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Title:
Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo | Scientific Reports
Description:
Reactivation of wild-type p53 (wt-p53) function is an attractive therapeutic approach to p53-defective cancers. An ideal p53-based gene therapy should restore wt-p53 production and reduces mutant p53 transcripts simultaneously. In this study, we described an alternative strategy named as trans-splicing that repaired mutant p53 transcripts in hepatocellular carcinoma (HCC) cells. The plasmids which encoded a pre-trans-splicing molecule (PTM) targeting intron 6 of p53 were constructed and then transfected into HCC cells carrying p53 mutation. Phenotypic changes of HCC cells induced by p53-PTM were analyzed through cell cycle, cell apoptosis and the expression of p53 downstream target genes. Spliceosome mediated RNA trans-splicing (SMaRT) reduced mutant p53 transcripts and produced functional wt-p53 protein after the delivery of p53-PTM plasmids, which resulted in phenotype correction of HCC cells. In tumor xenografts established by p53-mutated HCC cells, adenovirus encoding p53-PTM induced cell cycle arrest and apoptosis and then blocked the growth of tumors in mice. Collectively, our results demonstrated for the first time that mutant p53 transcripts were functionally corrected in p53-defective HCC cells and xenografts using trans-splicing, which indicated the feasibility of using trans-splicing to repair p53 mutation in p53-defective cancers.
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Keywords {π}
cells, mutant, article, pubmed, cancer, google, scholar, cell, hcc, cas, transcripts, plcprf, pptm, transsplicing, expression, tumor, figure, wtp, repair, tumors, growth, apoptosis, genes, transfected, nature, gene, mutation, cycle, smart, human, rna, mice, adenovirus, hepatocellular, carcinoma, demonstrated, genetic, xenograft, pdefective, study, mutations, liver, rtpcr, central, function, protein, correction, supplementary, vitro, therapy,
Topics {βοΈ}
nature portfolio privacy policy providing pcmv-neo-bam wtp53 plasmid pcmv-neo-bam wtp53 hyper-igm x-linked immunodeficiency advertising diverse nature spliceosome-mediated rna trans-splicing nature reviews evaluate trans-splicing-mediated repair p53 pre-trans-splicing molecules nature 415 nature p53-ptm-e7-11 trans-activated social media trans-splicing ribozymes-mediate repair ad-p53ptm-e7-11 group manifested pre-established plc/prf/5 xenografts trans-spliced p53 rnas 0/ reprints adenovirus encoding p53-ptm p53 research p53-based cancer therapies trans-spliced p53 rna vectors expressing p53-ptm italy trans splicing-mediated revision pre-trans-splicing molecule providing pcyclinb-prom-luc pre-mrna trans-splicing wild-type p53 activity trans-splicing-mediated repair plasmid carrying p53-ptm wild-type human p53 trans-activate downstream genes sybr green qrt-pcr p53-dependent downstream genes restores wt-p53 activity defective target pre-mrna restored wt-p53 activities mature wt-p53 transcripts activating cyclin-dependent kinase blocking mdm2-induced degradation yeast branch-point consensus wild-type p53 function restore wt-p53 production p53-dependent target genes plc/prf/5 cells led induces wt-p53 production research
Questions {β}
- Splicing out the West?
- P53 Isoforms: An Intracellular Microprocessor?
- P53-based cancer therapies: Is defective p53 the Achilles heel of the tumor?
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headline:Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo
description:Reactivation of wild-type p53 (wt-p53) function is an attractive therapeutic approach to p53-defective cancers. An ideal p53-based gene therapy should restore wt-p53 production and reduces mutant p53 transcripts simultaneously. In this study, we described an alternative strategy named as trans-splicing that repaired mutant p53 transcripts in hepatocellular carcinoma (HCC) cells. The plasmids which encoded a pre-trans-splicing molecule (PTM) targeting intron 6 of p53 were constructed and then transfected into HCC cells carrying p53 mutation. Phenotypic changes of HCC cells induced by p53-PTM were analyzed through cell cycle, cell apoptosis and the expression of p53 downstream target genes. Spliceosome mediated RNA trans-splicing (SMaRT) reduced mutant p53 transcripts and produced functional wt-p53 protein after the delivery of p53-PTM plasmids, which resulted in phenotype correction of HCC cells. In tumor xenografts established by p53-mutated HCC cells, adenovirus encoding p53-PTM induced cell cycle arrest and apoptosis and then blocked the growth of tumors in mice. Collectively, our results demonstrated for the first time that mutant p53 transcripts were functionally corrected in p53-defective HCC cells and xenografts using trans-splicing, which indicated the feasibility of using trans-splicing to repair p53 mutation in p53-defective cancers.
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