Expression profile of embryonic stem cell-associated genes Oct4, Sox2 and Nanog in human gliomas

Guo, Yongfeng; Liu, Shangming; Wang, Ping; Zhao, Shidou; Wang, Fuwu; Zhang, Yanmin; Ling, Eng‐Ang; Gao, Jiangang; Hao, Aijun

doi:10.1111/j.1365-2559.2011.03993.x

Cited by 174 publications

(161 citation statements)

References 59 publications

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“…Aided by FACS, we isolated CD146-enriched U87MG cells and demonstrated that these subpopulations show increased EMT and CSC traits. First, we observed that U87MG (++) cells presented higher expression of the stem cell markers Oct4, Sox2, Nanog, and LGR5 (27,31) and exhibited increased levels of both Slug and β-Catenin, overexpression of which have been proven sufficient to repress E-cadherin and drive EMT (8). Further, evaluation of prolonged in vitro exposure to YY146 in U87MG cells indicated that YY146 treatment reduces both mRNA and proteins levels of CD146 and foments the reversal of CSC and EMT phenotypes through the reactivation of E-cadherin expression and abrogation of migratory properties.…”

Section: Discussionmentioning

confidence: 93%

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Yang

Hernandez

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ2 = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.

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Section: Discussionmentioning

confidence: 93%

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Yang

Hernandez

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…At the top hierarchy of the Jak-Stat3 signaling pathway, OCT4, SOX2 and NANOG, are considered to serve the most important function in maintaining ESC properties (20). Previously, increased glioma progression was identified to be associated with upregulated OCT4, SOX2 and NANOG (21,22). Additionally, combinatorial expression levels of OCT4, NANOG and SOX2 were positively associated with increasing glioma malignancy (22).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

et al. 2017

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Abstract. Spalt-like transcription factor 4 (SALL4) is essential for the maintenance of the self-renewal and pluripotent properties in embryonic stem cells. Although the detailed mechanism remains unclear, dysregulation of SALL4 has been detected in various malignancies. Previously, the authors' of the present study reported that the expression level of SALL4 was associated with the poor prognosis of glioblastoma multiforme (GBM). The present study aimed to investigate the function of SALL4 in U251 human glioblastoma cells, including apoptosis and invasion inhibition. It was revealed that knockdown of SALL4 expression through RNA interference induced cell cycle arrest, enhanced early apoptosis and significantly inhibited invasion. Furthermore, downregulation of SALL4 was associated with a significantly lower expression level of the core transcription factors, including POU class 5 homeobox 1, SRY-box 2 and Nanog homeobox. In addition, inhibition of SALL4 significantly reduced the concentration of chemotherapeutic agent temozolomide required to inhibit cell growth by 50%, which decreased from 113.66±23.07 and 114.93±20.91 µg/ml to 68.34±3.52 and 67.44±4.71 µg/ml in two independent short interfering RNA transfected groups. These results indicate that SALL4 serves an important role in the GBM pathophysiology and targeting SALL4 may be a potential approach to the treatment of GBM. IntroductionGlioma is the most common subgroup type of brain tumor, with an incidence of 5-6/100,000 cases/year in the United States (1). Among all types of glioma, glioblastoma multiforme (GBM) accounts for ~50% of cases and has the most malignant phenotype (2). Despite the extensive developments that have been invested in surgical techniques and therapeutic agents, 88% of patients with GBM succumb to this disease within 3 years (3). GBM remains one of the most challenging malignancies worldwide.Embryonic stem cells (ESCs) are known for their potent pluripotency and are able to differentiate into >220 cell types in the adult body. The human homologue of the drosophila spalt-like transcription factor 4 (SALL4) is a zinc-finger transcription factor, which is responsible for maintaining pluripotency and longevity of ESCs (4-6). Previously, cancer stem cells (CSCs) have been identified in various types of malignancies (7,8) and demonstrate high self-renewal capabilities able to sustain tumor growth (9). Thus far, ESCs and CSCs have been revealed to share numerous biological similarities with the SALL4 expression pattern being one of them. In various types of tumors, high SALL4 expression level has been associated with increased malignancy, including increased metastasis, enhanced proliferation (10-12) and poor differentiation (13,14).In the authors' previous study, it was demonstrated that SALL4 was highly expressed in glioma and significantly associated with poor survival (15). The present study further investigated the biological role of SALL4 in the tumorigenesis of glioma and explored the underlying mechanism of action. It was revealed th...

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“…An embryonic stem cell gene signature is well known to correlate with a more undifferentiated phenotype in various cancers (28), and a large scale tissue microarray analysis including 80 low-grade and 98 high-grade gliomas showed an upregulated protein level of NANOG, KLF-4, OCT-4 and SOX-2 in highgrade gliomas (29). Several other studies also point to the relevance of neural and embryonic stem cell markers in GBM progression (30)(31)(32)(33)(34)(35)(36). In the present study we showed that both neural and embryonic stem cells markers are preferentially co-expressed with CXCR4 in matched samples of primary and recurrent GBM pairs, whereas CXCR7 was mostly found on stem cell marker negative cells.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas

Flüh¹,

Hattermann²,

Mehdorn³

et al. 2016

International Journal of Oncology

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Abstract. The chemokine CXCL12 (also termed SDF-1, stromal cell-derived factor-1) and its receptors CXCR4 and CXCR7 are known to play a pivotal role in tumor progression including glioblastomas (GBM). Previous investigations focused on the expression and functional roles of CXCR4 and CXCR7 in different GBM cell subpopulations, but comparative analysis in matched primary versus recurrent GBM samples are still lacking. Thus, here we investigated the expression of CXCR4 and CXCR7 on mRNA and protein level using matched primary and recurrent GBM pairs. Additionally, as GBM CXCR4-positive stem-like cells are supposed to give rise to recurrence, we compared the expression of both receptors in primary and recurrent GBM cells expressing either neural (MUSASHI-1) or embryonic stem cell markers (KLF-4, OCT-4, SOX-2, NANOG). We were able to show that both CXCR4 and CXCR7 were expressed at considerable mRNA and protein levels. CXCR7 was downregulated in relapse cases, and different groups regarding CXCR4/CXCR7 expression differences between primary and recurrent samples could be distinguished. A co-expression of both receptors was rare. In line with this, CXCR4 was co-expressed with all investigated neural and embryonic stem cell markers in both primary and recurrent tissues, whereas CXCR7 was mostly found on stem cell marker-negative cells, but was co-expressed with KLF-4 on a distinct GBM cell subpopulation. These results point to an individual role of CXCR4 and CXCR7 in stem cell marker-positive GBM cells in glioma progression and underline the opportunity to develop new therapeutic tools for GBM intervention.

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Expression profile of embryonic stem cell-associated genes Oct4, Sox2 and Nanog in human gliomas

Abstract: The present findings suggest that ESC-associated pathways are activated in human gliomas and that these may be involved in glioma progression, a role that is distinct from that in ESCs.

Cited by 174 publications

References 59 publications

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas

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Expression profile of embryonic stem cell-associated genes Oct4, Sox2 and Nanog in human gliomas

Abstract: The present findings suggest that ESC-associated pathways are activated in human gliomas and that these may be involved in glioma progression, a role that is distinct from that in ESCs.

Cited by 174 publications

References 59 publications

Targeting CD146 with a 64 Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Targeting CD146 with a 64 Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Knockdown of SALL4 expression using RNA interference induces cell cycle arrest, enhances early apoptosis, inhibits invasion and increases chemosensitivity to temozolomide in U251 glioma cells

Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas

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Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas