Novel Glioblastoma Markers with Diagnostic and Prognostic Value Identified through Transcriptome Analysis

Reddy, Sreekanth P; Britto, Ramona; Vinnakota, Katyayni; Hebbar, Aparna; Sreepathi, Hari Kishore; Thota, Balaram; Kumari, Arpana; Shilpa, B.M.; Vrinda, Marigowda; Srikantha, Umesh; Samuel, Cini; Shetty, Mitesh; Tandon, Ashwani; Pandey, Paritosh; Hegde, Shivanand; Hegde, Alangar Sattiyaranjandas; Balasubramaniam, Anandh; Chandramouli, Bangalore A.; Santosh, Vani; Kondaiah, Paturu; Somasundaram, Kumaravel; M, Rao

doi:10.1158/1078-0432.ccr-07-4821

Cited by 133 publications

(130 citation statements)

References 32 publications

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“…11,20,21 Copy number variation studies using genome-wide array-CGH profiles have identified many regions of amplification and deletions harboring many genes found to be important in glioma development. [22][23][24] However, these findings and related signatures are yet to be translated to utility in clinical settings suggesting that these studies require further characterization and validation.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma

2010

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Malignant astrocytoma includes anaplastic astrocytoma (grade III) and glioblastoma (grade IV). Among them, glioblastoma is the most common primary brain tumor with dismal responses to all therapeutic modalities. We performed a large-scale, genome-wide microRNA (miRNA) (n ¼ 756) expression profiling of 26 glioblastoma, 13 anaplastic astrocytoma and 7 normal brain samples with an aim to find deregulated miRNA in malignant astrocytoma. We identified several differentially regulated miRNAs between these groups, which could differentiate glioma grades and normal brain as recognized by PCA. More importantly, we identified a most discriminatory 23-miRNA expression signature, by using PAM, which precisely distinguished glioblastoma from anaplastic astrocytoma with an accuracy of 95%. The differential expression pattern of nine miRNAs was further validated by real-time RT-PCR on an independent set of malignant astrocytomas (n ¼ 72) and normal samples (n ¼ 7). Inhibition of two glioblastoma-upregulated miRNAs (miR-21 and miR-23a) and exogenous overexpression of two glioblastoma-downregulated miRNAs (miR-218 and miR-219-5p) resulted in reduced soft agar colony formation but showed varying effects on cell proliferation and chemosensitivity. Thus we have identified the miRNA expression signature for malignant astrocytoma, in particular glioblastoma, and showed the miRNA involvement and their importance in astrocytoma development.

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Section: Discussionmentioning

confidence: 99%

Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma

2010

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“…Fstl1 itself was identified as a TGF-β inducible gene [133] and has been implicated in inflammation and cardioprotection [134][135][136] . It has been suggested to act as a potential tumor suppressor in epithelial cancers [137][138][139][140] but is over-expressed in astrocytic brain tumors [141] . Considering hepatoma cells, we recently demonstrated that the expression of fstl1 is low in HepG2 cells, which show an epithelial morphology/proteome pattern and high in Hep3B cells with fibroblastoid characteristics.…”

Section: Follistatin-like Proteinsmentioning

confidence: 99%

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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“…Genetic heterogeneity in GBM has been proposed to explain the limitations in the effectiveness of current therapies, which necessitates the need for prognostic gene signature (2). Many genetic and epigenetic alterations as well as expression of some genes have been correlated with poor or better prognosis (3)(4)(5)(6)(7). In addition, molecular biomarkers like methyl guanine methyl transferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH1) mutation status, and Glioma-CpG Island Methylator Phenotype (G-CIMP) have been identified as GBM prognostic indicators (1,8,9).…”

Section: Introductionmentioning

confidence: 99%

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

et al. 2013

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Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n ¼ 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-kB pathway association with high-risk group. NF-kB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-kB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-kB activity by inhibiting AKT through a p53-PTENdependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-kB-activated highrisk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-kB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target. Cancer Res; 73(22); 6563-73. Ó2013 AACR.

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Novel Glioblastoma Markers with Diagnostic and Prognostic Value Identified through Transcriptome Analysis

Cited by 133 publications

References 32 publications

Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma

Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma

Activins and follistatins: Emerging roles in liver physiology and cancer

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

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