Identification of SHCBP1 as a novel downstream target gene of SS18-SSX1 and its functional analysis in progression of synovial sarcoma.
Identification of SHCBP1 as a novel downstream target gene of SS18-SSX1 and its functional analysis in progression of synovial sarcoma.
复制标题
SS18-SSX1下游靶基因SHCBP1的鉴定及其在滑膜肉瘤进展中的功能分析
DOI：
10.18632/oncotarget.11651
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发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Peng C;Zhao H;Chen W;Song Y;Wang X;Li J;Qiao Y;Wu D;Ma S;Wang X;Gao C
SS 18-SSX 1融合基因在滑膜肉瘤（synovial sarcoma，SS）的发生发展中起重要作用，但其分子机制及其下游靶基因尚不清楚。本研究通过基因芯片、实时荧光定量PCR（qPCR）和western blot等方法鉴定了SHC SH 2-domain binding protein 1（SHCBP 1），并证实其为SS 18-SSX 1的下游靶基因。SHCBP 1在SS细胞系和SS组织中的表达首次得到证实。然后通过细胞增殖、DNA复制、集落形成、流式细胞术分析研究SHCBP 1过表达或敲低对SS细胞增殖和致瘤性的影响，并在裸鼠体内测定其致瘤性。同时，在SS细胞中检测SHCBP 1的相关信号通路。结果表明，与癌旁组织相比，SS细胞和SS组织中SHCBP 1的表达明显增加。SHCBP 1的表达与SS 18-SSX 1水平呈正相关。SHCBP 1的过表达和去除分别促进和抑制SS细胞的增殖和致瘤性。SHCBP 1基因敲除可显著抑制SS细胞的生长，降低MAPK/ERK和PI 3 K/AKT/mTOR信号通路及cyclin D1的表达。我们的发现揭示了SHCBP 1是SS 18-SSX 1的一个新的下游靶基因，并证明癌基因SS 18-SSX 1通过增加SHCBP 1的表达促进肿瘤发生，SHCBP 1通常作为肿瘤促进因子。
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.