SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine
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ABSTRACT:
ORGANISM(S): Homo sapiens Homo
PROVIDER: GSE197533 | GEO | 2022/05/10
REPOSITORIES: GEO
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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: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:SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine
| PRJNA810846 | 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:SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing in promotion of pancreatic cancer resistance to gemcitabine I
| PRJNA809955 | ENA
Project description:Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.
| S-EPMC6778039 | biostudies-literature
Project description:The N6-methyladenosine (m6A) RNA modification can modify long non-coding RNAs (lncRNAs), thereby affecting the tumorigenesis and progression of tumors. However, the underlying role of m6A-modified lncRNAs in colorectal cancer (CRC) remains largely unknown. Therefore, our aim was to assess the prognostic value of m6A-modified lncRNAs in CRC patients. The gene expression and clinicopathological data of CRC were extracted from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was used to investigate the m6A-modified lncRNAs. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance of molecular subtypes was identified. The least absolute shrinkage and selection operator analysis (LASSO) was applied to establish a risk signature. Finally, a prognostic nomogram with risk score and clinicopathological variables was established. In total, 29 m6A-modified lncRNAs were identified as prognostic lncRNAs. Two molecular clusters were identified and significant differences were found with respect to clinicopathological features and prognosis. Cluster1 is associated with poor overall survival (OS), down-regulation of Programmed cell death ligand-1 (PD-L1) expression, lower immune score, and less immune cell infiltration. Then, an m6A-modified lncRNA signature for predicting OS was constructed in the TCGA training cohort. The signature demonstrated favorable prediction performance in both training and validation sets. Compared with low-risk patients, patients with high risk showed worse clinical outcomes, lower immune scores, and downregulated PD-L1 expression. Further analysis indicated that the signature was an independent prognostic indicator, and then a prognostic nomogram based on risk score, tumor location, and tumor stage was established. Our study identified a seven m6A-modified lncRNA signature and established a prognostic nomogram that reliably predicts OS in CRC. These findings may improve the understanding of m6A modifications in CRC and provide insights into the prognosis and treatment strategy of CRC.
| S-EPMC8472391 | biostudies-literature
Project description:Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic modification in eukaryotes mRNA, heralded the creation of the field of epi-transcriptomics. This post-transcriptional RNA modification is dynamic and reversible, and is regulated by methylases, demethylases and proteins that preferentially recognize m6A modifications. Altered m6A levels affect RNA processing, degradation and translation, thereby disrupting gene expression and key cellular processes, ultimately resulting in tumor initiation and progression. Furthermore, inhibitors and regulators of m6A-related factors have been explored as therapeutic approaches for treating cancer. In the present review, the mechanisms of m6A RNA modification, the clinicopathological relevance of m6A alterations, the type and frequency of alterations and the multiple functions it regulates in different types of cancer are discussed.
| S-EPMC7278081 | biostudies-literature
Project description:Objective:To comprehensively analyze the global N6-methyladenosine (m6A) modification pattern in ameloblastoma. Methods:m6A peaks in ameloblastoma and normal oral tissues were detected by MeRIP-seq. Differentially methylated m6A sites within messenger RNAs (mRNAs), long no-coding RNA (lncRNAs) and circular RNA (circRNAs) were identified, followed by functional enrichment analysis. By comprehensively analyzing MeRIP-seq and RNA-seq data, differentially expressed mRNAs, lncRNAs and circRNAs containing differentially methylated sites were identified. RNA binding proteins (RBPs) were then identified for differentially methylated m6A sites. Results:In total, 3,673 differentially methylated m6A sites within coding genes were detected, of which 16.2% (704/3,673) were significantly upmethylated sites in ameloblastoma compared to normal oral tissues. Furthermore, 4,975 differentially methylated m6A sites within lncRNAs were identified, of which 29.4% (1,465/4,975) were upmethylated sites in ameloblastoma. We also found 364 differentially methylated m6A sites within circRNAs, of which 22.5% (82/364) were upmethylated sites in ameloblastoma. Differentially methylated m6A was most often harbored in the CDS (54.10%), followed by 5'UTR (21.71%). Functional enrichment analysis revealed that m6A modification could be involved in the development of ameloblastoma by organism developmental processes. A total of 158 RBPs within differentially methylated m6A sites were identified, which were significantly involved in mRNA metabolic process, mRNA processing, RNA processing, RNA splicing and RNA transport. Conclusion:Our findings for the first time provide m6A landscape of human ameloblastoma, which expand the understanding of m6A modifications and uncover regulation of lncRNAs and circRNAs through m6A modification in ameloblastoma.
| S-EPMC7592903 | biostudies-literature
Project description:N6 -methyladenosine (m6 A) RNA modification, first discovered in 1974, is the most prevalent, abundant and penetrating messenger RNA (mRNA) modification in eukaryotes. This governs the fate of modified transcripts, regulates RNA metabolism and biological processes, and participates in pathogenesis of numerous human diseases, especially in cancer through the reciprocal regulation of m6 A methyltransferases ("writers") and demethylases ("erasers") and the binding proteins decoding m6 A methylation ("readers"). Accumulating evidence indicates a complicated regulation network of m6 A modification involving multiple m6 A-associated regulatory proteins whose biological functions have been further analysed. This review aimed to summarize the current knowledge on the potential significance and molecular mechanisms of m6 A RNA modification in the initiation and progression of cancer.
| S-EPMC7653258 | biostudies-literature