Identification of SHCBP1 as a novel downstream target gene of SS18-SSX1 and its functional analysis in progression of synovial sarcoma
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Changliang Peng1, Hui Zhao2, Wei Chen3, Yan Song4, Xiaoying Wang5, Ji Li1, Yong Qiao1, Dongjin Wu1, Shengzhong Ma1, Xiuwen Wang1, Chunzheng Gao1
1Department of Orthopaedics, Shandong University Second Hospital, Jinan, China
2Department of Orthopaedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
3Beijing Institute of Pharmacology and Toxicology, Beijing, China
4Nephrology Research Institute, Shandong University Second Hospital, Jinan, China
5Department of Pathology, Shandong University Second Hospital, Jinan, China
Chunzheng Gao, email: [email protected]
Xiuwen Wang, email: [email protected]
Keywords: synovial sarcoma, SS18-SSX1, SHCBP1, proliferation, apoptosis
Received: November 02, 2015 Accepted: August 21, 2016 Published: August 27, 2016
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.
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