Growth promoting signaling by tenascin-C [corrected].
Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of beta-catenin and stimulated the expression of the beta-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.
Ruiz
Christian
C
Friedrich Miescher Institute for Biomedical Research, Novartis Forschungsstiftung, Basel, Switzerland.
Huang
Wentao
W
Hegi
Monika E
ME
Lange
Katrin
K
Hamou
Marie-France
MF
Fluri
Erika
E
Oakeley
Edward J
EJ
Chiquet-Ehrismann
Ruth
R
Orend
Gertraud
G
D000199:Actins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D019063:Tenascin / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014335:Tropomyosin / Q000096:biosynthesis; D051153:Wnt Proteins
D000199:Actins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C490775:TPM1 protein, human; D019063:Tenascin; D014157:Transcription Factors; D014335:Tropomyosin; D051153:Wnt Proteins