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Cytoplasmic overexpression of RNA ‐binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia
Author(s) -
Gauchotte Guillaume,
Hergalant Sébastien,
Vigouroux Charlène,
Casse JeanMatthieu,
Houlgatte Rémi,
Kaoma Tony,
Helle Déborah,
Brochin Lydia,
Rech Fabien,
Peyre Matthieu,
Labrousse François,
Vallar Laurent,
Guéant JeanLouis,
Vignaud JeanMichel,
BattagliaHsu ShyueFang
Publication year - 2017
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4916
Subject(s) - gene knockdown , meningioma , cytoplasm , hypoxia (environmental) , rna binding protein , cancer research , rna , chemistry , pathology , microbiology and biotechnology , biology , medicine , apoptosis , biochemistry , gene , organic chemistry , oxygen
HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro‐oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti‐proliferative effects of HuR knockdown in two meningioma cell lines ( IOMM ‐Lee and Ben‐Men‐1) and conducted transcriptome‐wide analyses ( IOMM ‐Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade ( p = 1.2 × 10 −8 ) and negatively with progression‐free and overall survival ( p = 0.01) time in human meningioma tissues. In vitro, siHuR ‐induced HuR knockdown was shown to reduce the growth of both Ben‐Men‐1 ( p = 2 × 10 −8 ) and IOMM ‐Lee ( p = 4 × 10 −9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM ‐Lee cells to deregulate the HIF1A signalling pathway ( p = 1.5 × 10 −6 ) and to up‐regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide‐excision repair, poly(A)‐specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [ p ( FDR ) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.