Strong smooth muscle differentiation is dependent on myocardin gene amplification in most human retroperitoneal leiomyosarcomas.
Myocardin (MYOCD), a serum response factor (SRF) transcriptional cofactor, is essential for cardiac and smooth muscle development and differentiation. We show here by array-based comparative genomic hybridization, fluorescence in situ hybridization, and expression analysis approaches that MYOCD gene is highly amplified and overexpressed in human retroperitoneal leiomyosarcomas (LMS), a very aggressive well-differentiated tumor. MYOCD inactivation by shRNA in a human LMS cell line with MYOCD locus amplification leads to a dramatic decrease of smooth muscle differentiation and strongly reduces cell migration. Moreover, forced MYOCD expression in three undifferentiated sarcoma cell lines and in one liposarcoma cell line confers a strong smooth muscle differentiation phenotype and increased migration abilities. Collectively, these results show that human retroperitoneal LMS differentiation is dependent on MYOCD amplification/overexpression, suggesting that in these well-differentiated LMS, differentiation could be a consequence of an acquired genomic alteration. In this hypothesis, these tumors would not necessarily derive from cells initially committed to smooth muscle differentiation. These data also provide new insights on the cellular origin of these sarcomas and on the complex connections between oncogenesis and differentiation in mesenchymal tumors.
Pérot
Gaëlle
G
Genetics and Biology of Cancers, Institut Curie, Paris, France.
Derré
Josette
J
Coindre
Jean-Michel
JM
Tirode
Franck
F
Lucchesi
Carlo
C
Mariani
Odette
O
Gibault
Laure
L
Guillou
Louis
L
Terrier
Philippe
P
Aurias
Alain
A
D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002886:Chromosomes, Human, Pair 17; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007890:Leiomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009130:Muscle, Smooth / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012186:Retroperitoneal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation; D000099251:Myocardin
D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099251:Myocardin