STAT3 Regulation of Glioblastoma Pathogenesis

Department of Pathology, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115, USA.
Current Molecular Medicine (Impact Factor: 3.62). 08/2009; 9(5):580-90. DOI: 10.2174/156652409788488739
Source: PubMed


Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease.

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Available from: Nuria de la Iglesia, Mar 18, 2014
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    • "STAT3 activation coexisted with EGFR (epidermal growth factor receptor) expression in 27.2% of primary high-grade gliomas, and coexpression with EGFR and its constitutively active variant EGFRvIII in glioblastoma cell lines have been detected [24]. STAT3 can play tumor suppressive or oncogenic roles in gliomas depending on the tumor genetic background [6] [7] [8], but its target genes are largely unknown. A recent ChIP-seq study has provided information regarding putative STAT3 targets in sub types of glioblastoma and its cooperation with the TCF4 transcription factor [25]. "
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    ABSTRACT: Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown. Results: We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells. Conclusions: Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.
    Full-text · Article · Aug 2014 · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
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    • "needed moving forward , SHP2 inhibitors might eventually offer an attractive alternative in the treatment of GBM where resistance to other inhibitors arises . Of course , our data support the potential usefulness of STAT3 inhibitors in treating GBM . STAT3 has previously been identified as a key regulator of GBM cell survival ( Lo et al . , 2008 ; de la Iglesia et al . , 2009 ) and at least one clinical trial ( ClinicalTrials . gov NCT01904123 ) is scheduled to begin recruiting patients later this year to test the efficacy of STAT3 inhibition in cancers including GBM ."
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    ABSTRACT: Information from multiple signaling axes is integrated in the determination of cellular phenotypes. Here, we demonstrate this aspect of cellular decision making in glioblastoma multiforme (GBM) cells by investigating the multivariate signaling regulatory functions of the protein tyrosine phosphatase SHP2. Specifically, we demonstrate that SHP2's ability to simultaneously drive ERK and antagonize STAT3 pathway activities produces qualitatively different effects on the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition. While the ERK and STAT3 pathways independently promote proliferation and resistance to EGFR and c-MET co-inhibition, SHP2-driven ERK activity is dominant in driving cellular proliferation, and SHP2's antagonism of STAT3 phosphorylation prevails in promoting GBM cell death in response to EGFR and c-MET co-inhibition. Interestingly, the extent of these SHP2 signaling regulatory functions is diminished in glioblastoma cells expressing sufficiently high levels of the EGFR variant III (EGFRvIII) mutant, which is commonly expressed in GBM. In cells and tumors expressing EGFRvIII, SHP2 also antagonizes EGFRvIII and c-MET phosphorylation and drives expression of HIF-1/2α, adding complexity to the evolving understanding of SHP2's regulatory functions in GBM.
    Full-text · Article · Jun 2014 · Journal of Cell Science
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    • "Malignant gliomas is known as one of the most lethal tumors in humans and currently, the conventional cancer therapies fail to exert positive effects on glioma cells 26. Patients suffering from glioblastomas usually have extremely poor prognosis which may be partly explained by the low efficiency of targeting their inherent apoptosis-resistant phenotype. "
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    ABSTRACT: Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Bufalin is the major component of Chan-Su (a traditional Chinese medicine) extracts from the venom of Bufo gargarizan. In this study, we evaluated the growth inhibitory effect of bufalin on glioma cells and explored the underlying molecular mechanisms. Our results showed that bufalin inhibited the growth of glioma cells significantly. Mechanistic studies demonstrated that bufalin induced apoptosis through mitochondrial apoptotic pathway. In addition, bufalin was also found to induce ER stress-mediated apoptosis, which was supported by the up- regulation of ER stress markers, CHOP and GRP78, and augmented phosphorylation of PERK and eIF2α as well as cleavage of caspase-4. Downregulation of CHOP using siCHOP RNA attenuated bufalin-induced apoptosis, further confirming the role of ER stress response in mediating bufalin-induced apoptosis. Evidence of bufalin-induced autophagy included formation of the acidic vesicular organelles, increase of autophagolysosomes and LC3-II accumulation. Further experiments showed that the mechanism of bufalin-induced autophagy associated with ATP deleption involved an increase in the active form of AMPK, decreased phosphorylation levels of mTOR and its downstream targets 4EBP1 and p70S6K1. Furthermore, TUDC and silencing of eIF2α or CHOP partially blocked bufalin-induced accumulation of LC3-II, which indicated that ER stress preceded bufalin-induced autophagy and PERK/eIF2α/CHOP signaling pathway played a major part in the process. Blockage of autophagy increased expression of ER stress associated proteins and the ratio of apoptosis, indicating that autophagy played a cytoprotective role in bufalin induced ER stress and cell death. In conclusion, bufalin inhibits glioma cell growth and induces interplay between apoptosis and autophagy through endoplasmic reticulum stress. It will provide molecular bases for developing bufalin into a drug candidate for the treatment of maglinant glioma.
    Preview · Article · Feb 2014 · International journal of biological sciences
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