Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma

Department of Orthopaedic Surgery, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Clinical Cancer Research (Impact Factor: 8.72). 10/1998; 4(9):2273-7.
Source: PubMed


The Y-box-binding protein, YB-1, is a member of the DNA-binding protein family. It binds to the Y-box, an inverted CCAAT box, in the promoter region of the human multidrug resistance 1 gene, which encodes P-glycoprotein (P-gp). Nuclear localization of YB-1 protein has been reported to be associated with the intrinsic expression of P-gp in human breast cancer. We studied the immunohistochemical expression of YB-1 protein in 69 untreated biopsy specimens of conventional osteosarcomas and compared it with the expression of P-gp. Furthermore, cell proliferation, as determined by the MIB-1-labeling index (MIB-1-LI), was measured by immunohistochemistry. In all 69 untreated osteosarcomas, YB-1 protein was expressed in the cytoplasm. In 32 of 69 (46%) cases, YB-1 was also localized in the nucleus. The expression of P-gp was evident in 23 of these 32 cases, and there was a significant correlation between the nuclear expression of YB-1 and P-gp expression (P < 0.0001). Chondroblastic osteosarcoma expressed YB-1 in the nucleus more frequently (eight of nine cases) than did other types of osteosarcoma, whereas P-gp was also frequently expressed in chondroblastic subtype. There was no correlation between the nuclear expression of YB-1 and histological grade. The MIB-1-LI was significantly higher in cases showing the nuclear expression of YB-1 (MIB-1-LI averaged 22.56 in cases with only cytoplasmic expression of YB-1 but averaged 28.20 in cases with cytoplasmic and nuclear expression of YB-1; P = 0.0477). In human osteosarcoma, nuclear localization of YB-1 protein was associated with the expression of P-gp, suggesting that YB-1 could be a prognostic marker for multidrug resistance in osteosarcoma.


Available from: Takeshi Uchiumi, May 28, 2015
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    • "Indeed, elevated expression of YB-1 correlates with poor patient survival and drug resistance in diverse tumor types, and YB-1 levels are elevated in metastatic tumors (Lovett et al., 2010; Eliseeva et al., 2011; Wu et al., 2012). Human sarcomas are aggressive bone and soft tissue tumors with high YB-1 expression (Oda et al., 1998, 2008; Fujiwara- Okada et al., 2013). We recently used a novel Click-SILAC mass spectrometry approach to show that in human sarcomas, YB-1 regulates acute synthesis of proteins involved in diverse biological pathways including metabolism, cell stress responses, mitochondrial functions, protein folding, and mRNA translation (Somasekharan et al., 2012). "
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    ABSTRACT: Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5' untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression. © 2015 Somasekharan et al.
    The Journal of Cell Biology 03/2015; 208(7). DOI:10.1083/jcb.201411047 · 9.83 Impact Factor
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    • "Therefore, we believe that targeting YB-1 with siRNA and atelocollagen could be a novel and effective treatment for OS (Takeshita et al, 2005). We previously found that nuclear expression of YB-1 is closely associated with P-gp expression in human OS samples (Oda et al, 1998). However, controversy still surrounds whether P-gp is a prognostic factor for the response to chemotherapy and clinical prognosis in patients with OS (Pakos and Ioannidis, 2003). "
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    ABSTRACT: Background: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. Methods: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. Results: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. Conclusion: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.
    British Journal of Cancer 03/2013; 108(4):836-47. DOI:10.1038/bjc.2012.579 · 4.84 Impact Factor
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    • "Early immunohistochemical observations showed that YB-1 protein is elevated in ∼75% of breast cancers [11]. This was subsequently extended to a wide range of common human cancers, including cancers of the prostate [12], lung [13], skin [14], bone [15], and others [16], [17], [18]. However, there is disagreement as to whether nuclear YB-1 is a significant prognostic factor and there are discrepancies in the literature as to whether YB-1 is present in normal tissues. "
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    ABSTRACT: The literature concerning the subcellular location of Y-box binding protein 1 (YB-1), its abundance in normal and cancer tissues, and its prognostic significance is replete with inconsistencies. An explanation for this could be due in part to the use of different antibodies in immunohistochemical and immunofluorescent labeling of cells and tissues. The inconsistencies could also be due to poor resolution of immunohistochemical data. We analyzed two cohorts of breast tumours for both abundance and subcellular location of YB-1 using three different antibodies; two targeting N-terminal epitopes (AB-a and AB-b) and another (AB-c) targeting a C-terminal epitope. We also investigated stress-induced nuclear translocation of YB-1 in cell culture. We report that both AB-a and AB-c detected increased YB-1 in the cytoplasm of high-grade breast cancers, and in those lacking estrogen and progesterone receptors; however the amount of YB-1 detected by AB-a in these cancers is significantly greater than that detected by AB-c. We confirm our previously published findings that AB-b is also detecting hnRNP A1, and cannot therefore be used to reliably detect YB-1 by immunohistochemistry. We also report that AB-a detected nuclear YB-1 in some tumour tissues and stress treated cells, whereas AB-c did not. To understand this, cancer cell lines were analyzed using native gel electrophoresis, which revealed that the antibodies detect different complexes in which YB-1 is a component. Our data suggest that different YB-1 antibodies show different staining patterns that are determined by the accessibility of epitopes, and this depends on the nature of the YB-1 complexes. It is important therefore to standardize the protocols if YB-1 is to be used reproducibly as a prognostic guide for different cancers.
    PLoS ONE 06/2011; 6(6):e20603. DOI:10.1371/journal.pone.0020603 · 3.23 Impact Factor
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