Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth.
In epithelial cells, hepatocyte growth factor (HGF) activates a genetic program involving cell-cell dissociation ("scattering"), growth and invasiveness. The full program is not elicited by other growth factors like epidermal growth factor, and is aberrantly activated during cancer progression to the invasive-metastatic phenotype. To identify genes involved in the onset of invasive growth, we explored by cDNA microarrays the in vitro transcriptional response to HGF of mouse embryo liver cells. We identified osteopontin (OPN), a secreted matrix protein, as a major HGF transcriptional target. The wave of OPN induction is maximal at 6 h, in concomitance with the initiation of scattering, and is specific, because no other matrix protein among those explored by the microarray is affected. Interestingly, HGF, but not epidermal growth factor, promotes cell adhesion to OPN via the CD44 receptor. Scattering is significantly impaired by antibodies against OPN and CD44; conversely, constitutive OPN overexpression dramatically increases the motile and invasive responses to HGF, leading to disruption of the ordered morphogenetic program triggered by this ligand.
Medico
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E
Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo (TO), Italy. emedico@ircc.unito.it
Gentile
A
A
Lo Celso
C
C
Williams
T A
TA
Gambarotta
G
G
Trusolino
L
L
Comoglio
P M
PM
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000502:physiology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation
D018960:Hyaluronan Receptors; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D017228:Hepatocyte Growth Factor