NPM1 Silencing Reduces Tumour Growth and MAPK Signalling in Prostate Cancer Cells

Loubeau, Gaëlle; Boudra, Rafik; Maquaire, Sabrina; Lours-Calet, Corinne; Beaudoin, Claude; Verrelle, Pierre; Morel, Laurence

doi:10.1371/journal.pone.0096293

Cited by 24 publications

(20 citation statements)

References 25 publications

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“…Previous studies have reported that B23 is a positive regulator of the ERK signaling pathway and may promote cell proliferation via ERK activity in prostate cancer (14–16). Therefore, to investigate whether B23 affected bladder cancer cell growth via the ERK signaling pathway, the present study detected the protein expression levels of p-ERK, and it was observed that the phosphorylation of ERK was inhibited by B23 knockdown; however, the total protein expression levels of ERK remained unaltered (Fig.…”

Section: Resultsmentioning

confidence: 99%

High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma

Wang

Gang

Zhao

et al. 2016

Molecular Medicine Reports

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B23, a multifunctional nucleolar protein, is overexpressed in numerous cancers and is associated with tumorigenesis. However, the clinical significance and potential role of B23 in bladder urothelial carcinoma remains to be elucidated. The present study observed that the mRNA and protein expression levels of B23 were increased in bladder cancer cells and tissues. The overexpression of B23 contributed to tumorigenesis and was associated with poor prognosis in bladder cancer patients. Silencing of B23 by short hairpin RNA inhibited tumor cell growth and colony formation. In addition, knockdown of B23 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), resulting in the inactivation of the ERK signaling pathway. Therefore, the present study indicated that B23 promotes bladder cancer cell growth via activation of the ERK signaling pathway and is a novel potential biomarker for the diagnosis and prognosis of bladder cancer.

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Section: Resultsmentioning

confidence: 99%

High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma

Wang

Gang

Zhao

et al. 2016

Molecular Medicine Reports

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“…Certainly, in our analysis, we found RBPs that were already reported to contribute to the aggressiveness of the high grade cancers. These included IGF2BP3 [34, 54], S100A4 [59, 60], METTL1 [51], NPM1 [61, 62], BST2 [63], and EIF4E2 [64]. We also validated the role of two upregulated and aggressiveness related RBPs (METTL1 and OAS1) in chemoresistance of LN229 glioma cells to temozolomide.…”

Section: Discussionmentioning

confidence: 98%

Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

et al. 2016

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RNA binding proteins (RBPs) have been implicated in cancer development. An integrated bioinformatics analysis of RBPs (n = 1756) in various datasets (n = 11) revealed several genetic and epigenetically altered events among RBPs in glioblastoma (GBM). We identified 13 mutated and 472 differentially regulated RBPs in GBM samples. Mutations in AHNAK predicted poor prognosis. Copy number variation (CNV), DNA methylation and miRNA targeting contributed to RBP differential regulation. Two sets of differentially regulated RBPs that may be implicated in initial astrocytic transformation and glioma progression were identified. We have also identified a four RBP (NOL3, SUCLG1, HERC5 and AFF3) signature, having a unique expression pattern in glioma stem-like cells (GSCs), to be an independent poor prognostic indicator in GBM. RBP risk score derived from the signature also stratified GBM into low-risk and high-risk groups with significant survival difference. Silencing NOL3, SUCLG1 and HERC5 inhibited GSC maintenance. Gene set enrichment analysis of differentially regulated genes between high-risk and low-risk underscored the importance of inflammation, EMT and hypoxia in high-risk GBM. Thus, we provide a comprehensive overview of genetic and epigenetic regulation of RBPs in glioma development and progression.

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“…A vast amount of tumors display aberrant mTOR activity including prostate tumors for which high level of Npm1 is proposed to enhance tumor cells aggressiveness. 21,22 However, it is currently unknown to which extent these two key regulators of cell proliferation might interact to regulate common biological functions with implications in diseases and cancers.…”

Section: Introductionmentioning

confidence: 99%

mTOR transcriptionally and post-transcriptionally regulates Npm1 gene expression to contribute to enhanced proliferation in cells with Pten inactivation

et al. 2016

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The mammalian target of rapamycin (mTOR) plays essential roles in the regulation of growth-related processes such as protein synthesis, cell sizing and metabolism in both normal and pathological growing conditions. These functions of mTOR are thought to be largely a consequence of its cytoplasmic activity in regulating translation rate, but accumulating data highlight supplementary role(s) for this serine/threonine kinase within the nucleus. Indeed, the nuclear activities of mTOR are currently associated with the control of protein biosynthetic capacity through its ability to regulate the expression of gene products involved in the control of ribosomal biogenesis and proliferation. Using primary murine embryo fibroblasts (MEFs), we observed that cells with overactive mTOR signaling displayed higher abundance for the growth-associated Npm1 protein, in what represents a novel mechanism of Npm1 gene regulation. We show that Npm1 gene expression is dependent on mTOR as demonstrated by treatment of wild-type and Pten inactivated MEFs cultured with rapamycin or by transient transfections of small interfering RNA directed against mTOR. In accordance, the mTOR kinase localizes to the Npm1 promoter gene in vivo and it enhances the activity of a human NPM1-luciferase reporter gene providing an opportunity for direct control. Interestingly, rapamycin did not dislodge mTOR from the Npm1 promoter but rather strongly destabilized the Npm1 transcript by increasing its turnover. Using a prostate-specific Pten-deleted mouse model of cancer, Npm1 mRNA levels were found up-regulated and sensitive to rapamycin. Finally, we also showed that Npm1 is required to promote mTOR-dependent cell proliferation. We therefore proposed a model whereby mTOR is closely involved in the transcriptional and posttranscriptional regulation of Npm1 gene expression with implications in development and diseases including cancer.

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NPM1 Silencing Reduces Tumour Growth and MAPK Signalling in Prostate Cancer Cells

Cited by 24 publications

References 25 publications

High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma

High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma

Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

mTOR transcriptionally and post-transcriptionally regulates Npm1 gene expression to contribute to enhanced proliferation in cells with Pten inactivation

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