SOX9 Overexpression Promotes Glioma Metastasis via Wnt/β-Catenin Signaling

Liu, Hongwei; Liu, Zhixiong; Jiang, Bing; Peng, Renjun; Ma, Zhiming; Lu, Jinmiao

doi:10.1007/s12013-015-0647-z

Cited by 55 publications

(46 citation statements)

References 22 publications

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“…While Sox9 superenhancers do not appear to be overrepresented in our QTL and we get mixed results for generic Sox9 ChIP‐seq results (Liu et al, 2015), we have a clear signal for the enrichment of Sox9 Class II ChIP‐seq peaks (Ohba et al, 2015) in our QTL in both the F 34 ‐only analysis and in the combined F 2 /F 34 analysis. The Sox9 Class II features are known to be highly tissue‐specific and involved in regulating chondrocytes through the direct binding of Sox9 complexes to the DNA itself (Pellegrini et al, 2001), thus making the Sox9 Class II regulatory mode a prime candidate mechanism for understanding how individual differences in pelvic form are generated.…”

Section: Discussionmentioning

confidence: 42%

“…Likewise, Sox9 Class II ChIP‐seq peaks, indicative of Sox9 binding in chondrocytes, were also highly enriched relative to chance in both tests. In the results from the F 34 alone, generic Sox9 ChIP‐seq peaks, as identified by Liu et al (2015), were also enriched at the Bonferroni‐corrected level but only at the single test ( p = .05) level in the combined F 2 /F 34 QTL. Conversely the Sox9 Class I ChIP‐seq peaks were not overrepresented in QTL from the F 34 ‐only analysis but were in the combined F 2 /F 34 QTL.…”

Section: Resultsmentioning

confidence: 69%

“…In a second analysis, we tested to see if the QTLs identified were enriched for these features relative to random locations in the genome. We examined potential Pbx1 and Emx2 dimerization motifs (Capellini et al, 2011), chromatin immunoprecipitation (ChIP)‐seq‐identified Pitx1 binding peaks (Infante, Park, Mihala, Kingsley, & Menke, 2013), ChIP‐seq‐identified Sox9‐binding peaks (Generic and Class I and II; Liu et al, 2015; Ohba, He, Hojo, & McMahon, 2015), Sox9 superenhancers (Liu & Lefebvre, 2015; Ohba et al, 2015), H3K27ac marked regulatory elements (of the flank and hind limb expressed at age E11.5; Infante et al, 2013), and DNase I hypersensitivity data from the ENCODE database generated on hind limb and flank tissues (ascertained at age E11.5; ENCODE Project Consortium, 2007).…”

Section: Methodsmentioning

confidence: 99%

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Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features

et al. 2020

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Variation in pelvic morphology has a complex genetic basis and its patterning and specification is governed by conserved developmental pathways. Whether the mechanisms underlying the differentiation and specification of the pelvis also produce the morphological covariation on which natural selection may act, is still an open question in evolutionary developmental biology. We use high‐resolution quantitative trait locus (QTL) mapping in the F34 generation of an advanced intercross experiment (LG,SM‐G34) to characterize the genetic architecture of the mouse pelvis. We test the prediction that genomic features linked to developmental patterning and differentiation of the hind limb and pelvis and the regulation of chondrogenesis are overrepresented in QTL. We find 31 single QTL trait associations at the genome‐ or chromosome‐wise significance level coalescing to 27 pleiotropic loci. We recover further QTL at a more relaxed significance threshold replicating locations found in a previous experiment in an earlier generation of the same population. QTL were more likely than chance to harbor Pitx1 and Sox9 Class II chromatin immunoprecipitation‐seq features active during development of skeletal features. There was weak or no support for the enrichment of seven more categories of developmental features drawn from the literature. Our results suggest that genotypic variation is channeled through a subset of developmental processes involved in the generation of phenotypic variation in the pelvis. This finding indicates that the evolvability of complex traits may be subject to biases not evident from patterns of covariance among morphological features or developmental patterning when either is considered in isolation.

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Section: Discussionmentioning

confidence: 42%

Section: Resultsmentioning

confidence: 69%

Section: Methodsmentioning

confidence: 99%

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Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features

et al. 2020

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“…Recent studies have identified molecular changes affecting the WNT pathway in malignant gliomas (33, 72–74). These and other research suggest that ligand-driven upregulation of WNT is involved in glioma pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Wnt Inhibition Reduces Proliferation, Survival, and Clonogenicity of Glioblastoma Cells

Kahlert¹,

Suwala

Koch

et al. 2015

J Neuropathol Exp Neurol

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Wingless (WNT) signaling has been shown to be an important pathway in gliomagenesis and in the growth of stem-like glioma cells. Using immunohistochemistry to assess translocation of β-catenin protein, we identified intranuclear staining, which suggest WNT pathway activation, in 8 of 43 (19%) adult and 9 of 30 (30%) pediatric glioblastoma patient surgical samples. WNT activity, evidenced by nuclear β-catenin in our cohort and high expression of its target AXIN2 in published glioma datasets, was associated with shorter patient survival, although this was not statistically significant. We determined the effects of the porcupine inhibitor LGK974 in 3 glioblastoma cell lines with elevated AXIN2 and found that it reduced WNT pathway activity by 50% or more as assessed by T cell factor-luciferase reporters. WNT inhibition led to suppression of growth and proliferation in the cultures and a modest induction of cell death. LGK974 reduced NANOG mRNA levels and the fraction of cells expressing the stem cell marker CD133 in neurosphere cultures, induced glial differentiation, and suppressed clonogenicity. These data indicate that LGK974 represents a promising new agent that can inhibit the canonical WNT pathway in vitro, slow tumor growth and deplete stem-like clonogenic cells, thereby providing further support for targeting WNT in patients with glioblastoma.

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“…β-catenin, a key signal transducer of Wnt pathway, is overexpressed in glioma and knockdown of it reduces the invasiveness of glioma cells [17]. Although previous findings confirmed Wnt/β-catenin signalling as a metastasis driver in glioma, more target genes need to be identified to better understand the pathway[18]. …”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Fra1 expression by Wnt/β-catenin signalling promotes glioma aggressiveness through epithelial–mesenchymal transition

Zhang

Liu

et al. 2017

Bioscience Reports

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Aberrant expression of Fos-related antigen-1 (Fra1) is commonly elevated in various malignant cancers and is strongly implicated in invasion and metastasis. However, the molecular mechanisms underlying its dysregulation in human glioma remain poorly understood. In the present study, we demonstrate that up-regulation of Fra1 plays a crucial role in the glioma aggressiveness and epithelial–mesenchymal transition (EMT) activated by Wnt/β-catenin signal pathway. In glioma cells, activation of Wnt/β-catenin signalling by Wnt3a administration obviously induced EMT and directly activated the transcription of Fra1. Phenotype experiments revealed that up-regulation of Fra1 induced by Wnt/β-catenin signalling drove the EMT of glioma cells. Furthermore, it was found that the cisplatin resistance acquired by Wnt/β-catenin signalling activation depended on increased expression of Fra1. Analysis of clinical specimens verified a positive correlation between Fra1 and β-catenin as well as a poor prognosis in glioma patients with double-high expressions of them. These findings indicate that an aberrant Wnt/β-catenin signalling leads to the EMT and drug resistance of glioma via Fra1 induction, which suggests novel therapeutic strategies for the malignant disease.

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SOX9 Overexpression Promotes Glioma Metastasis via Wnt/β-Catenin Signaling

Cited by 55 publications

References 22 publications

Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features

Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features

Pharmacologic Wnt Inhibition Reduces Proliferation, Survival, and Clonogenicity of Glioblastoma Cells

Dysregulation of Fra1 expression by Wnt/β-catenin signalling promotes glioma aggressiveness through epithelial–mesenchymal transition

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