المؤلفون: Binder, Zev A., Siu, I-Mei, Eberhart, Charles G., ap Rhys, Colette, Bai, Ren-Yuan, Staedtke, Verena, Zhang, Hao, Smoll, Nicolas R., Piantadosi, Steven, Piccirillo, Sara G., DiMeco, Francesco, Weingart, Jon D., Vescovi, Angelo, Olivi, Alessandro, Riggins, Gregory J., Gallia, Gary L.

المصدر: PLoS ONE; Oct2013, Vol. 8 Issue 10, p1-15, 15p

مصطلحات موضوعية: GLIOBLASTOMA multiforme, SIALOGLYCOPROTEINS, GENE expression, CANCER stem cells, BRAIN tumors, BIOINFORMATICS, HEALTH outcome assessment

مستخلص: Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor and is associated with poor survival. Recently, stem-like cell populations have been identified in numerous malignancies including GBM. To identify genes whose expression is changed with differentiation, we compared transcript profiles from a GBM oncosphere line before and after differentiation. Bioinformatic analysis of the gene expression profiles identified podocalyxin-like protein (PODXL), a protein highly expressed in human embryonic stem cells, as a potential marker of undifferentiated GBM stem-like cells. The loss of PODXL expression upon differentiation of GBM stem-like cell lines was confirmed by quantitative real-time PCR and flow cytometry. Analytical flow cytometry of numerous GBM oncosphere lines demonstrated PODXL expression in all lines examined. Knockdown studies and flow cytometric cell sorting experiments demonstrated that PODXL is involved in GBM stem-like cell proliferation and oncosphere formation. Compared to PODXL-negative cells, PODXL-positive cells had increased expression of the progenitor/stem cell markers Musashi1, SOX2, and BMI1. Finally, PODXL expression directly correlated with increasing glioma grade and was a marker for poor outcome in patients with GBM. In summary, we have demonstrated that PODXL is expressed in GBM stem-like cells and is involved in cell proliferation and oncosphere formation. Moreover, high PODXL expression correlates with increasing glioma grade and decreased overall survival in patients with GBM. [ABSTRACT FROM AUTHOR]

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المؤلفون: Ren-Yuan Bai¹ rbai1@jhmi.edu, Staedtke, Verena¹, Lidov, Hart G.², Eberhart, Charles G.³, Riggins, Gregory J.¹ griggin1@jhmi.edu

المصدر: Cancer Research. Nov2012, Vol. 72 Issue 22, p5988-6001. 14p.

مصطلحات موضوعية: *MEDULLOBLASTOMA, *CEREBELLAR tumors, *GENE expression, *RNA, *CANCER cells

مستخلص: The brain development transcription factor OTX2 is overexpressed and/or genomically amplified in most medulloblastomas, but the mechanistic basis for its contributions in this setting are not understood. In this study, we identified OTX2 as a transcriptional repressor and a gatekeeper of myogenic and neuronal differentiation in medulloblastoma cells. OTX2 binds to the MyoD1 core enhancer through its homeobox domain, and the remarkable repressor activity exhibited by the homeobox domain renders OTX2 transcriptionally repressive. RNA interference--mediated attenuation of OTX2 expression triggered myogenic and neuronal differentiation in vitro and prolonged the survival in an orthotopic medulloblastoma mouse model. Conversely, inducing myogenic conversion of medulloblastoma cells led to the loss of OTX2 expression. In medullomyoblastoma, a medulloblastoma subtype containing muscle elements, myogenic cells share cytogenetic signatures with the primitive tumor cells and OTX2 expression was lost in the differentiated myogenic cells. Thus, OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. Together, our findings illustrate the origin of muscle cells in medullomyoblastomas and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential. [ABSTRACT FROM AUTHOR]