Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival

Cochet, Olivia; Frelin, Catherine; Peyron, Jean‐François; Imbert, Véronique

doi:10.1016/j.cellsig.2005.05.010

Cited by 48 publications

(46 citation statements)

References 25 publications

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“…Study has suggested that lack of interferon-β induced radiosensitization in four out of five human glioblastoma cell lines, IFN enhances cell survival after radiation. Up-regulation of components of the IFN-related signaling pathway plays a role in tumor radioresistance (27,28). Therefore, we can infer that up-regulated genes IFI44L, IFIH1, IFIT1, IFIT2, IFIT1, STAT1, STAT2, ISG15, OASL might relate with tumor radioresistance by promoting tumor cell survival.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes involved in radioresistance of nasopharyngeal carcinoma by integrating gene ontology and protein-protein interaction networks

Guo

Zhu

et al. 2011

Int J Oncol

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Abstract. Radioresistance remains one of the important factors in relapse and metastasis of nasopharyngeal carcinoma. Thus, it is imperative to identify genes involved in radioresistance and explore the underlying biological processes in the development of radioresistance. In this study, we used cDNA microarrays to select differential genes between radioresistant CNE-2R and parental CNE-2 cell lines. One hundred and eighty-three significantly differentially expressed genes (p<0.05) were identified, of which 138 genes were upregulated and 45 genes were downregulated in CNE-2R. We further employed publicly available bioinformatics related software, such as GOEAST and STRING to examine the relationship among differentially expressed genes. The results show that these genes were involved in type I interferon-mediated signaling pathway biological processes; the nodes tended to have high connectivity with the EGFR pathway, IFN-related pathways, NF-κB. The node STAT1 has high connectivity with other nodes in the protein-protein interaction (PPI) networks. Finally, the reliability of microarray data was validated for selected genes by semi-quantitative RT-PCR and Western blotting. The results were consistent with the microarray data. Our study suggests that microarrays combined with gene ontology and protein interaction networks have great value in the identification of genes of radioresistance in nasopharyngeal carcinoma; genes involved in several biological processes and protein interaction networks may be relevant to NPC radioresistance; in particular, the verified genes CCL5, STAT1-α, STAT2 and GSTP1 may become potential biomarkers for predicting NPC response to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification of genes involved in radioresistance of nasopharyngeal carcinoma by integrating gene ontology and protein-protein interaction networks

Guo

Zhu

et al. 2011

Int J Oncol

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“…Nevertheless, JAK2 overexpression was described in primary mediastinal large B-cell lymphoma and might explain the constitutive STAT6 activation (Guiter et al, 2004). Moreover, amplification of the JAK2 gene was observed in Hodgkin's lymphoma (Joos et al, 2000(Joos et al, , 2003, were STAT3 and STAT5 are often phosphorylated (Kube et al, 2001;Cochet et al, 2006), and in some cases of acute myeloid leukemia (Rucker et al, 2006). Overexpression of JAKs is not sufficient to fully transform BaF3 cells, but a significant number of JAKoverexpressing cells can progress toward this stage, which can never be reached spontaneously by parental cells.…”

Section: Activated Signaling Pathways In Autonomous Clonesmentioning

confidence: 99%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokineindependent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.

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“…[28][29][30] These include STAT1 and c-MET; both are known transcriptional targets of LMP1. [31][32][33] We confirmed the changes in the expression of several Bmi-1-induced genes, including hexokinase 2 (HK2), Bcl-2/adenovirus E1B 19-kDa interacting protein-3 (BNIP3), and prolyl 4-hydroxylase alpha subunit (P4HA1) ( Figure 5); these genes are induced by LMP1.…”

Section: Gene Expression Profiling Reveals Bmi-1-regulated Genes In Hmentioning

confidence: 99%

“…Consistent with a recent study in which human embryonic fibroblasts were depleted of PRC1 and PRC2 proteins, 40 we observed that Bmi-1 down-regulated a large number of differentiation-related genes; several of these were B-cell lineage markers (CD20/MS4A1, BLK, LY9) previously shown to be down-regulated in HRS cells. 41 Thus, Bmi-1 may contribute to the loss of B-cell identity, which is characteristic of HL.Bmi-1 up-regulated a number of genes, including STAT1 and c-MET, which are overexpressed in HL [28][29][30] and which are also known transcriptional targets of LMP1. [31][32][33] MET is the receptor tyrosine kinase for hepatocyte growth factor that induces ERK and PI3K activation and contributes to oncogenesis in other lymphomas.…”

mentioning

confidence: 99%

Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells

Dutton

Woodman

Chukwuma

et al. 2006

Blood

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IntroductionClassical Hodgkin lymphoma (HL) is derived from germinal center (GC) B cells and is characterized by malignant Hodgkin/ReedSternberg (HRS) cells in a background of nonmalignant "reactive" cells. 1 The Epstein-Barr virus (EBV) is present in HRS cells in approximately half of all patients with HL, in whom it expresses a restricted set of virus-latent genes; these include the major EBV oncogene latent membrane protein-1 (LMP1). 2 By mimicking a constitutively active CD40 receptor, LMP1 activates signaling pathways, such as NF-B, which enhance B-cell survival and are essential for EBV-induced transformation. 3,4 Polycomb group (PcG) genes are necessary for the maintenance and renewal of embryonic and adult stem cells, embryogenesis, and cell cycle regulation. 5,6 Two polycomb repressive complexes, PRC1 and PRC2, are required for the initiation and maintenance of gene silencing, respectively. 7-9 Bmi-1/PCGF4 (B lymphoma Mo-MLVinsertion region/ polycomb group ring finger 4) is a component of PRC1. 10,11 Bmi-1 induces lymphoid proliferation and the development of lymphomas in transgenic mice. 12-15 Bmi-1 is highly expressed in high-grade large B-cell lymphomas, mantle cell lymphoma, and nonlymphoid malignancies, such as colorectal cancer and non-small cell lung cancer. [16][17][18] Although Bmi-1 is highly expressed in HRS cells, 19-21 its regulation and contribution to the pathogenesis of HL are unknown. We show here that Bmi-1 is a transcriptional target of LMP1, that the expression of Bmi-1 promotes the survival of HL cells, and that Bmi-1 induces transcriptional changes in HL cells that include the down-regulation of the ataxia telangiectasia mutated (ATM) gene. Materials and methodsThe work undertaken in the study received ethical approval from the South Birmingham Research Ethics Committee (LREC no.0844). Cell lines and tissue samplesEBV-negative cell lines from mixed cellularity (MC) HL (KM-H2) and nodular sclerosis (NS) HL (L428) 22 were maintained in RPMI 1640 supplemented with 10% fetal calf serum, 2 mM L-glutamine, and 1% penicillin-streptomycin solution (Sigma-Aldrich, Poole, United Kingdom). An EBV-positive cell line from a patient with NS HL (L591) and an EBV-negative clone of this line (L591-SD3) were grown in the same way. 23 Paraffin-embedded HL biopsies were obtained from Queen Elizabeth Hospital, (Birmingham, United Kingdom), and their EBV status was determined by immunohistochemical staining for LMP1. 24 Transient transfection of HL linesTransfection of HL-derived cell lines was performed using the nucleofector unit supplied by Amaxa GmbH and described by Schakowski et al. 25 In brief, 2 ϫ 10 6 KM-H2 cells and 4 ϫ 10 6 other HL cell lines were pelleted at 1500g for 9 minutes. After resuspension in 100 L freshly prepared nucleofector solution kit T (catalog no. VCA-1002; Amaxa, Cologne, Germany), 2 g plasmid DNA was added to KM-H2 and 4 g was added to the other HL cells. Subsequently, KM-H2 cells were pulsed using program T-01, and the other HL cells were pulsed using program U-09; cells ...

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Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival

Cited by 48 publications

References 25 publications

Identification of genes involved in radioresistance of nasopharyngeal carcinoma by integrating gene ontology and protein-protein interaction networks

Identification of genes involved in radioresistance of nasopharyngeal carcinoma by integrating gene ontology and protein-protein interaction networks

JAK kinases overexpression promotes in vitro cell transformation

Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells

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