Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels
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ABSTRACT:
PROVIDER: PRJNA702489 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13732911_1.fastq.gz | Fastqsanger.gz | |||
| SRR13732911_2.fastq.gz | Fastqsanger.gz | |||
| SRR13732912_1.fastq.gz | Fastqsanger.gz | |||
| SRR13732912_2.fastq.gz | Fastqsanger.gz | |||
| SRR13732913_1.fastq.gz | Fastqsanger.gz |
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Project description:Tumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication. In this study using conditioned medium from the culture of OPNc (exon 4 excluded shorter form of OPN) overexpressing cells, we found that the survival of NSCLC cells treated with cisplatin was increased, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent translocation of nuclear factor of activated T cells c2 (NFATc2). The results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment.
2024-02-17 | GSE166966 | GEO
Project description:BackgroundTumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication, however, the exact role and regulation of the OPN splicing isoforms was not well understood.MethodsIn this study, the effects of conditioned medium from the culture of OPN splicing isoforms overexpressing cells on cell functions were evaluated. The methods of nuclear calcium reporter assays and subcellular distribution of nuclear factor of activated T cells c2 (NFATc2) assays were used to investigate the molecular mechanism underlining the roles of OPN splicing isoforms.ResultsWe found that the survival of NSCLC cells treated with cisplatin was increased by secretory OPNc in the condition medium, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent nuclear translocation of NFATc2.ConclusionsThe results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment.
| S-EPMC8243455 | biostudies-literature
Project description:RNA-seq on NFATC2 knock-down (siRNA) on melanoma cell line A375
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Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.
2021-09-15 | GSE158496 | GEO
Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.
2021-09-15 | GSE158495 | GEO
Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.
2021-09-15 | GSE158498 | GEO
Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.
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