Autocrine control of glioma cells adhesion and migration through IRE1α-mediated cleavage of SPARC mRNA.
The endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells because of dramatic changes in the microenvironment of solid tumors, thereby leading to the activation of an adaptive mechanism named the unfolded protein response (UPR). The activation of the UPR sensor IRE1α has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1α signaling on the adaptation of glioma cells to their microenvironment. We show that the characteristics of U87 cell migration are modified under conditions where IRE1α activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1α signaling mostly resulted in the upregulation of genes encoding extracellular matrix proteins. Among these genes, Sparc, whose mRNA is a direct target of IRE1α endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1α inactivation. Hence, our data demonstrate that IRE1α is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the crucial contribution of IRE1α to tumor growth, infiltration and invasion and extend the paradigm of secretome control in tumor microenvironment conditioning.
INSERM U1053, 146 rue Léo Saignat, 33076 Bordeaux,  France.
Nicolas
N
Dejeans
Olivier
O
Pluquet
Stéphanie
S
Lhomond
Florence
F
Grise
Marion
M
Bouchecareilh
Amélie
A
Juin
Maud
M
Meynard-Cadars
Aurélien
A
Bidaud-Meynard
Catherine
C
Gentil
Violaine
V
Moreau
Frédéric
F
Saltel
Eric
E
Chevet
D008841:Actin Cytoskeleton / Q000378:metabolism; D019898:Autocrine Communication / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000473:pathology; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D015676:Osteonectin; D012333:RNA, Messenger; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D020742:rhoA GTP-Binding Protein