Survivin deficient Hepatocellular carcinoma and non-cancerous tissue of mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64804 | GEO | 2016/06/22
SECONDARY ACCESSION(S): PRJNA271907
REPOSITORIES: GEO
Similar Datasets
Project description:The liver possesses remarkable regenerative capacity in response to injury. Upon partial hepatectomy (PHx), terminally differentiated hepatocytes in the remaining liver enter the cell cycle and restore the liver mass and function within weeks. However, liver regeneration is often impaired in livers with chronic diseases. Survivin, an inhibitor of apoptosis protein (IAP) and member of chromosome passenger complex (CPC), plays versatile roles in cell mitosis and apoptosis. We and others found that the expression of Survivin was highly increased in liver during PHx-induced liver regeneration, which indicated that Survivin played important roles in this process. However, the function of Survivin in liver regeneration remains largely undefined. Here, using mice with genetic deletion of Survivin, we found that during PHx-induced liver regeneration Survivin regulated both hepatocyte G1/S phase transition by inhibiting the expression of p21 and G2/M phase transition by regulating the localization of CPC. Moreover, restoration of Survivin expression in Survivin-deficient hepatocytes inhibited p21 expression and promote both hepatocyte G1/S and G2/M transition during PHx-induced liver regeneration.
2017-01-01 | GSE83598 | GEO
Project description:ChIPseq analysis of survivin chromatin binding in activated CD4+ T cells
2022-11-29 | GSE190354 | GEO
Project description:There is increasing evidence that microRNA and transcription factors interact in an instructive fashion in normal and malignant hematopoiesis. We explored the impact of TEL-AML1 (ETV6-RUNX1), the most common fusion protein in childhood leukemia, on miRNA expression and the leukemic phenotype. Using RNA interference, miRNA expression arrays, and quantitative PCR, we identified miRNA-494 and miRNA-320a to be upregulated upon TEL-AML1 silencing independently of TEL expression. Chromatin immunoprecipitation analysis identified miRNA-494 as a direct miRNA target of the fusion protein TEL-AML1. Using bioinformatic analysis as well as functional luciferase experiments we demonstrate that survivin is a target of the two miRNAs. MiRNA-494 and -320a were introduced to the cells by transfection and survivin expression determined by western blot analysis. These miRNAs blocked survivin expression and resulted in apoptosis in a similar manner as TEL-AML1 silencing by itself; this silencing was also shown to be DICER-dependent. MiRNAs-494 and -320a are expressed at lower levels in TEL-AML1+ leukemias compared to immunophenotype-matched non-TEL-AML1 ALL subtypes, and within TEL-AML1+ leukemias their expression is correlated to survivin levels. In summary our data suggest that TEL-AML1 might exert its anti-apoptotic action at least in part by suppressing miRNA-494 and miRNA-320a, lowering their expression causing enhanced survivin expression. DNAs from REH cells were pulled down using ChIP antibodies to TEL and hybridized to microRNA promoter tiling arrays.
2010-08-28 | E-GEOD-23842 | biostudies-arrayexpress
Project description:Background: Survivin was described as strongly expressed in human cancer. To date, little is known about the association between Survivin splice variants and the other apoptosis-related genes. In this study, we analyzed the apoptosis gene signature of Survivin and its variant expression in breast cancer. Methods: Expression of the 5 transcripts was measured by RT-PCR in 135 breast carcinomas. Human Apoptosis Gene Arrays were used to screen the genes that could be associated with Survivin variants. Cox survival analysis was analyzed according to the breast cancer patient outcome. Results: Significant associations between Survivin transcript and the apoptotic gene array were found. Interestingly, Survivin-3B variant showed major inverse correlations with the pro-apoptotic gene array. Overexpression of Survivin-3B strongly inhibits 5-fluorouracil/epirubicin/Cyclophosphamide induced-apoptosis in breast tumor cell lines. In breast carcinomas, uni- and multivariate analysis showed patients with high level of survivin-3B expression had a shorter overall (p=0.030 and p=0.042, respectively) and disease-free (p=0.024 and p=0.009) survival. Conclusion: Our data indicate Survivin-3B could have an anti-apoptotic activity and its expression level might be used as a prognostic marker in breast carcinoma.
2010-10-06 | GSE24556 | GEO
Project description:Background: Survivin was described as strongly expressed in human cancer. To date, little is known about the association between Survivin splice variants and the other apoptosis-related genes. In this study, we analyzed the apoptosis gene signature of Survivin and its variant expression in breast cancer. Methods: Expression of the 5 transcripts was measured by RT-PCR in 135 breast carcinomas. Human Apoptosis Gene Arrays were used to screen the genes that could be associated with Survivin variants. Cox survival analysis was analyzed according to the breast cancer patient outcome. Results: Significant associations between Survivin transcript and the apoptotic gene array were found. Interestingly, Survivin-3B variant showed major inverse correlations with the pro-apoptotic gene array. Overexpression of Survivin-3B strongly inhibits 5-fluorouracil/epirubicin/Cyclophosphamide induced-apoptosis in breast tumor cell lines. In breast carcinomas, uni- and multivariate analysis showed patients with high level of survivin-3B expression had a shorter overall (p=0.030 and p=0.042, respectively) and disease-free (p=0.024 and p=0.009) survival. Conclusion: Our data indicate Survivin-3B could have an anti-apoptotic activity and its expression level might be used as a prognostic marker in breast carcinoma. The expression of 96 apoptosis genes and was analyzed in 41 breast carcinomas and 1 pool of normal mammary tissues. In parallel, every survivin isoform expression was quantified by real-time quantitative PCR. Data obtained with the macro-array were correlated with survivin isoform levels detected by RT-PCR.
2010-10-06 | E-GEOD-24556 | biostudies-arrayexpress
Project description:Transcriptional profiling of human embryonic kidney 293 cells comparing transfected control pEGFP-C1 (empty vector) with pEGFP (survivin vector). One condition experiment; survivin transfected cell as test sample vs empty vector transfected cell as reference; one dye swap replicate
2014-10-21 | E-GEOD-43817 | biostudies-arrayexpress
Project description:Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation. We used RNA-seq of IMR90 cells with inducible expression of oncogenic RasV12 that were synchronised in mitosis, to characterise the nature of mitotic defects that lead to multinucleation of oncogene-induced senescent cells
2015-08-13 | E-GEOD-70668 | biostudies-arrayexpress
Project description:Cellular senescence is a key cell-fate program that leads to an essentially irreversible proliferative arrest in potentially damaged cells. Cytokine production and signaling play a significant role in senescence. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways and key regulatory genes linking inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show TNFα induces permanent growth arrest and increased senescence markers such as p21, p16, and senescence-associated β-galactosidase (SA-β-gal), accompanied by persistent DNA damage and ROS. By gene expression profiling and pathway analysis, we identify the crucial involvement of inflammatory networks, an interferon signature, and persistent activation of the Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway in TNFα-mediated senescence. TNFα initiates a STAT-dependent autocrine loop leading to sustained inflammation, DNA damage, and expression of interferon response genes to lock cells into senescence. Further, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from TNFα-mediated senescence. Rather, blockade of STAT activation accelerated senescence, suppressed genes that control the cell cycle, and modulated TNFα-induced senescence. Our findings suggest a positive feedback mechanism via a STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.
2017-03-10 | GSE92655 | GEO
Project description:Cellular senescence is a key cell-fate program that leads to an essentially irreversible proliferative arrest in potentially damaged cells. Cytokine production and signaling play a significant role in senescence. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways and key regulatory genes linking inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show TNFα induces permanent growth arrest and increased senescence markers such as p21, p16, and senescence-associated β-galactosidase (SA-β-gal), accompanied by persistent DNA damage and ROS. By gene expression profiling and pathway analysis, we identify the crucial involvement of inflammatory networks, an interferon signature, and persistent activation of the Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway in TNFα-mediated senescence. TNFα initiates a STAT-dependent autocrine loop leading to sustained inflammation, DNA damage, and expression of interferon response genes to lock cells into senescence. Further, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from TNFα-mediated senescence. Rather, blockade of STAT activation accelerated senescence, suppressed genes that control the cell cycle, and modulated TNFα-induced senescence. Our findings suggest a positive feedback mechanism via a STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.
2017-04-24 | GSE98081 | GEO
Project description:Esophageal cancer is one of the most common cancers where TP53 is mutated frequently. Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer, and is one of the most lethal cancers worldwide. ESCC evolves often to lung metastasis, which is associated with a dismal prognosis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC, or cancers in general, remains to be elucidated. To investigate p53R175H mediated molecular mechanisms, we utilized germline Trp53R172H/- mice, and generated esophageal specific Trp53-/- mice and Trp53+/+ mice treated with the 4-NQO esophageal-specific carcinogen (a common exposure in humans) to model ESCC. In the primary Trp53R172H/- tumor cell lines established from these mouse models, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, to understand the molecular basis for mutant p53 driven lung metastasis, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We performed Gene Set Enrichment Analysis (GSEA) and identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H mediated metastasis. As a target gene of YAP, BIRC5 encodes an anti-apoptotic protein, namely survivin. We demonstrate that survivin expression increases in the presence of Trp53R172H but not wild-type Trp53. Furthermore, depletion of survivin decreases Trp53R172H driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce survivin expression. Furthermore, survivin high expression level is associated with increased metastasis in several GI cancer, suggesting that survivin may be a key regulator to metastasis. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.
2020-12-01 | GSE143696 | GEO