Differential expression of CCN1/CYR61, CCN3/NOV, CCN4/WISP1, and CCN5/WISP2 in neurofibromatosis type 1 tumorigenesis.
The hallmark of neurofibromatosis type 1 is the development of dermal and plexiform neurofibromas. Neurofibromatosis type 1 patients with plexiform neurofibromas are at risk of developing malignant peripheral nerve sheath tumors. We applied a 22,000-oligonucleotide microarray transcriptomic approach to a series of plexiform neurofibromas in comparison with dermal neurofibromas, and results were confirmed with real-time quantitative reverse transcription-polymerase chain reaction. Thirteen genes were upregulated and 10 were downregulated in plexiform neurofibromas. The upregulated genes mainly encode molecules involved in cell adhesion, extracellular matrix, fibrogenesis, and angiogenesis. Several CCN gene family members were dysregulated in neurofibromatosis type 1 tumorigenesis; the angiogenic gene CCN1/CYR61 was specifically upregulated in the plexiform neurofibromas; CCN4/WISP1 was upregulated, and CCN3/NOV and CCN5/WISP2 were downregulated in paired comparisons of plexiform neurofibroma and malignant peripheral nerve sheath tumor from the same patients. CCN1 and CCN3 proteins were detected by immunohistochemistry in neurofibromatosis type 1-associated tumors. Upregulation of S100A8, S100A9, and CD36 was also observed and suggests a role of this pathway in inflammation-associated genesis of plexiform neurofibromas. In summary, a limited number of pathways are potentially involved in plexiform neurofibroma development. Some of the genes identified, particularly CCN1, might be useful diagnostic or prognostic markers or form the basis for novel therapeutic strategies.
Pasmant
Eric
E
UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. eric.pasmant@etu.univ-paris5.fr
Ortonne
Nicolas
N
Rittié
Laure
L
Laurendeau
Ingrid
I
Lévy
Pascale
P
Lazar
Vladimir
V
Parfait
Béatrice
B
Leroy
Karen
K
Dessen
Philippe
P
Valeyrie-Allanore
Laurence
L
Perbal
Bernard
B
Wolkenstein
Pierre
P
Vidaud
Michel
M
Vidaud
Dominique
D
Bièche
Ivan
I
D000293:Adolescent; D000328:Adult; D055511:CCN Intercellular Signaling Proteins; D015197:Carcinogenicity Tests / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics / Q000378:metabolism; D009455:Neurofibroma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D012583:Schwann Cells / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D055511:CCN Intercellular Signaling Proteins; C501848:CCN1 protein, human; C526319:CCN3 protein, human; C116396:CCN4 protein, human; C413323:CCN5 protein, human; D055515:Cysteine-Rich Protein 61; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors