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SHCBP1 Promotes Synovial Sarcoma Cell Metastasis Via Targeting TGF-Β1

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SHCBP1 Promotes Synovial Sarcoma Cell Metastasis Via Targeting TGF-Β1 Peng et al. Journal of Experimental & Clinical Cancer Research (2017) 36:141 DOI 10.1186/s13046-017-0616-z RESEARCH Open Access SHCBP1 promotes synovial sarcoma cell metastasis via targeting TGF-β1/Smad signaling pathway and is associated with poor prognosis Changliang Peng1, Hui Zhao2, Yan Song3, Wei Chen4, Xiaoying Wang5, Xiaoli Liu6, Cheng Zhang1, Jie Zhao1,JiLi1, Guanghui Cheng7, Dongjin Wu1, Chunzheng Gao1 and Xiuwen Wang1* Abstract Background: Our previous studies reported that SHC SH2-domain binding protein 1 (SHCBP1) functions as an oncogene via promoting cell proliferations in synovial sarcoma (SS) cells. However, whether SHCBP1 has any effect on tumor metastasis remains unexplored. Methods: The expression of SHCBP1 was analyzed in 76 SS tissues and two SS cell lines by immunohistochemistry and real-time RT-PCR. The relationship between SHCBP1 expression and the clinicopathological features of SS was investigated. The role of SHCBP1 in SS cell adhesion, migration, invasion and angiogenesis was explored by adhesion, Wound healing, Transwell, and Matrigel tube formation assays. Western blotting was conducted to detect the protein expressions of TGF-β1/Smad signaling pathway and EMT-related markers. The key molecules associated with migration, invasion and EMT were evaluated by immunohistochemistry in tumor specimens. Results: In current study, we demonstrated that SHCBP1 overexpression significantly enhanced adhesion, migration, invasion and angiogenesis of SS cells. In contrast, SHCBP1 knockdown elicited the opposite effects on these phenotypes in vitro. SHCBP1 promoted tumor metastasis through inducing epithelial-mesenchymal transition (EMT) in SS cells. SHCBP1 knockdown could block the incidence of metastasis and EMT in SS cells. Furthermore, transforming growth factor-β1 (TGF-β1) induced SHCBP1 expression in a time-dependent pattern and SHCBP1 knockdown inhibited TGF-β1-induced EMT. The activation of the TGF-β1/Smad signaling pathway was involved in the oncogenic functions of SHCBP1 in SS. In addition, high expression of SHCBP1 in SS patients was associated with tumor progression and decreased survival as well as poor prognosis. Conclusions: Taken together, our results indicate that SHCBP1 may promote the metastasis of SS by inducing EMT through targeting TGF-β1/Smad signaling pathway and can be a potential molecular target for SS therapy. Keywords: SHCBP1, EMT, Synovial sarcoma, Invasion, Metastasis, TGF-β1 * Correspondence: [email protected] 1Department of Orthopaedics, The Second Hospital of Shandong University, Shandong University, Jinan, China Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Peng et al. Journal of Experimental & Clinical Cancer Research (2017) 36:141 Page 2 of 12 Background of breast cancer cells [20]. Tao HC et al. [19] also found As a high-grade aggressive soft tissue tumor, synovial that SHCBP1 is remarkably upregulated in samples of sarcoma (SS) accounts almost 10% in soft tissue sarco- human hepatocellular carcinoma (HCC), and decreasing mas. Although SS may occur at all ages, the morbidity the expression of SHCBP1 can significantly inhibit the in adolescent and young adults is more higher [1]. Char- proliferation and colony formation of HCC cells [19]. acterized by local recurrence and distant metastasis Meanwhile, several lines of studies also confirmed (found in more than 80% of SS patients), SS can occur upregulation of SHCBP1 in certain leukemia/lymphoma almost anywhere in the body [2, 3]. However, the 5-year in both rodents and humans [21–23]. Moreover, survival rate is estimated to be only around 27% to 55% research on the mechanism of SHCBP1 in growth of with current available therapies including surgery, adju- tumor showed that the upregulation of SHCBP1 might vant chemotherapy and radiotherapy [4, 5]. Even more, be correlated with the activation of MEK/ERK signaling no effective treatment is available currently to patients pathway [19]. SHCBP1 overexpression can increase with metastasis, which often have a more poorer prog- cyclin-dependent kinase (CDK) inhibitor p21, and nosis, and the 5-year overall survival rate usually lowers decrease the Cyclin B1 and CDK1 [20]. These findings than 10% [6]. Therefore, elucidating the molecular collectively signified that SHCBP1 functions as an onco- mechanism involved in the metastasis of SS cell is des- gene and represents as an attractive anti-cancer target. perately needed, which undoubtedly will greatly contrib- Our previous study indicated that as a novel down- ute to the development of novel therapeutic strategies stream target gene of SS18-SSX1, SHCBP1 is overex- for the treatment of SS. pressed in SS and can promote the proliferation of SS The metastasis of tumor cell is a complex and multi- cells, thus promoting its tumorigenesis [24]. However, stage process, which includes adhesion, migration, whether SHCBP1 is involved in SS cell’s invasion and invasion, angiogenesis, and eventually unremitting pro- metastasis, and the related regulating mechanisms are liferation in distant target organs [7–9]. During this still not clear. Thus, the expression of SHCBP1 in SS malignant process, tumor cells express mesenchymal specimens was examined, and the correlation between markers, including vimentin, N-cadherin, and fibronec- its expression levels with SS patients’ survival was tin, as well as lose the expression of epithelial markers, assayed in current study. Furthermore, the promotive including E-cadherin and a-catenin, which results in effect of SHCBP1 on the invasion and migration was epithelial-mesenchymal transition (EMT), and subse- also investigated. Additionally, since EMT is a key quent local and distant metastases occur. The occur- process associated with the progression of SS, we hence rence and development of EMT are stimulated by some investigated the mechanism of SHCBP1 on the process cytokines and growth factors, such as TGF-β1, hepato- of TGF-β1-induced EMT in SS cells. cyte growth factor (HGF) and epidermal growth factor (EGF) etc. TGF-β1 is the strongest inducer among them and is overexpressed in many types of human cancers, Methods including SS [10]. However, the regulatory mechanisms Patients, specimens, and cell lines of TGF-β1 signaling pathway in EMT are largely Investigation has been conducted in accordance with the unknown, although EMT is considered to take part in ethical standards and according to the Declaration of SS metastasis [11, 12]. Helsinki and according to national and international SHCBP1(initially designated as murine protein of acti- guidelines and has been approved by the ethics commit- vated lymphocytes (mPAL)) that mapped on a region of tee of the Second Hospital of Shandong University. Each chromosome 16q11.2, is first identified by its direct patient had signed an informed consent. A total of interaction with the adapter protein p52Shc [13, 14]. seventy-six SS tissue specimens were obtained from Evolutionarily SHCBP1 is conserved in eukaryotes, patients who underwent surgical treatment without prior human SHCBP1 sequence shares 78% identity with radiotherapy or chemotherapy from the years between mouse’s and 23% with the Drosophila melanogaster 2005 and 2015 at the Department of Orthopaedics, the homolog Nessun Dorma’s [15]. Recent studies Second Hospital of Shandong University (Shandong, demonstrated that SHCBP1 plays critical roles in cell China). All tissue specimens were diagnosed clinically proliferation, migration, adhesion, and cell cycle and pathologically and routinely fixed in 10% formalin progression, especially in the carcinogenesis [16–20]. and embedded in paraffin for immunohistochemical Colak D et al. [18] found that SHCBP1 is highly staining. Histological grade was used by the Federation expressed in breast cancer and significantly correlated Natinale des centres de Lutte Cotre le Cancer with metastatic potential, advanced stage, and poor (FNCLCC) grading system, and disease stage according prognosis. Whereas silencing the expression of SHCBP1 to the International Union Against Cancer (UICC) through RNA interference can inhibit the proliferation staging system. Peng et al. Journal of Experimental & Clinical Cancer Research (2017) 36:141 Page 3 of 12 The human SS cell line HS-SY-II was kindly provided PCR assay kit (TAKARA, Otsu, Japan) on an ABI by Dr. Yi Guo (University of California, Irvine, USA), PRISM 7300 Sequence Detection System (Applied and cultured in Dulbecco’s modified Eagle’s medium Biosystems, Foster City, California, USA). The level of (DMEM, Gibco, NY, USA). Human SS cell line SW982 GAPDH was used as an internal control. Fold changes ΔΔ (HTB-93) was obtained from the ATCC (American Type in expression were calculated using the 2- Ct method. Culture Collection, Manassas, VA, USA), and main- tained in L-15 medium (Gibco). Human umbilical vascu- Vector construction and lentivirus infection lar endothelial cells (HUVECs, ATCC) were cultured in
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