The transcriptome-wide CPSF6-induced APA alterations in gastric cancer cells
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ABSTRACT:
PROVIDER: PRJEB42340 | ENA |
REPOSITORIES: ENA
Dataset's files
primary
| Action | DRS | |||
|---|---|---|---|---|
| ERR5043170_1.fastq.gz | Fastqsanger.gz | |||
| ERR5043170_2.fastq.gz | Fastqsanger.gz | |||
| ERR5043171_1.fastq.gz | Fastqsanger.gz | |||
| ERR5043171_2.fastq.gz | Fastqsanger.gz | |||
| ERR5043172_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we showed that knockdown of CPSF6 inhibited GC cell growth and promoted apoptosis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we performed an APA profiling analysis in wild-type and CPSF6-knockdown AGS cells, using 3T-seq method.
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Project description:In this study, we showed that CPSF6 promoted HCC cell growth, migration and metastasis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we aimed to perform a APA profiling analysis in hepatocyte and hepatoma carcinoma cells under different CPSF6 expression conditions using 3T-seq method.
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Project description:In this study, we showed that knockdown of CPSF6 inhibited GC cell growth and promoted apoptosis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we performed an APA profiling analysis in wild-type and CPSF6-knockdown AGS cells, using 3T-seq method.
2021-07-31 | E-MTAB-9980 | ArrayExpress
Project description:In this study, we showed that CPSF6 promoted HCC cell growth, migration and metastasis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we aimed to perform a APA profiling analysis in hepatocyte and hepatoma carcinoma cells under different CPSF6 expression conditions using 3T-seq method.
2021-04-01 | E-MTAB-9458 | ArrayExpress
Project description:The transcriptome-wide CPSF6-induced APA alterations in HCC cells
| PRJEB40139 | ENA
Project description:Alternative polyadenylation (APA) is an important RNA post-transcriptional process, which can generate diverse mRNA isoforms. Increasing evidence shows that APA is involved in cell self-renewal, development, immunity, and cancer. CPSF6 is one of the core proteins of CFIm complex and can modulate the APA process. Although it has been reported to play oncogenic roles in cancer, the underlying mechanisms remain unclear. The aim of the present study was to characterize CPSF6 in human gastric cancer (GC). We observed that CPSF6 was upregulated in GC. Knockdown of CPSF6 inhibited proliferation and enhanced apoptosis of GC cells both <i>in vitro</i> and <i>in vivo</i>. Global APA site profiling analysis revealed that knockdown of CPSF6 induced widespread 3'UTR shortening of genes in GC cells, including <i>VHL</i>. We also found CPSF6 negatively regulated the expression of VHL through APA and <i>VHL</i> short-3'UTR isoform enhanced apoptosis and inhibited cell growth in GC cells. Our data suggested that CPSF6-induced cell proliferation and inhibition of apoptosis were mediated by the preferential usage of poly(A) in <i>VHL</i>. Our data provide insights into the function of CPSF6 and may imply potential therapeutic targets against GC.
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Project description:<h4>Background</h4>Alternative polyadenylation (APA) is an important mechanism of gene expression regulation through generation of RNA isoforms with distinct 3' termini. Increasing evidence has revealed that APA is actively involved in development and disease, including hepatocellular carcinoma (HCC). However, how APA functions in tumor formation and progression remains elusive. In this study, we investigated the role of cleavage factor I (CFIm) subunit CPSF6 in human hepatocellular carcinoma (HCC).<h4>Methods</h4>Expression levels of CPSF6 in clinical tissues and cell lines were determined by qRT-PCR and western blot. Functional assays, including the cell number, MTT, colony formation and transwell, were used to determine the oncogenic role of CPSF6 in HCC. Animal experiments were used to determine the role of CPSF6 in HCC tumorigenicity in vivo. Deep sequencing-based 3?T-seq was used to profile the transcriptome-wide APA sites in both HCC cells and CPSF6 knockdown HCC cells. The function of CPSF6-affected target NQO1 with distinct 3'UTRs was characterized by metabolism assays.<h4>Results</h4>We observed CPSF6 was upregulated in HCC and the high expression of CPSF6 was associated with poor prognosis in patients. Overexpression of CPSF6 promoted proliferation, migration and invasion of HCC cells in vitro and in vivo. Transcriptome-wide APA profiling analysis indicated that high expression of CPSF6 promoted the favorable usage of the proximal poly(A) site in the 3'UTR of NQO1. We demonstrated CPSF6-induced tumorigenic activities were mediated by the NQO1 isoform with short 3'UTR. Furthermore, we found that CPSF6 induced metabolic alterations in liver cells through NQO1.<h4>Conclusion</h4>CPSF6 plays a critical role in HCC progression by upregulating NQO1 expression through APA. These findings provide evidence to demonstrate that APA of NQO1 contributes to HCC progression and may have implications for developing new therapeutic strategy against this disease.
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Project description:Cleavage factor I mammalian (CFIm) complex, composed of cleavage and polyadenylation specificity factor 5 (CPSF5) and serine/arginine-like protein CPSF6, regulates alternative polyadenylation (APA). Loss of CFIm function results in proximal polyadenylation site usage, shortening mRNA 3' untranslated regions (UTRs). Although CPSF6 plays additional roles in human disease, its nuclear translocation mechanism remains unresolved. Two ?-karyopherins, transportin (TNPO) 1 and TNPO3, can bind CPSF6 in vitro, and we demonstrate here that while the TNPO1 binding site is dispensable for CPSF6 nuclear import, the arginine/serine (RS)-like domain (RSLD) that mediates TNPO3 binding is critical. The crystal structure of the RSLD-TNPO3 complex revealed potential CPSF6 interaction residues, which were confirmed to mediate TNPO3 binding and CPSF6 nuclear import. Both binding and nuclear import were independent of RSLD phosphorylation, though a hyperphosphorylated mimetic mutant failed to bind TNPO3 and mislocalized to the cell cytoplasm. Although hypophosphorylated CPSF6 largely supported normal polyadenylation site usage, a significant number of mRNAs harbored unnaturally extended 3' UTRs, similar to what is observed when other APA regulators, such as CFIIm component proteins, are depleted. Our results clarify the mechanism of CPSF6 nuclear import and highlight differential roles for RSLD phosphorylation in nuclear translocation versus regulation of APA.
| S-EPMC6511849 | BioStudies
Project description:BACKGROUND: EGFR overexpression has been described in many human tumours including gastric cancer. In NSCLC patients somatic EGFR mutations, within the kinase domain of the protein, as well as gene amplification were associated with a good clinical response to EGFR inhibitors. In gastric tumours data concerning structural alterations of EGFR remains controversial. Given its possible therapeutic relevance, we aimed to determine the frequency and type of structural alterations of the EGFR gene in a series of primary gastric carcinomas. METHODS: Direct sequencing of the kinase domain of the EGFR gene was performed in a series of 77 primary gastric carcinomas. FISH analysis was performed in 30 cases. Association studies between EGFR alterations and the clinical pathological features of the tumours were performed. RESULTS: Within the 77 primary gastric carcinomas we found two EGFR somatic mutations and several EGFR polymorphisms in exon 20. Six different intronic sequence variants of EGFR were also found. Four gastric carcinomas showed balanced polysomy or EGFR gene amplification. We verified that gastric carcinoma with alterations of EGFR (somatic mutations or copy number variation) showed a significant increase of tumour size (p = 0.0094) in comparison to wild-type EGFR carcinomas. CONCLUSION: We demonstrate that EGFR structural alterations are rare in gastric carcinoma, but whenever present, it leads to tumour growth. We considered that searching for EGFR alterations in gastric cancer is likely to be clinically important in order to identify patients susceptible to respond to tyrosine kinase inhibitors.
| S-EPMC2244615 | BioStudies
Project description:Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
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