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P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5.

ABSTRACT: Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating the nuclear factor-?B signaling pathway by a downstream molecular mechanism that remains incompletely understood. In this study, we found that dual specificity phosphatase 5 (DUSP5) is a downstream target of p68, using microarray analysis, and that p68 negatively regulates DUSP5. Upregulating DUSP5 in stably expressing cell lines (U87 and LN-229) suppressed proliferation, invasion, and migration in glioma cells in vitro, consistent with the downregulation of p68. Furthermore, upregulating DUSP5 inhibited ERK phosphorylation, whereas downregulating DUSP5 rescued the level of ERK phosphorylation, indicating that DUSP5 might negatively regulate ERK signaling. Additionally, we show that DUSP5 levels were lower in high-grade glioma than in low-grade glioma. These results suggest that the p68-induced negative regulation of DUSP5 promoted invasion by glioma cells and mediated the activation of the ERK signaling pathway.

SUBMITTER: Wang R

PROVIDER: S-EPMC6317933 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5.

Wang Rui R Bao Hong-Bo HB Du Wen-Zhong WZ Chen Xiao-Feng XF Liu Huai-Lei HL Han Da-Yong DY Wang Li-Gang LG Wu Jia-Ning JN Wang Chun-Lei CL Yang Ming-Chun MC Liu Zhan-Wen ZW Zhang Na N Teng Lei L

Cancer science 20181203 1

Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating ...[more]

PMID: 30387548

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Project description:BackgroundRelA/p65 a crucial member of NF-?B signaling pathway plays diverse role in mediating oncogenesis. Limited knowledge prevails on the mechanistic insights of RelA gene regulation. RNA helicase p68 apart from being a vital player of RNA metabolism acts as a transcriptional coactivator of several oncogenic transcription factors including ?-catenin and is highly implicated in cancer progression. In this study, we aim to discern the molecular mechanism of how an RNA helicase, p68 deploys a major oncogenic signaling pathway, Wnt/ ?-catenin to regulate the expression of RelA, an indispensable component of NF-?B signaling pathway towards driving colon carcinogenesis.MethodsImmunoblotting and quantitative RT-PCR was performed for determining the protein and mRNA expressions of the concerned genes respectively. Luciferase assay was employed for studying the promoter activity of RelA. Chromatin immunoprecipitation was used to evaluate the occupancy of transcription factors on the RelA promoter. Immunohistochemical analysis was conducted using FFPE sections derived from normal human colon and colon cancer patient samples. Finally, a syngeneic colorectal allograft mouse model was used to assess physiological significance of the in vitro findings.Resultsp68, ?-catenin and RelA proteins were found to bear strong positive correlation in normal and colon carcinoma patient samples. Both p68 and ?-catenin increased RelA mRNA and protein expression. p68, ?-catenin and Wnt3a elevated RelA promoter activity. Conversely, p68 and ?-catenin knockdown diminished RelA promoter activity and led to reduced RelA mRNA and protein expression. p68 was perceived to occupy RelA promoter with ?-catenin at the TCF4/LEF (TBE) sites thereby potentiating RelA transcription. p68 and ?-catenin alliance positively modulated the expression of signature NF-?B target genes. Enhanced NF-?B target gene expression by p68 was corroborated by findings in clinical samples. Tumors generated in mice colorectal allograft model, stably expressing p68 further reinforced our in vitro findings.ConclusionsWe report for the first time a novel mechanism of alliance between p68 and ?-catenin in regulating the expression of RelA and stimulating the NF-?B signaling axis towards driving colon carcinogenesis. This study unravels novel modes of p68-mediated colon carcinogenesis, marking it a potential target for therapy.

Project description:BackgroundThe present study is aimed at exploring the specific expression of miR-193a-3p and the mechanism underlying miR-193a-3p-mediated mesenchymal transition (MT), invasion, and migration in glioma.MethodsThe gene expression profile datasets of GSE39486 and GSE25676 were downloaded from the National Center for Biotechnology (NCBI). Data regarding the expression of miR-193a-3p and survival curves were derived from Chinese Glioma Genome Atlas (CGGA). Online websites including miRWalk, DIANA, and starbase were employed to predict the target genes for miR-193a-3p. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by the Omicsbean online software. Module analysis of the protein-protein interaction (PPI) networks was performed by the plug-in Molecular Complex Detection (MCODE), and the degrees of genes were calculated by CytoHubba plug-in of Cytoscape. Survival curves were based on the Gene Expression Profile Interaction Analysis (GEPIA). Transwell, wound healing, and Western blot experiments were performed to investigate the effects of miR-193a-3p and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) on the invasion, migration, and MT of glioma.ResultsmiR-193a-3p was highly expressed in glioma tissues and significantly correlated with poor survival in patients with glioma. The target genes for miR-193a-3p were involved in many cancer-related signaling pathways. The PPI showed 11 genes with both high degrees and MCODE scores in the network. Survival analysis demonstrated that the expression of BTRC was significantly correlated with the prognosis of patients with glioma. The results from the transwell, wound healing, and Western blot analyses suggested that miR-193a-3p promoted the invasion, migration, and MT of glioma cells, which could be reversed by BTRC.ConclusionsmiR-193a-3p was upregulated in patients with glioma and could affect the invasion, migration, and MT of glioma by regulating BTRC.

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P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5.

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P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5.

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