Epigenetic silencing of JAM3 promoted progression in serous ovarian carcinoma through PI3K/AKT pathway
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PROVIDER: PRJNA1266070 | ENA |
REPOSITORIES: ENA
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Project description:Junctional adhesion molecule 3 (JAM3) is frequently epigenetically silenced in cancers, but its functional role and regulatory mechanisms in serous ovarian carcinoma (SOC) remained poorly defined. This study integrated RNA sequencing (RNA-seq) with functional assays to delineate JAM3-driven pathways in SOC. RNA-seq analysis of JAM3-overexpressing SOC cells revealed significant downregulation of PI3K/AKT signaling components, a finding validated by Western blot. JAM3 promoter methylation, assessed via bisulfite sequencing and qMSP, was elevated in SOC tissues and inversely correlated with JAM3 expression. Functional studies demonstrated that JAM3 overexpression suppressed proliferation, migration, and invasion while inducing apoptosis, whereas JAM3 knockdown exacerbated aggressive phenotypes. Rescue experiments using the AKT inhibitor MK2206 confirmed PI3K/AKT pathway dependency in JAM3-mediated tumor suppression. Clinically, reduced JAM3 expression correlated with advanced tumor stage and poor prognosis. These results establish JAM3 as a tumor suppressor in SOC, acting through epigenetic modulation of PI3K/AKT signaling, and highlight its potential as a therapeutic target.
2025-07-08 | GSE297734 | GEO
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.
2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress
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).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE35701: CP001: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy GSE35703: CP003: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy Refer to individual Series
2012-07-21 | E-GEOD-35705 | biostudies-arrayexpress
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.
2013-05-01 | GSE42762 | GEO
Project description:Background: Investigations regarding the function of ferroptosis in prostate cancer (PCa) progression are still rare. Therefore, this study revealed the function of long noncoding RNA P53RRA (P53RRA)-mediated ferroptosis in PCa. Methods: The levels of P53RRA, TFR1, IREB2, SLC7A11, and GPX4 in DU145 cells were examined by quantitative real-time PCR and Western blot. Besides, cell proliferation was tested by Cell Counting Kit-8; GSH, MDA, and reactive oxygen species (ROS) levels were examined using the corresponding kits, flow cytometry, or fluorescence. Additionally, P53RRA silenced DU145 cells were treated with an AKT inhibitor to confirm the role of the AKT signaling pathway in P53RRA-mediated ferroptosis. Then, transcriptome RNA sequencing (RNA-seq) obtained the mRNA expression profiling. Results: P53RRA was down-expressed in PCa cells compared with normal human prostate epithelial cells. Silencing of P53RRA decreased the levels of TFR1 and IREB2 while promoted the expression of SLC7A11 and GPX4. Knockdown of P53RRA promoted the proliferation ability and GSH level while decreased ROS and MDA levels. Additionally, the bioinformatics analysis showed that P53RRA silencing enriched in phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway causes the aberrantly expressed mRNAs. Besides, P53RRA silencing induced the phosphorylation of AKT. Interestingly, AZD5363 treatment increased TFR1 and IREB2 levels inhibited by P53RRA silence and decreased SLC7A11 and GPX4 levels stimulated by P53RRA silence. Besides, AZD5363 administration partly reversed the silencing of P53RRA-mediated proliferation promotion, increased the level of GSH, and inhibition on MDA/ROS levels. Conclusions: Silencing of P53RRA suppressed ferroptosis by activating the AKT signaling pathway to modulate the development of prostate cancer.
2025-05-30 | GSE268705 | GEO
Project description:Ectopic TAL1 expression is frequently associated with PI3K-AKT pathway mutations in T-ALL. Here we developed inducible mouse models demonstrating cooperation between TAL1 and PI3K-AKT signaling and we used these models to study the effects of targeted inhibitors.
2022-04-02 | GSE199823 | GEO
Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors. Two-subset of B cells, QF vs PF. 8 samples of 4 patients.
2014-05-15 | E-GEOD-53236 | biostudies-arrayexpress
Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors. B cells from Chronic Lymphpcytic Leukaemia patients were isolated from blood. By sorting experiments we purify the QF from PF from progressive patients. We extract the total RNA from 8 samples and perform microRNA arrays.
2014-05-15 | E-GEOD-53235 | biostudies-arrayexpress
Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration 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 the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.
2016-06-13 | E-MTAB-4263 | biostudies-arrayexpress