Abstract
The SS18-SSX1 fusion gene has been shown to play important roles in the development of synovial sarcoma (SS), but the underlying molecular mechanisms and its downstream target genes are still not clear. Here SHC SH2-domain binding protein 1 (SHCBP1) was identified and validated to be a novel downstream target gene of SS18-SSX1 by using microarray assay, quantitative real-time (qPCR) and western blot. Expression of SHCBP1 was firstly confirmed in SS cell line and SS tissues. The effects of SHCBP1 overexpression or knockdown on SS cell proliferation and tumorigenicity were then studied by cell proliferation, DNA replication, colony formation, flow cytometric assays, and its in vivo tumorigenesis was determined in the nude mice. Meanwhile, the related signaling pathways of SHCBP1 were also examined in SS cells. The results indicated that SHCBP1 was significantly increased in SS cells and SS tissues compared with adjacent noncancerous tissues. The expression of SHCBP1 was demonstrated to be positively correlated with the SS18-SSX1 level. Overexpression and ablation of SHCBP1 promoted and inhibited, respectively, the proliferation and tumorigenicity of SS cells in vitro. SHCBP1 knockdown also significantly inhibited SS cell growth in nude mice, and lowered the MAPK/ERK and PI3K/AKT/mTOR signaling pathways and cyclin D1 expression. Our findings disclose that SHCBP1 is a novel downstream target gene of SS18-SSX1, and demonstrate that the oncogene SS18-SSX1 promotes tumorigenesis by increasing the expression of SHCBP1, which normally acts as a tumor promoting factor.
Highlights
As an aggressive tumor of soft tissue, synovial sarcoma (SS) represents approximately ten percent in total soft tissue sarcomas, which affect predominantly children and young adults [1]
We found the expression of SHCBP1, NID2 and HOXC11 was decreased in SS18SSX1-siRNA cells (Figure 1C)
Our previous study indicated that inhibition of SS18-SSX by siRNA could prevent the proliferation of SS cells [14]
Summary
As an aggressive tumor of soft tissue, synovial sarcoma (SS) represents approximately ten percent in total soft tissue sarcomas, which affect predominantly children and young adults [1]. Reciprocal t(X; 18) translocation that results in formation of a fusion protein product SS18-SSX (1–4) is a characterization of SS. This chromosomal translocation usually originates from the fusion of the SS18 gene that locates on chromosome 18 p11 to the SSX1 or SSX2, or occasionally the SSX4 gene that locates on chromosome Xq11 [4, 5]. This SS18-SSX fusion is expressed in more than 95% of cases [6]. Molecular detection the transcripts of the SS18-SSX fusion represents the most specific and sensitive diagnostic method for SS [7, 8]
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