1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Oncogene. 2014 May 1;33(18):2354-62. doi: 10.1038/onc.2013.188. Epub 2013 Jun 3.
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and young adults, is characterized by a partially differentiated myogenic phenotype. We have previously shown that the blocking of tumor growth and resumption of differentiation can be achieved by re-expression of miR-206, a muscle-enriched microRNA missing in RMS. In this work, we focused on BAF53a, one of the genes downregulated in miR-206-expressing RMS cells, which codes for a subunit of the SWI/SNF chromatin remodeling complex. Here we show that the BAF53a transcript is significantly higher in primary RMS tumors than in normal muscle, and is a direct target of miR-206. Sustained expression of BAF53a interferes with differentiation in myogenic cells, whereas its silencing in RMS cells increases expression of myogenic markers and inhibits proliferation and anchorage-independent growth. Accordingly, BAF53a silencing also impairs embryonal RMS and alveolar RMS tumor growth, inducing their morphological and biochemical differentiation. These results indicate that failure to downregulate the BAF53a subunit may contribute to the pathogenesis of RMS, and suggest that BAF53a may represent a novel therapeutic target for this tumor.
横纹肌肉瘤（RMS）是儿童和青年中最常见的软组织肉瘤，其特征是部分分化的肌源性表型。我们之前已经表明，通过重新表达 miR-206 可以阻止肿瘤生长并恢复分化，miR-206 是一种在 RMS 中缺失的富含肌肉的 microRNA。在这项工作中，我们专注于 BAF53a，它是在 miR-206 表达的 RMS 细胞中下调的基因之一，编码 SWI/SNF 染色质重塑复合物的一个亚基。在这里，我们表明 BAF53a 转录物在原发性 RMS 肿瘤中明显高于正常肌肉，并且是 miR-206 的直接靶标。BAF53a 的持续表达会干扰成肌细胞的分化，而在 RMS 细胞中沉默 BAF53a 会增加肌源性标记物的表达并抑制增殖和锚定独立生长。因此，BAF53a 沉默也会损害胚胎 RMS 和肺泡 RMS 肿瘤的生长，诱导其形态和生化分化。这些结果表明，未能下调 BAF53a 亚基可能有助于 RMS 的发病机制，并表明 BAF53a 可能成为该肿瘤的新治疗靶点。
