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Survivin deficient Hepatocellular carcinoma and non-cancerous tissue of mice

ABSTRACT: Hepatocellular carcinoma (HCC) is a deadly cancer lacking efficacious therapies. Latest studies show that cellular senescence and inflammation play key roles in HCC development, likely reflecting its etiological nature of chronic infection. A better understanding of these intertwined processes would facilitate development of therapies for malignant HCCs. Here, we show that malignant HCCs are drastically reduced after deletion of Survivin, an inhibitor of apoptosis protein. Survivin deficiency induces mitosis defect-caused metabolism reprogram and senescence in HCC cells. Survivin additionally protects both senescent and neighboring non-senescent cancer cells from cell death triggered by senescence-associated inflammatory factor TNFα. Importantly, combination of mitosis inhibitor and pro-apoptosis drug, but not alone, synergistically eliminates HCCs, recapitulating the therapeutic effect of genetic deletion of Survivin. By uncovering the role of Survivin in controlling the interaction of senescence and inflammation responses, our findings propose a strategy for HCC therapy by inducing senescence and boosting TNFα-mediated cell death.

ORGANISM(S): Mus musculus

PROVIDER: GSE64804 | GEO | 2016/06/22

SECONDARY ACCESSION(S): PRJNA271907

REPOSITORIES: GEO

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Survivin deficient liver of mice after partial hepatectomy

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

Survivin ChIPseq

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A Metabolic Switch Controlling Liver Cancer Evolution from Senescent NASH Hepatocytes

Project description:Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis.

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TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a

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

TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a

2010-08-28 | GSE23842 | GEO

Apoptosis gene signature of Survivin and its splice variant expression in breast carcinoma

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.

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Apoptosis gene signature of Survivin and its splice variant expression in breast carcinoma

2010-10-06 | E-GEOD-24556 | biostudies-arrayexpress

Human HEK 293T cells transfected with pEGFP-survivin gene

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

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

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

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