Overexpression of Paxillin Correlates with Tumor Progression and Predicts Poor Survival in Glioblastoma

Sun, Lihua; Yang, Fusheng; Zhang, Chuanbao; Wu, Yiping; Liang, Jingshan; Jin, Sanli; Wang, Zheng; Wang, Hongjun; Bao, Zhaoshi; Yang, Zhengxiang; Jiang, Tao

doi:10.1111/cns.12606

Cited by 33 publications

(30 citation statements)

References 40 publications

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“…Our genetic data also indicate that Pxn is a downstream target of Ccnd1‐Cdk4 in human GBM cells. Interestingly, Pxn seems to behave as an oncogene in glioma progression and its overexpression is associated with high‐grade gliomas . Also, a positive correlation between GBM invasiveness and Pxn phosphorylation at tyrosine 118 has been reported .…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

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Guasch‐Vallés

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et al. 2019

The Journal of Pathology

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Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cemeli

Guasch‐Vallés

Nàger

et al. 2019

The Journal of Pathology

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“…In the GBM cell line u87, super enhancers targeting CCND1 , CDK6 , EGFR , JUN , MET , MYC , NOTCH2 and RUNX1 have been identified [ 23 ]. In our study, super enhancer targets marked by 5hmC in common between IDH1 mt and IDH1 wt tumors and previously implicated in gliomagenesis included EGFR , MYC , CDK6 , NOTCH2 , RUNX1 , PDGFRB , PXN , ID3 , IGF1R , NEDD9 , and MSI2 [ 13 , 27 , 34 , 42 , 50 , 58 , 64 ]. Additional IDH1 wt super-enhancers marked by 5hmC in our dataset and implicated in GBM pathogenesis included WDR1 , TGFBI and PVT1 [ 11 , 36 , 43 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

et al. 2018

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Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1821-3) contains supplementary material, which is available to authorized users.

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“…Among these, glioblastoma multiforme (GBM), the most common and malignant type of glioma, remains one of the most lethal cancers in the central nervous system (CNS). Recent studies have demonstrated that the overexpression of paxillin at the RNA and protein level is associated with GBM tumor malignancy and hence, predictive of poor survival [ 107 ]. These data identify paxillin as a novel prognostic biomarker with potential anti-invasion therapeutic implications in GBM.…”

Section: Paxillin In Pathological Conditionsmentioning

confidence: 99%

Paxillin: a crossroad in pathological cell migration

et al. 2017

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Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK)-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0418-y) contains supplementary material, which is available to authorized users.

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Overexpression of Paxillin Correlates with Tumor Progression and Predicts Poor Survival in Glioblastoma

Cited by 33 publications

References 40 publications

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

Paxillin: a crossroad in pathological cell migration

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