Silencing of STEAP3 suppresses cervical cancer cell proliferation and migration via JAK/STAT3 signaling pathway
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PROVIDER: PRJNA1198873 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the mechanisms of STEAP3 in cervical cancer cell proliferation and migration, we established HeLa cell lines in which STEAP3 gene has been knocked down by shRNA. We then performed gene expression profiling analysis and enrichment analysis using data obtained from RNA-seq of NC and KD cells.
2024-12-31 | GSE284355 | GEO
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
2015-02-01 | GSE63092 | GEO
Project description:We performed RNAseq analysis to dissect the dynamic transcriptome change during mouse iPSC induction, with or without blocking the Jak/Stat3 activity. We described Jak/Stat3 activity-specific global gene expression patterns, biological events, and regulation of key pluripotent genes, epigenetic modulators, and non-coding RNAs during the reprogramming process. We further demonstrated that Jak/Stat3 activity is essential for proper imprint of Dlk1-Dio3 region that is necessary for complete pluripotency establishment. Functional analysis revealed that one Jak/Stat3 downstream targets identified in our study - Esrrb significantly rescues reprogramming despite the inhibition of Jak/Stat3 activity. Our data illustrated novel mechanism in Jak/Stat3 promoted pluripotency establishment, which is valuable for further improvement of naïve-state iPSC generation across different species.
2017-08-18 | GSE97261 | GEO
Project description:NFIC1, the longest isoform of NFIC, is essential for the regulation on spatiotemporal expressions of drug-metabolizing genes in liver. However, the role of NFIC1 in breast cancer is not clear. Here we showed that increased expression of NFIC1 suppressed the migration and invasion of MCF-7 cells. The activation of interferon-associated Jak-STAT pathway was enhanced with NFIC1 overexpression. NFIC1 overexpression upregulated the expression of IFNB1, IFNL1, IFNL2 and IFNL3. Treatment with Jak-STAT pathway inhibitors, Filgotinib or Ruxolitinib, reversed the suppressive effects of NFIC1 overexpression on migration and invasion. In addition, we found that MX1 and MX2 were the target genes of NFIC1- activated Jak-STAT pathway, which mediated the migration and invasion of MCF-7 cells. These results demonstrated that NFIC1 inhibited the migration and invasion in MCF-7 cells through interferon mediated activation of Jak-STAT pathway, indicating that Jak-STAT pathway might be a potential therapeutic target for preventing breast cancer metastasis.
2023-03-01 | GSE197755 | GEO
Project description:RNA sequencing was carried out to identify the signaling pathways and hallmarks that change following MEK and/or JAK/STAT3 pathway inhibition.
2022-07-04 | GSE165960 | GEO
Project description:MicroRNAs (miRNAs or miRs) play essential roles in the initiation and progression of human tumors, including cervical cancer. However, the mechanisms underlying their actions in cervical cancer remain unclear. The present study aimed to evaluate the functional role of miR‑130a‑3p in cervical cancer. Cervical cancer cells were transfected with a miRNA inhibitor (anti‑miR‑130a‑3p) and a negative control. Adhesion‑independent cell proliferation, migration and invasion were evaluated. The findings presented herein demonstrated that miR‑130a‑3p was overexpressed in HeLa, SiHa, CaSki, C‑4I and HCB‑514 cervical cancer cells. The inhibition of miR‑130a‑3p significantly reduced the proliferation, migration and invasion of cervical cancer cells. The canonical delta‑like Notch1 ligand (DLL1) was identified as a possible direct target of miR‑103a‑3p. The DLL1 gene was further found to be significantly downregulated in cervical cancer tissues. On the whole, the present study demonstrates that miR‑130a‑3p contributes to the proliferation, migration and invasion of cervical cancer cells. Therefore, miR‑130a‑3p may be used as a biomarker to determine cervical cancer progression.
2023-03-10 | GSE224301 | GEO
Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.
2017-08-22 | GSE96048 | GEO
Project description:To investigate potential links between Stat3 transcriptional activity and other signaling pathways in breast cancer, we determined the gene expression profiles of three breast cancer cell lines treated with JAK, PTGIS, PFKFB3, CXCR2, HAS1, or NQO1 inhibitor (all of which decreased Stat3 transcriptional activity in Hs 578T cells except for the NQO1 inhibitor), inhibitor treatment vehicle alone (DMSO), STAT3 siRNAs, or non-targeting siRNAs. Using the resulting data, we identified a gene signature that was significantly regulated by STAT3 siRNAs and similarly affected by the JAK and at least 3 other inhibitors (or by 4 other inhibitors) but not by the NQO1 inhibitor in Hs 578T cells that was enriched in genes involved in development and correlated with shorter distant metastasis-free survival in primary lymph-node-negative invasive breast tumors. These results emphasize the central importance of Stat3 in CD44+/CD24- stem-cell-like breast cancer cells. This study includes SAGE-Seq libraries obtained using 27 samples that each underwent individual protocols. There are nine samples of each of three cell lines - Hs 578T, MCF7, and SUM159PT. The samples in each group were treated with either one of the six inhibitors, DMSO only (the background control for inhibitor-treated cells), STAT3 siRNAs, or non-targeting siRNAs (the background control for STAT3 siRNAs).
2011-09-08 | E-GEOD-22917 | biostudies-arrayexpress
Project description:BackgroundIntegrin β6 (ITGB6), a key submonomer of integrin αvβ6, plays an important role in epithelial-to-mesenchymal transition (EMT), wound healing, epithelial-derived tumor growth, fibrosis, and epithelial repair. However, the role of ITGB6 in cervical carcinoma (CC) remains elusive.MethodsThe expression levels of ITGB6 in CC tissues and cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony-forming, flow cytometry, and Transwell assay, respectively. The expression of related proteins, including EMT markers and the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling markers, were detected using western blotting.ResultsThe ITGB6 expression in CC tissues and cells (C-33A, Hela, SiHa, and Caski) was remarkably higher than that in paracarcinoma tissues and ECT1/E6E7 cells. The data from The Cancer Genome Atlas (TCGA) data set suggested that patients with CC with high ITGB6 expression showed poorer overall survival (OS). Compared with the empty transfection group (si-NC), si-ITGB6 restrained the proliferation, migration, and invasion of SiHa and Hela cells, while promoting cell apoptosis. si-ITGB6 suppression decreased the expression of Snail, vimentin, and N-cadherin, while increasing E-cadherin expression. Further research showed that si-ITGB6 reduced p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 expression in the JAK/STAT3 signaling pathway. Interestingly, proliferation, migration, invasion, and the expressions of the molecular markers of the JAK/STAT3 signaling pathway and EMT pathway induced by ITGB6 were altered by RO8191 (JAK/STAT3 pathway activator). Furthermore, the protein expression levels of Snail, vimentin, N-cadherin, p-STAT3/STAT3, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues were higher than those in adjacent normal tissue, while the expression level of E-cadherin was downregulated in tumor tissues.ConclusionsSilencing of ITGB6 restrains cell proliferation, migration and invasion, and promotes apoptosis in CC by inhibiting JAK/STAT signaling pathways. Thus, ITGB6 may perhaps be a new and useful candidate target for treating CC.
| S-EPMC8246156 | biostudies-literature