Effect of RTVP-1 on the mesenchymal transformation of glioma stem cells (GSCs) and their self-renewal and migration.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2073-2073
Author(s):  
Chaya Brodie ◽  
Nissim Giladi ◽  
Amotz Ziv-Av ◽  
Hae Kyung Lee ◽  
Susan Finniss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Array ◽  
Tumor Grade ◽  
Small Population ◽  
Array Analysis ◽  
Self Renewal ◽  
Human Neural Stem Cells ◽  
Gene Array Analysis ◽  
And Migration ◽  
Mesenchymal Transformation

2073 Background: Glioblastoma (GBM), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. GBM are categorized into proneural, neural, classical and mesenchymal subgroups, the latter being characterized by increased invasion and poor prognosis. We recently reported that RTVP-1 is highly expressed in GBM and its expression is correlated with astrocytic tumor grade. Methods: We employed promoter and Chip analyses, analysis of tumor specimens submitted to TCGA , GSC self-renewal and migration assays, mesenchymal and neural differentiation, gene array analysis and pull-down assay followed by FRET. Results: The RTVP-1 promoter binds STAT3 and C/EBPb, the transcription factors that regulate mesenchymal transformation of GBM. The expression of RTVP-1 is higher in mesenchymal GBM and is inversely correlated with patient survival in the proneural group. We examined the expression and functions of RTVP-1 in GSCs, a small population of cancer stem cells that are implicated in the increased migration, radio- and chemo-resistance of GSCs and tumor recurrence. RTVP-1 was expressed in the different GSCs but not in the normal human neural stem cells (NSCs). Overexpression of RTVP-1 in NSCs induced their mesenchymal transformation, whereas silencing of RTVP-1 in GSCs decreased their mesenchymal and increased their neural phenotypes. Moreover, RTVP-1 promoted the self-renewal and migration of GSCs. Using gene array analysis of RTVP-1 silenced cells we identified IL-6 and CXCR4 as major mediators of RTVP-1 effects on the mesenchymal transformation and self-renewal of GSCs. In addition, using a pull down assay with His-tagged RTVP-1 we identified N-WASP and hnRNPK as novel interacting proteins of RTVP-1 that mediate its effects on glioma cell migration. Conclusions: RTVP-1 expression is associated with mesenchymal transformation of GSCs. RTVP-1 promotes self-renewal and migration of GSCs and these effects are mediated by the increased expression of IL-6 and CXCR4 and via interaction with N-WASP and hnRNPK. Collectively, these results suggest that RTVP-1 may represent a novel diagnostic marker and a therapeutic target in GBM.

scholarly journals BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets

2021 ◽  
Vol 22 (8) ◽  
pp. 3913
Author(s):  
Satoshi Nakata ◽  
Ming Yuan ◽  
Jeffrey A. Rubens ◽  
Ulf D. Kahlert ◽  
Jarek Maciaczyk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Tandem Duplication ◽  
Target Genes ◽  
Cellular Growth ◽  
Central Nervous System Tumor ◽  
Internal Tandem Duplication ◽  
Invasion And Migration ◽  
Human Neural Stem Cells ◽  
And Migration

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

The Balance Between Self-Renewal and Differentiation of Human Neural Stem Cells Requires the Amyloid Precursor Protein

2021 ◽  
Author(s):  
Khadijeh Shabani ◽  
Julien Pigeon ◽  
Marwan Benaissa Touil Zariouh ◽  
Tengyuan Liu ◽  
Azadeh Saffarian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Self Renewal ◽  
Human Neural Stem Cells

scholarly journals DICER1 and PRKRA in Colon Adenocarcinoma

2008 ◽  
Vol 3 ◽  
pp. BMI.S600 ◽  
Author(s):  
S. Chiosea ◽  
M. Acquafondata ◽  
J. Luo ◽  
SF. Kuan ◽  
RR. Seethala
Keyword(s):  
Rna Interference ◽  
Gene Array ◽  
Colon Adenocarcinoma ◽  
Clinicopathologic Features ◽  
Array Analysis ◽  
Gene Array Analysis ◽  
Microrna Profile ◽  
The Status ◽  
And Function ◽  
Dicer1 Expression

Differential microRNA expression in colon adenocarcinoma (CA) was previously reported. MicroRNA biogenesis and function requires a set of proteins designated as the microRNA machinery, which includes DICER1 and PRKRA. Loss of heterozygosity at 14q32.13 DICER1 locus was detected in up to 60% of CA cases. The in silico gene array analysis of CA showed down-regulation of DICER1 and an up-regulation of PRKRA. Immunohistochemically, DICER1 expression was abnormal in 65% of CA (95 of 147 cases). PRKRA was deregulated in 70% of CA (32 of 46 cases). Expression of DICER1 and PRKRA was correlated with clinicopathologic features of CA. DICER1 up-regulation was seen more commonly in women. Only 10 of 46 cases immunostained for both DICER1 and PRKRA showed normal levels of both DICER1 and PRKRA. Microsatellite status of 32 cases was determined. Microsatellite instable cases showed DICER1 up-regulation more commonly when compared to microsatellite stable cases; however, this trend was not statistically significant. Abnormal DICER1 and/or PRKRA expression might explain the observed changes in microRNA profile. The status of the endogenous DICER1 and PRKRA in CA may help to predict the response to future RNA interference-based therapy.

Stability of gene expression in postmortem brain revealed by cDNA gene array analysis

2002 ◽  
Vol 942 (1-2) ◽  
pp. 120-123 ◽  
Author(s):  
Stacey A. Trotter ◽  
Louis B. Brill II ◽  
James P. Bennett
Keyword(s):  
Gene Expression ◽  
Gene Array ◽  
Postmortem Brain ◽  
Array Analysis ◽  
Gene Array Analysis

Gene array analysis of the expression profile associated with intestinal cell differentiation

2001 ◽  
Vol 120 (5) ◽  
pp. A88
Author(s):  
Qingding Wang ◽  
Robert Thomas ◽  
Nan Li ◽  
Xiaofu Wang ◽  
B. Mark Evers
Keyword(s):  
Cell Differentiation ◽  
Expression Profile ◽  
Gene Array ◽  
Intestinal Cell ◽  
Array Analysis ◽  
Gene Array Analysis

ABCG2 Is Expressed in a Small Population of Circulating CLL B-Cells Characterized by Expression of Self-Renewal and Early B-Cell Development Genes and Resistance to Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3156-3156 ◽  
Author(s):  
Grzegorz S. Nowakowski ◽  
Xiaosheng Wu ◽  
Jennifer L. Abrahamzon ◽  
Renee Tschumper ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
B Cells ◽  
B Cell ◽  
Residual Disease ◽  
Cell Development ◽  
Small Population ◽  
B Cell Development ◽  
Self Renewal ◽  
Resistance To Therapy

Abstract Background: Normal and tumor stem cells are characterized by high activity of multidrug resistance (MDR) transporters. One of these, ABCG2 (ATP-binding cassette, sub-family G member 2 protein), is an ATP dependent transporter and putative stem cell marker responsible for verapamil sensitive Hoechst efflux. While ABCG2 is known to be expressed in normal and leukemic stem cells, as well as a small population of normal lymphocytes and some B-cell malignancies, its expression in chronic lymphocytic leukemia (CLL) is unknown. It has been postulated that leukemic stem cells due to their quiescent nature and expression of MDR transporters represent a population resistant to therapy and that this residual population is critical for tumor persistence and recurrence. Hypothesis: We hypothesized that ABCG2 is expressed in a small percentage of primary CLL B cells; gene expression profiles of ABCG2 positive versus ABCG2 negative CLL B cells differ in respect to expression of self renewal and lymphoid development genes; the frequency of ABCG2+ CLL B cells increases after treatment in patients responding to therapy. Methods: We analyzed ABCG2 expression by primary CD5+, CD19+ CLL-B cells from untreated CLL patients of all Rai stages by flow cytometry. In a subset of patients we used fluorescence activated cell sorting (FACS) to sort CD19+, CD5+ ABCG2+ and CD19+, CD5+ ABCG2- cells. Gene expression profiling was then performed using the U133 plus 2.0 Affymetrix microarray platform. In a separate cohort of patients treated in a clinical trial of pentostatin, cyclophosphamide and rituximab (PCR), the percentage of ABCG2+, CD19+, CD5+, CD79b dim cells at baseline and then two months after completion of 6 cycles of PCR therapy where patients had minimal residual disease (MRD) was assessed and correlated with clinical response. Results: ABCG2+ CD19+, CD5+ detectable populations were seen in all 20 CLL assessed patients (median percentage 0.6%; range 0.08%–3.8%). There was no difference in percentage of ABCG2+ cells based on Rai stage, IGVH mutational status, Zap70 or CD38 expression. Preliminary analysis of the gene expression profiling of ABCG2 positive versus negative CLL B cells from four randomly selected patients revealed significantly higher expression of genes associated with self-renewal, cell cycle and early B-cell development including: cyclin-dependent kinase inhibitor 1C (CDKN1C, p=0.034), transcription factor 7-like 2 (TCF7L2, involved in WNT pathway regulation, p=0.016), beta-catenin (p=0.034) and pre-B-cell colony enhancing factor 1 (PBEF-1, p=0.037). Flow based assessment of the levels of ABCG2 positive populations at baseline and after therapy with PCR in patients with minimal residual disease showed a dramatic increase in frequency of ABCG2 positive CLL B cells. The percentage of ABCG2+ cells went from a median level of 0.19% (range 0.04%–0.19%) prior to therapy to a median level of 10.93% (range 0.15%–25.12%), p<0.001. In contrast two patients who did not reach MRD (partial responses by NCI-WG criteria) had no significant increase in percentage of ABCG2 positive cells (0.14%; 0.23% and 0.16%; 0.21% prior and after therapy, respectively, p=0.68). Conclusion: Our data indicate that ABCG2 positive CLL B-cells constitute 0.1–3.8% of circulating CLL B-cells in untreated patients. The frequency of ABCG2+ CLL B-cells appears to dramatically increase after therapy in the MRD state; this could be related to their relative resistance to therapy and/or a shift from extravascular compartments post therapy. Since ABCG2 positive CLL B-cells demonstrate expression of early B-cell development and self-renewal genes we believe that that this population could represent a putative self renewing CLL B-cell compartment. Further studies to characterize features of ABCG2 CLL-B –cells in relation to their capacity to be self renewing and resistance to therapy are warranted.

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