Gene Expression Patterns of Hemizygous and Heterozygous KIT Mutations Suggest Distinct Oncogenic Pathways: A Study in NIH3T3 Cell Lines and GIST Samples

Abstract : Objective: Most gain of function mutations of tyrosine kinase receptors in human tumours are hemizygous. Gastrointestinal stromal tumours (GIST) with homozygous mutations have a worse prognosis. We aimed to identify genes differentially regulated by hemizygous and heterozygous KIT mutations. Materials and Methods: Expression of 94 genes and 384 miRNA was analysed with low density arrays in five NIH3T3 cell lines expressing the full-length human KIT cDNA wild-type (WT), hemizygous KIT mutation with del557-558 (D6) or del564-581 (D54) and heterozygous WT/D6 or WT/D54. Expression of 5 of these genes and 384 miRNA was then analysed in GISTs samples. Results: Unsupervised and supervised hierarchical clustering of the mRNA and miRNA profiles showed that heterozygous mutants clustered with KIT WT expressing cells while hemizygous mutants were distinct. Among hemizygous cells, D6 and D54 expressing cells clustered separately. Most deregulated genes have been reported as potentially implicated in cancer and severals, as ANXA8 and FBN1, are highlighted by both, mRNA and miRNA analyses. MiRNA and mRNA analyses in GISTs samples confirmed that their expressions varied according to the mutation of the alleles. Interestingly, RGS16, a membrane protein of the regulator of G protein family, correlate with the subcellular localization of KIT mutants and might be responsible for regulation of the PI3K/AKT signalling pathway. Conclusion : Patterns of mRNA and miRNA expression in cells and tumours depend on heterozygous/hemizygous status of KIT mutations, and deletion/presence of TYR568 & TYR570 residues. Thus each mutation of KIT may drive specific oncogenic pathways.
Type de document :
Article dans une revue
PLoS ONE, Public Library of Science, 2013, 8 (4), pp.e61103. 〈10.1371/journal.pone.0061103〉
Liste complète des métadonnées

Littérature citée [64 références]  Voir  Masquer  Télécharger

http://hal.upmc.fr/hal-01537119
Contributeur : Gestionnaire Hal-Upmc <>
Soumis le : lundi 12 juin 2017 - 13:17:36
Dernière modification le : jeudi 8 février 2018 - 11:10:18
Document(s) archivé(s) le : jeudi 14 septembre 2017 - 12:39:43

Fichier

journal.pone.0061103.PDF
Publication financée par une institution

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Collections

Citation

Jean-Baptiste Bachet, Séverine Tabone-Eglinger, Sophie Dessaux, Anthony Besse, Sabrina Brahimi-Adouane, et al.. Gene Expression Patterns of Hemizygous and Heterozygous KIT Mutations Suggest Distinct Oncogenic Pathways: A Study in NIH3T3 Cell Lines and GIST Samples. PLoS ONE, Public Library of Science, 2013, 8 (4), pp.e61103. 〈10.1371/journal.pone.0061103〉. 〈hal-01537119〉

Partager

Métriques

Consultations de la notice

87

Téléchargements de fichiers

30