SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA810846 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Serine/arginine-rich splicing factor 3 (SRSF3) functions to regulate mRNA alternative splicing, a molecular mechanism to process more than 90% of the protein-coding genes and provides an essential source for the biological versatility and targeting of SRSF3 could be a novel approach for cancer therapy. This study identify that SRSF3 expression was upregulated in pancreatic cancer tissues and associated with drug resistance and poor prognosis. Thus, we found that SRSF3 regulated ANRIL splicing and modified m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrated that the m6A methylation on lncRNA-ANRIL was essential for splicing process. Meanwhile, we also found that the different isoforms of ANRIL were differentially expressed in drug-resistant pancreatic cancer cell lines, and SRSF3 promotes gemcitabine resistance by regulating the expression of ANRIL-208. In addition, ANRIL-208 regulated pancreatic cancer cell chemoresistance by forming a complex with Ring1b and EZH2 and enhanced DNA homologous recombination repair (HR) capacity. In conclusion, the current study first established the link among SRSF3, m6A modification, lncRNA splicing, and DNA HR repair in pancreatic cancer, and first demonstrated that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.
2022-05-11 | GSE197352 | GEO
Project description:Serine/arginine-rich splicing factor 3 (SRSF3) functions to regulate mRNA alternative splicing, a molecular mechanism to process more than 90% of the protein-coding genes and provides an essential source for the biological versatility and targeting of SRSF3 could be a novel approach for cancer therapy. This study identify that SRSF3 expression was upregulated in pancreatic cancer tissues and associated with drug resistance and poor prognosis. Thus, we found that SRSF3 regulated ANRIL splicing and modified m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrated that the m6A methylation on lncRNA-ANRIL was essential for splicing process. Meanwhile, we also found that the different isoforms of ANRIL were differentially expressed in drug-resistant pancreatic cancer cell lines, and SRSF3 promotes gemcitabine resistance by regulating the expression of ANRIL-208. In addition, ANRIL-208 regulated pancreatic cancer cell chemoresistance by forming a complex with Ring1b and EZH2 and enhanced DNA homologous recombination repair (HR) capacity. In conclusion, the current study first established the link among SRSF3, m6A modification, lncRNA splicing, and DNA HR repair in pancreatic cancer, and first demonstrated that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.
2022-05-11 | GSE197532 | GEO
Project description:SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine I
| PRJNA809955 | ENA
Project description:SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine II
| PRJNA810847 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-05-10 | GSE197533 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with limited therapeutic options, and gemcitabine insensitivity remains a major challenge. N6-methyladenosine (m6A) is a prevalent nucleotide modification in mRNA that has been linked to various biological processes in human diseases, yet its role in drug sensitivity of cancer remains largely unknown. Herein, by detecting the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified the key role of hyper-m6A modification of the master G0/G1 regulator Fizzy and Cell Division Cycle 20 Related 1 (FZR1) in regulating gemcitabine sensitivity. Targeting m6A modification of FZR1 improves the gemcitabine treatment response of gemcitabine-insensitive PDAC cells in vitro and in vivo. Mechanistically, Gem Nuclear Organelle Associated Protein 5 (GEMIN5) was identified as a novel m6A mediator that specifically binds to m6A-modified FZR1 and recruits the eIF3 translation initiation complex to accelerate FZR1 translation. Upregulation of FZR1 maintains the G0/G1 quiescent state and impairs gemcitabine sensitivity of PDAC cells. Further clinical analysis showed that both high levels of FZR1 m6A modification and FZR1 protein indicated a poor response to gemcitabine. These findings unveil the critical function for m6A modification in regulating gemcitabine sensitivity in PDAC and identify the m6A-FZR1 axis as a potential target to enhance gemcitabine response.
2023-06-08 | GSE206969 | GEO
Project description:Coronary artery disease (CAD) is the most common cardiovascular disease and the leading cause of death worldwide. To date, the 9p21.3 locus is the most robust and frequently replicated risk locus of CAD among >90 CAD risk loci identified by GWAS. More than 50 CAD-associated genomic variants were identified at the 9p21.3 CAD locus and many of them are located within a long non-coding gene ANRIL, which was initially referred to as Antisense Non-coding RNA in INK4 Locus. The causal role of ANRIL in CAD and the underlying molecular mechanism are unknown. We used gene expression microarray to identify the downstream target genes of ANRIL and to explore molecular mechanisms by which ANRIL might contribute to the risk development of CAD.
2019-01-16 | GSE117676 | GEO
Project description:The antisense non-coding RNA in the INK locus (ANRIL), which originates from the CDKN2A/B (INK4-ARF) locus, has been identified as a hotspot for genetic variants associated with cardiometabolic disease including coronary artery disease (CAD) and Type 2 diabetes (T2D). We recently found that ANRIL abundance in human pancreatic islets was increased in donors carrying certain T2D risk-SNPs, and that a T2D risk-SNP located within exon2 of ANRIL conferred reduced beta cell proliferation index, pointing to a role for ANRIL in the regulation of T2D pathogenicity via an impact on insulin secretory capacity. Recent studies in other cell types have found that the balance between linear and circular species of ANRIL is linked to the regulation of cardiovascular disease phenotypes. Less is known about circular ANRIL expression in diabetes-relevant cell types and how their abundance might influence the risk of T2D. Herein, we use high-throughput and divergent primer sequencing of circular RNA in human pancreatic islet cells to quantify and characterize circular isoforms of ANRIL. We identified several circular ANRIL isoforms that are more abundant than linear ANRIL and whose expression was correlated across dozens of individuals. Back-splicing did not occur with equal probability at all ANRIL splice sites. Rather, some specific splice sites were found to have a higher propensity to be involved in back-splicing and are weakly enriched for sequence features known to promote back-splicing. Finally, we found that islets from carriers of the T2D risk allele at rs564398 in exon 2 of ANRIL had a higher ratio of circular ANRIL relative to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL ratio was associated with a decreased beta cell proliferation index. Together, our study points to the combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies to understand the molecular mechanisms by which ANRIL impacts cellular function in human pancreatic islets.
2022-05-11 | GSE192541 | GEO
Project description:Herein, by detecting the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified the key role of hyper-m6A modification of the master G0/G1 regulator Fizzy and Cell Division Cycle 20 Related 1 (FZR1) in regulating gemcitabine sensitivity. Targeting m6A modification of FZR1 improves the gemcitabine treatment response of gemcitabine-insensitive PDAC cells in vitro and in vivo. Mechanistically, Gem Nuclear Organelle Associated Protein 5 (GEMIN5) was identified as a novel m6A mediator that specifically binds to m6A-modified FZR1 and recruits the eIF3 translation initiation complex to accelerate FZR1 translation. Upregulation of FZR1 maintains the G0/G1 quiescent state and impairs gemcitabine sensitivity of PDAC cells. Further clinical analysis showed that both high levels of FZR1 m6A modification and FZR1 protein indicated a poor response to gemcitabine.
2023-06-09 | GSE206968 | GEO
Project description:Long non-coding RNAs（LncRNAs）have important cellular functions and some have roles in different mechanisms of gene regulation. LncRNA-antisense noncoding RNA in the INK4 locus (ANRIL) were found to affect cell inflammation,Nevertheless, the potential genes related to the inflammatory response regulated by ANRIL remain unclear. In this study, we investigated the potential function of ANRIL in regulating expression and alternative splicing. ANRIL-regulated human umbilical vein endothelial (HUVEC) cell transcriptome achieved by high-throughput RNA sequencing(RNA-seq) was obtained to investigate the potential role of ANRIL. Lipofectamine 2000 was used for plasmid transfection. The gene expression profile and alternative splicing pattern of HUVEC overexpressed by ANRIL were analyzed by RNA-seq and compared with the control group. ANRIL overexpression (ANRIL-OE) widely affects the transcription levels of genes related to inflammatory response, NF-κB pathway, type I interferon-mediated signal transduction pathway, and innate immune response. ANRIL extensively regulates the alternative splicing of hundreds of genes through functions such as gene expression, translation, DNA repair, RNA processing, and NF-κB pathway. Many of these genes have an indispensable role in the inflammatory response. ANRIL regulated inflammatory response may be achieved by regulating alternating splicing and potential transcription, which broadens the understanding of ANRIL-mediated gene regulation mechanisms and clarifies the role of ANRIL in mediating inflammatory response mechanisms.
2023-01-11 | GSE197115 | GEO