Abstract
Soft-tissue sarcomas (STS) are rare tumors whose oncogenesis remains unknown and for which no common therapeutic target has yet been identified. Analysis of 318 STS by CGH array evidenced a frequent deletion affecting the DMD gene (encoding dystrophin isoforms) in 16.5% of STS, including sarcomas with complex genomics, gastrointestinal tumors (GIST), and synovial sarcomas (SS). These deletions are significantly associated with metastatic progression, thus suggesting the role of DMD downregulation in the acquisition of aggressive phenotypes. We observed that targeted deletions of DMD were restricted to the 5’ region of the gene, which is responsible for the transcription of Dp427. Analysis of STS tumors and cell lines by RNA sequencing revealed that only the Dp71 isoform was widely expressed. Dp427 depletion had no effect on cell growth or migration. However, Dp71 inhibition by shRNA dramatically reduced the cell proliferation and clonogenicity of three STS cell lines, likely by altering the cell cycle progression through the G2/M-phase. Our work demonstrates that DMD deletions are not restricted to myogenic tumors and could be used as a biomarker for metastatic evolution in STS. Dp71 seems to play an essential role in tumor growth, thus providing a potential target for future STS treatments.
Highlights
DMD is one of the longest genes in the human genome, spanning 2.2 Mb [1]
To elucidate the oncogenic impact of DMD in sarcoma oncogenesis, we studied the genomic status of DMD in 318 sarcomas, mainly those with complex genomic profiles but alsosynovial sarcomas and gastrointestinal tumors (GIST)
We investigated isoform expression and performed functional analyses to decipher the role of Dp427 and Dp71, which are the two isoforms expressed in these sarcomas
Summary
DMD is one of the longest genes in the human genome, spanning 2.2 Mb [1]. It is composed of 79 exons coding for a full-length transcript of 14 kb. DMD is located within a common fragile site (CFS), which is a region of profound genomic instability. CFS regions often comprise genes that are frequently deleted or altered in cancers and act as tumor-suppressor genes [2]. The role of DMD as a tumor suppressor in sarcomas is strengthened by the observation that dystrophin-deficient mdx mice, which
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