Upregulation of MTHFD2 is associated with PD-L1 activation in bladder cancer via the PI3K/AKT pathway
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ABSTRACT:
PROVIDER: PRJNA900546 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22262271_1.fastq.gz | Fastqsanger.gz | |||
| SRR22262271_2.fastq.gz | Fastqsanger.gz | |||
| SRR22262272_1.fastq.gz | Fastqsanger.gz | |||
| SRR22262272_2.fastq.gz | Fastqsanger.gz | |||
| SRR22262273_1.fastq.gz | Fastqsanger.gz |
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Project description:Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors, although its exact role in bladder cancer (BC) remains to be explored. The present study determined the upregulation of MTHFD2 in BC tissues using expression data from The Cancer Genome Atlas (TCGA), a commercial BC tissue microarray (TMA) and patients’ tissues collected by surgery. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death-ligand 1 (PD-L1) expression. Next, using small interfering RNA, the expression of MTHFD2 in BC cell lines was knocked down, and the results revealed that the tumor cell proliferation and colony-formation abilities were greatly reduced, as well as the expression of PD-L1. In a xenograft nude mouse model, these findings were confirmed. Simultaneously, it was found that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA-sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression of PI3K and AKT. The activation of PI3K and AKT was enhanced after stimulation with 740Y-P, a PI3K activator, and their cellular activities and PD-L1 expression levels were restored. Finally, it was found that the MTHFD2 levels were positively correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K-AKT-targeted drugs by analyzing the Genomics of Drug Sensitivity in Cancer (GDSC) database. Overall, the present findings revealed that elevation of MTHFD2 was associated with PD-L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.
2022-11-17 | GSE217785 | GEO
Project description:Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors; however, its exact role in bladder cancer (BC) remains to be explored. Through reverse transcription‑quantitative PCR, western blotting and immunohistochemistry detection of BC tissue, combined with The Cancer Genome Atlas (TCGA) database analysis, the present study demonstrated that MTHFD2 was upregulated in BC tissues. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death‑ligand 1 (PD‑L1) expression. Subsequently, using short hairpin RNA, the expression levels of MTHFD2 were knocked down in BC cell lines, and the results revealed that the tumor cell proliferation and colony formation abilities of cells were greatly reduced, as determined by Cell Counting Kit 8 and colony formation assays, as was the expression of PD‑L1, as determined by western blotting. These findings were also confirmed in a xenograft nude mouse model. Simultaneously, it was revealed that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA‑sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression levels of PI3K and AKT by western blotting. The activation of PI3K and AKT was enhanced in BC cells (T24) following stimulation with 740Y‑P, a PI3K activator, and cellular activities and PD‑L1 expression levels were restored. Finally, it was demonstrated that the MTHFD2 levels were correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K/AKT‑targeted drugs, as determined by analyzing the Genomics of Drug Sensitivity in Cancer database. Overall, the present findings revealed that upregulation of MTHFD2 was associated with PD‑L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.
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Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
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Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
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Project description:Microtubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro- inflammatory state via integrin activation, causing them to release unknown neurotoxic factors. Here we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors. These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated astrogliosis and a target for anti-inflammation-based Alzheimer’s therapy.
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Project description:Microtubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro- inflammatory state via integrin activation, causing them to release unknown neurotoxic factors. Here we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors. These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated astrogliosis and a target for anti-inflammation-based Alzheimer’s therapy.
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Project description:The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1(SPP1), a potential downstream target gene of NOTCH3，by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA.
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