Strong Smooth Muscle Differentiation Is Dependent on Myocardin Gene Amplification in Most Human Retroperitoneal Leiomyosarcomas

¹Genetics and Biology of Cancers, Institut Curie; ²Institut National de la Santé et de la Recherche Médicale U830, Paris, France; ³Department of Pathology, Institut Bergonié, Bordeaux, France; ⁴Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and ⁵Department of Pathology, Institut Gustave Roussy, Villejuif, France

^* To whom correspondence should be addressed. E-mail: alain.aurias{at}curie.fr.

	Abstract

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. [Cancer Res 2009;69(6):2269–78]

Key Words: Myocardin, smooth muscle differentiation, leiomyosarcomas, undifferentiated sarcomas, migration