coincided with increased PTBP1 expression in HCC.Conclusions:PTBP1-guided AS of the MAPT gene enhances tumorigenicity in HCC through activation of the MAPK/ERK pathways.展开更多
Coat color is an important characteristic of various breeds of domestic animal species.Variation in farm animal coat color is of considerable interest for concealment,communication and protection against solar radiat...Coat color is an important characteristic of various breeds of domestic animal species.Variation in farm animal coat color is of considerable interest for concealment,communication and protection against solar radiation（Slominski et al.,2004）.It also plays an important role in the regulation of physiological processes（Miyagi and Terai,2013）.展开更多
Mitochondrial fission promotes glioma progression.The function and regulation mechanisms of lncRNAs in glioma mitochondrial fission are unclear.The expression of LINC00475 and its correlation with clinical parameters ...Mitochondrial fission promotes glioma progression.The function and regulation mechanisms of lncRNAs in glioma mitochondrial fission are unclear.The expression of LINC00475 and its correlation with clinical parameters in glioma were analyzed using bioinformatics.Then,in vitro and in vivo assays were performed to explore the function of spliced variant LINC00475(LINC00475-S)in gliomas.To explore the mechanisms,RNA-seq,MeRIP,RIP,pulldown-IP,dCas9-ALKBH5 editing system,LC/MS,and Western blotting were utilized.LINC00475 was confirmed to be overexpressed and with higher frequencies of AS events in gliomas compared to normal brain tissue and was associated with worse prognosis.In vitro and animal tumor formation experiments demonstrated that the effect of LINC00475-S on proliferation,metastasis,autophagy,and mitochondrial fission of glioma cells was significantly stronger than that of LINC00475.Mechanistically,METTL3 induced the generation of LINC00475-S by splicing LINC00475 through m6A modification and subsequently promotes mitochondrial fission in glioma cells by inhibiting the expression of MIF.Pull-down combined LC/MS and RIP assays identified that the m6A recognition protein HNRNPH1 bound to LINC00475 within GYR and GY domains and promoted LINC00475 splicing.METTL3 facilitated HNRNPH1 binding to LINC00475 in an m6A-dependent manner,thereby inducing generation of LINC00475-S.METTL3 facilitated HNRNPH1-mediated AS of LINC00475,which promoted glioma progression by inducing mitochondrial fission.Targeting AS of LINC00475 and m6A editing could serve as a therapeutic strategy against gliomas.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81972771,82173062)the Key Areas Project of Education Department of Guangdong Province(No.2021ZDZX2017)+3 种基金the Tertiary Education Scientific Research Project of Guangzhou Municipal Education Bureau(No.202235387)the Guangzhou Science and Technology Project of Guangzhou Municipal Science and Technology Bureau(No.2023A03J0428)the Natural Science Foundation of Guangdong Province,China(No.2024A1515013082)the Guangdong Basic and Applied Basic Research 21 Foundation(No.2021A1515010403).
文摘Background:Alterations in splicing factors contribute to aberrant alternative splicing(AS),which subsequently promotes tumor progression.The splicing factor polypyrimidine tract binding protein 1(PTBP1)has been shown to facilitate cancer progression by modulating oncogenic variants.However,its specific role and underlying mechanisms in hepatocellular carcinoma(HCC)remain to be elucidated.Methods:PTBP1 expression was evaluated in HCC tissues and cell lines.Subsequently,cells were transfected with vectors designed for PTBP1 overexpression or downregulation.The biological function of PTBP1 was assessed in vitro and in vivo using MTS assays,colony formation assays,transwell assays,xenograft formation,tail vein injection,and orthotopic models.Transcriptome analysis was conducted to elucidate the underlying molecular mechanisms.Results:Our findings demonstrated that PTBP1 exhibited elevated expression in HCC cell lines and tissues.Furthermore,its expression positively correlated with overall and disease-free survival rates,as well as tumor grade and stage.PTBP1 knockdown reduced HCC cell proliferation,migration,and invasion in vitro and suppressed hepatocarcinoma xenograft growth and infiltration in vivo.RNA sequencing(RNA-Seq)analysis identified the AS events associated with PTBP1.PTBP1 functionally enhanced cell proliferation,invasion,and migration by modulating the AS of the microtubule-associated protein tau(MAPT)gene and promoting oncogene expression.Notably,the dysregulation of MAPT splicing coincided with increased PTBP1 expression in HCC.Conclusions:PTBP1-guided AS of the MAPT gene enhances tumorigenicity in HCC through activation of the MAPK/ERK pathways.
基金supported by the National Basic Research Program of China (Nos. 2011CBA0100, 2011CB944100, 2011BAI15B02, and se2012BAI39B04)the National High Technology Research and Development Program of China (No. 2012AA020602)+1 种基金the Strategic Priority Research Program of CAS (Nos. XDA08000000 and XDA01030400)the National Natural Science Foundation of China (Nos. 31272440 and 81671274)
文摘Coat color is an important characteristic of various breeds of domestic animal species.Variation in farm animal coat color is of considerable interest for concealment,communication and protection against solar radiation（Slominski et al.,2004）.It also plays an important role in the regulation of physiological processes（Miyagi and Terai,2013）.
基金supported by the National Natural Science Foundation of China(nos.81672496 and no.82173593)Guangzhou Municipal Science and Technology Bureau(nos.202201020603 and 202201020640)Guangzhou Municipal Science and Technology Program key projects(no.202206010006).
文摘Mitochondrial fission promotes glioma progression.The function and regulation mechanisms of lncRNAs in glioma mitochondrial fission are unclear.The expression of LINC00475 and its correlation with clinical parameters in glioma were analyzed using bioinformatics.Then,in vitro and in vivo assays were performed to explore the function of spliced variant LINC00475(LINC00475-S)in gliomas.To explore the mechanisms,RNA-seq,MeRIP,RIP,pulldown-IP,dCas9-ALKBH5 editing system,LC/MS,and Western blotting were utilized.LINC00475 was confirmed to be overexpressed and with higher frequencies of AS events in gliomas compared to normal brain tissue and was associated with worse prognosis.In vitro and animal tumor formation experiments demonstrated that the effect of LINC00475-S on proliferation,metastasis,autophagy,and mitochondrial fission of glioma cells was significantly stronger than that of LINC00475.Mechanistically,METTL3 induced the generation of LINC00475-S by splicing LINC00475 through m6A modification and subsequently promotes mitochondrial fission in glioma cells by inhibiting the expression of MIF.Pull-down combined LC/MS and RIP assays identified that the m6A recognition protein HNRNPH1 bound to LINC00475 within GYR and GY domains and promoted LINC00475 splicing.METTL3 facilitated HNRNPH1 binding to LINC00475 in an m6A-dependent manner,thereby inducing generation of LINC00475-S.METTL3 facilitated HNRNPH1-mediated AS of LINC00475,which promoted glioma progression by inducing mitochondrial fission.Targeting AS of LINC00475 and m6A editing could serve as a therapeutic strategy against gliomas.
