Interactomic approach for evaluating nucleophosmin‐binding proteins as biomarkers for Ewing's sarcoma

Haga, Ayako; Ogawara, Yoko; Kubota, Daisuke; Kitabayashi, Issay; Murakami, Yasufumi; Kondo, Tadashi

doi:10.1002/elps.201200661

Cited by 13 publications

(5 citation statements)

References 46 publications

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“…Our protein profiles consistently identified 90 proteins regulated by EWS/FLI1 expression across four ES cell lines. A proteomic study using ES surgical samples identified high protein expression of NPM1 and confirmed that the expression was significantly associated with tumor malignancy and the prognosis in ES patients [ 18 , 23 ]. In our profiles of proteins associated with the inhibition of EWS/FLI1, NPM1 was also identified as a downregulated protein.…”

Section: Discussionmentioning

confidence: 95%

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

et al. 2018

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Ewing's sarcoma (ES) is the second-most frequent pediatric bone tumor. Chromosomal translocation t(11;22)(q24:q12) results in the formation of EWS/FLI1 gene fusion, which is detected in approximately 90% of tumors of the Ewing family. Several transcriptome studies have provided lists of genes associated with EWS/FLI1 expression. However, the protein expression profiles associated with EWS/FLI1 have yet to be elucidated. In this study, to identify the regulated proteins associated with EWS/FLI1 and therapeutic targets in ES, we conducted proteomic studies using EWS/FLI1 knockdown in four Ewing's sarcoma cell lines and human mesenchymal stem cells (hMSCs) expressing EWS/FLI1. Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified more than 2,000 proteins regulated by the EWS/FLI1 fusion. In addition, the network analyses identified several critical pathways, including XBP1, which was ranked the highest. XBP1 is a protein well known to play an important role in the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress through the IRE1α-XBP1 pathway. We confirmed the high mRNA expression of XBP1 (spliced XBP1 and unspliced XBPl) in surgical samples and cell lines in ES. The silencing of XBP1 significantly suppressed the cell viabilities in ES cell lines. In the inhibitor assays using IRE1α-XBP1 inhibitors, including toyocamycin, we confirmed that these agents significantly suppressed the cell viabilities, leading to apoptosis in ES cells both in vitro and in vivo. Our findings suggested that IRE1α-XBP1 inhibitors might be useful for developing novel therapeutic strategies in ES.

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Section: Discussionmentioning

confidence: 95%

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

et al. 2018

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“…biology. Previously, we investigated the proteins interacting with nucleophosmin, a prognostic biomarker for Ewing's sarcoma discovered by proteomics 19) , and identified novel prognostic proteins 20) , suggesting the utility of interactome approach to biomarker discovery. Although a previous study demonstrated the interaction of SBP1 with glutathione peroxidase 1 selenoprotein in colorectal cancer cells 12) , comprehensive studies of the SBP1 protein complex in cancer have yet to be conducted.…”

Section: Discussionmentioning

confidence: 99%

Interactome analysis reveals molecular mechanisms underlying the association between selenium binding protein 1 expression and the malignant features of tumor cells

et al. 2015

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The potential biological and clinical significance of selenium binding protein 1 (SBP1) has been suggested in various types of cancer. To evaluate the role of SBP1 and reveal the molecular basis for its function, we examined the SBP1 protein complex. A gene transfection assay revealed that overexpression of SBP1 promoted proliferation and migration of A549 lung adenocarcinoma cells. Halo-tag-based affinity purification coupled with liquid chromatography-tandem mass spectrometry identified 23 components of the SBP1 protein complex. The functional classification of these 23 proteins suggests that the SBP1 complex participates in critical biological events including cell structure, protein translation, stress response, chaperone, and apoptosis. Moreover, the SBP1 complex includes several proteins that are aberrantly expressed in cancers. These finding indicate that SBP1 may function coordinately with these multiple proteins to facilitate cancer progression. A comprehensive study of the multiple proteins associated with SPB1 together with an examination of individual proteins will be required to elucidate the roles of aberrant SBP1 regulation in cancer progression.

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“…Immunohistochemistry analysis revealed that elevated NPM expression could potentially predict poor prognosis in Ewing's sarcoma. Later, Haga et al . reported that NPM promoted the growth and invasion of Ewing's sarcoma cells and was bound to a number of proteins implicated in other malignancies, as evidenced by the interactome approach.…”

Section: Proteomics In Ewing's Sarcoma Researchmentioning

confidence: 99%

Current Status of Proteomics in Ewing's Sarcoma

Kondo

2018

Proteomics Clinical Apps

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Ewing's sarcoma is an extremely rare mesenchymal malignancy of the bone, which predominantly occurs in children and young adolescents. Ewing's sarcoma is characterized by chromosomal translocations resulting in the formation of chimeric fusions between the EWS gene and transcription factors of the ETS family, such as EWS-FLI-1. The clinical outcome of Ewing's sarcoma remains poor, and novel therapeutic approaches are required. Proteomic analyses have been applied to identify the functions of the fusion gene product, and a novel mechanism of EWS-FLI-1 turnover has been proposed. Furthermore, proteomics has revealed the regulation of IL-6 secretion by EWS-FLI-1, which may promote malignant behavior in tumor cells. In addition, proteomic approaches have been used to assess the effects of unique genes and drugs on Ewing's sarcoma and to determine specific biomarker candidates for the prediction of drug resistance and recurrence. By identifying the proteins relevant to the molecular backgrounds of clinical characters of Ewing's sarcoma, we can understand the biology of Ewing's sarcoma and develop clinical applications. Fundamental research systems such as tumor cell and tissue biobanks and databases are required to make effective use of the limited clinical materials and promote research into Ewing's sarcoma.

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Interactomic approach for evaluating nucleophosmin‐binding proteins as biomarkers for Ewing's sarcoma

Cited by 13 publications

References 46 publications

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

Interactome analysis reveals molecular mechanisms underlying the association between selenium binding protein 1 expression and the malignant features of tumor cells

Current Status of Proteomics in Ewing's Sarcoma

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