IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1

Sun, Yin; Gao, Dingcheng; Liu, Y; Huang, Jiankun; Lessnick, Stephen L.; Tanaka, Shinya

doi:10.1038/sj.onc.1209143

Cited by 76 publications

(61 citation statements)

References 49 publications

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“…Due to the heterogeneity of sarcoma, >100 distinct subtypes have been described to date, with new subtypes frequently reported (4). Synovial sarcoma, a soft-tissue tumor, is characterized by a reciprocal t(X;18) translocation, in which the SS18 gene on chromosome 18 fuses with the SSX1, SSX2 or, less commonly, SSX4 gene on the X chromosome (5,6). Ewing's sarcoma has a relatively simple genetic signature, consisting of a t(11;22) translocation (7,8).…”

Section: Introductionmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

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Section: Introductionmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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“…TUNEL and in Vivo Tumor Formation Assay-TUNEL assay on cells grown in methylcellulose was performed as described (23). Tumor formation assay in immunocompromised mice was done also as described (23) with the measurement of tumor volume as the (1/2)L1(L2) 2 where L1 is the long axis and L2 is the short axis of the tumor mass measured with a caliper in millimeter.…”

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confidence: 99%

“…Tumor formation assay in immunocompromised mice was done also as described (23) with the measurement of tumor volume as the (1/2)L1(L2) 2 where L1 is the long axis and L2 is the short axis of the tumor mass measured with a caliper in millimeter.…”

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confidence: 99%

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Sun¹,

Perera

Rubin

et al. 2011

Journal of Biological Chemistry

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Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.

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“…This could In synovial sarcoma, in vitro studies have found that the SS18-SSX oncogene induces IGF2 expression which seems critical to convey tumorigenic properties. [48][49][50] IGF2 expression was associated with both the ÀSSX1 and ÀSSX2 translocation subtypes. 48 In this study, we present evidence that in primary synovial sarcoma tumor specimens, IGF2 is highly expressed at the protein level, supporting translational relevance to patients of these experimental findings, and attempts to target this pathway in patients using IGF signaling inhibitors.…”

Section: Discussionmentioning

confidence: 97%

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

et al. 2009

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The insulin-like growth factor (IGF) system plays an important role in the growth and development of cells and has been implicated in oncogenesis and tumor progression. Gene expression profiling studies on limited numbers of specimens have shown high expression of IGF2, encoding the activating ligand for this system, in gastrointestinal stromal tumors (GISTs) and in synovial sarcomas. This data may have concrete clinical implications, as several reports exist of patients with GISTs suffering from severe hypoglycemia, a predicted effect of IGF2. Furthermore, new drugs targeting IGF signaling are entering clinical trials. The purpose of this study is to survey IGF2 expression at the protein level on a broad number of mesenchymal tumors representing all major diagnostic classes. By immunostaining tissue microarrays, results were obtained for 51 diagnostic categories of bone and soft-tissue tumors representing 1288 cases. Distinct membranous and/or cytoplasmic IGF2 immunoreactivity was assessed according to published criteria. Solitary fibrous tumors had the highest expression. Of 20 tumor types represented by more than 10 cases, synovial sarcomas, myxoid liposarcomas, GISTs, malignant peripheral nerve sheath tumors, chondrosarcomas, undifferentiated pleomorphic sarcomas (MFH), Ewing's sarcomas and tenosynovial giant cell tumors showed high levels of expression in more than 20% of cases. Of the 445 GIST cases with clinical information, those with high expression of IGF2 had a significantly worse outcome than those with low or no expression. IGF2 protein expression among mesenchymal tumors is largely consistent with gene expression studies and suggests a potential for molecular therapy targeting the IGF signaling pathway system in these neoplasms.

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IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1

Cited by 76 publications

References 49 publications

The importance of Src signaling in sarcoma

The importance of Src signaling in sarcoma

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

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