Microarray-based identification of tenascin C and tenascin XB, genes possibly involved in tumorigenesis associated with neurofibromatosis type 1.
OBJECTIVE
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies.


METHODS
To identify new signaling pathways involved in the malignant transformation of plexiform neurofibromas, we applied a 22,000-oligonucleotide microarray approach to a series of plexiform neurofibromas and malignant peripheral nerve sheath tumors. Changes in the expression of selected genes were then confirmed by real-time quantitative reverse transcription-PCR.


RESULTS
We identified two tenascin gene family members that were significantly deregulated in both human NF1-associated tumors and NF1-deficient primary cells: Tenascin C (TNC) was up-regulated whereas tenascin XB (TNXB) was down-regulated during tumor progression. TNC activation is mainly due to the up-regulation of large TNC splice variants. Immunohistochemical studies showed that TNC transcripts are translated into TNC protein in TNC-overexpressing tumors. Aberrant transcriptional activation of TNC seems to be principally mediated by activator protein transcription factor complexes.


CONCLUSIONS
TNXB and TNC may be involved in the malignant transformation of plexiform neurofibromas. Anti-TNC antibodies, already used successfully in clinical trials to treat malignant human gliomas, may be an appropriate new therapeutic strategy for NF1.
Lévy
Pascale
P
Laboratoire de Génétique Moléculaire-Institut National de la Sante et de la Recherche Medicale U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, 4 avenue de l'Observatoire, Paris, France.
Ripoche
Hugues
H
Laurendeau
Ingrid
I
Lazar
Vladimir
V
Ortonne
Nicolas
N
Parfait
Béatrice
B
Leroy
Karen
K
Wechsler
Janine
J
Salmon
Isabelle
I
Wolkenstein
Pierre
P
Dessen
Philippe
P
Vidaud
Michel
M
Vidaud
Dominique
D
Bièche
Ivan
I
D017398:Alternative Splicing; D002454:Cell Differentiation; D016000:Cluster Analysis; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D015398:Signal Transduction; D019063:Tenascin / Q000096:biosynthesis*; D016896:Treatment Outcome
D019063:Tenascin; C081865:tenascin X