Nuclear expression of Y‐box‐binding protein‐1 correlates with P‐glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma

Abstract

Nuclear expression of the Y-box-binding protein (YB-1) has been reported to correlate with the expression of P-glycoprotein in breast cancer and osteosarcoma. Overexpression of the ATP-binding cassette (ABC) superfamily, such as P-glycoprotein/multi-drug resistance (MDR) 1 and MDR-associated protein (MRP) 1, 2 and 3, has been reported in various malignant neoplasms. Fifty-four surgically resected synovial sarcomas were examined immunohistochemically for nuclear expression of YB-1 and intrinsic expression of P-glycoprotein, MRP1, MRP2, and topoisomerase II alpha, and the findings were compared with clinicopathological parameters, proliferative activities as evaluated by MIB-1 labelling index (LI), and the patients' prognoses. In addition, MDR1, MRP1, MRP2, and MRP3 mRNA levels were assessed using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method in 22 concordant frozen specimens from these cases and the findings were compared with six control skeletal muscle tissues. Independent prognostic factors were investigated using the Cox proportional hazards regression model. Nuclear expression of YB-1 protein correlated with P-glycoprotein expression (p = 0.0126). Moreover, cases with nuclear expression of YB-1 correlated with poor survival (p = 0.0495) and showed a high topoisomerase II alpha labelling index (topo II alpha LI) (p = 0.0056) and a high MIB-1 LI (p = 0.01). Multivariate Cox analysis showed that only the nuclear expression of YB-1 (p = 0.0136) and high American Joint Committee on Cancer (AJCC) stage (ie stage III or IV) (p < 0.0001) were independent factors for poor prognosis, while the expression of the YB-1 responsive gene products examined was not. These results indicate that the nuclear expression of YB-1 protein is associated with P-glycoprotein expression and proliferative activity as shown by the topo II alpha LI and the MIB-1 LI, and that expression of this protein is an important independent prognostic factor in synovial sarcoma.

Expression of Y-box-binding protein dbpC/contrin, a potentially new cancer/testis antigen

“…Placental trophoblasts were also positive for dbpC (not shown). The results on the immunolocalisation of these dbps in normal human tissues are summarised in Table 1. Expression of dbpA and dbpC in human carcinomas in various organs (Figure 2 and Table 2) As the expression of dbpB/YB-1 has been well studied in many types of human carcinoma cells (Bargou et al, 1997;Oda et al, 1998;Kamura et al, 1999;Shibao et al, 1999;Gu et al, 2001;Oda et al, 2003), we focused on the expression of dbpA and dbpC in human tumour cells in this report. We collected the cancer tissues of the alimentary and respiratory tracts, breast, kidney, prostate, and ovary (10 cases each).…”

“…The dbpA gene was first identified in 1988 (Sakura et al, 1988) and cloned in 1995, encoding a protein highly expressed in skeletal muscle (Kudo et al, 1995), and that of dbpC/contrin was cloned in 1999 as coding for a testis-specific protein distinct from other Y-box-binding proteins . The ubiquitous expression of the dbpB/YB-1 gene in human normal and neoplastic tissues has been well studied and found to be closely associated with the expression of p-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, in breast cancers (Bargou et al, 1997), osteosarcomas (Oda et al, 1998), ovarian cancers (Kamura et al, 1999), and synovial sarcomas (Oda et al, 2003). It is also associated with the expression of DNA topoisomerase II and proliferating cell nuclear antigen in colon (Shibao et al, 1999) and lung (Gu et al, 2001) cancers.…”

Genotoxic stress-induced nuclear localization of oncoprotein YB-1 in the absence of proteolytic processing

“…Immunohistochemistry has established an association between high levels of nuclear YB-1, tumor progression and drug resistance; nuclear YB-1 is therefore regarded as a poor prognostic indicator of patient outcome (Oda et al, 1998(Oda et al, , 2003Shibahara et al, 2001;Kohno et al, 2003;Gimenez-Bonafe et al, 2004;Chatterjee et al, 2008). We sought to evaluate the proposed proteolytic mechanism of YB-1 nuclear activation, given its direct relevance to the validity of the numerous immunohistochemical studies performed with C-terminal YB-1 antibodies.…”

“…MDR1 induction by YB-1 is manifest by the correlation between drug resistance of breast cancers and YB-1 overexpression (Bargou et al, 1997). Furthermore, immunohistochemical analysis of a variety of drug-resistant cancers and cell lines has established a relationship between nuclear YB-1, tumor drug resistance and poor patient outcome (Oda et al, 1998(Oda et al, , 2003Shibahara et al, 2001;Kohno et al, 2003;Gimenez-Bonafe et al, 2004;Chatterjee et al, 2008).…”

“…Immunohistochemical studies of different human malignancies have used antibodies directed against both the N-and C-terminal regions of YB-1, often revealing high levels of YB-1 in the nucleus (Oda et al, 1998(Oda et al, , 2003Shibahara et al, 2001;Ito et al, 2003;GimenezBonafe et al, 2004;Chatterjee et al, 2008). However, if YB-1 requires proteolytic removal of the C-terminal cytoplasmic anchor for nuclear translocation, then immunohistochemical studies performed with C-terminal antibodies have presumably detected an alternate protein and require re-evaluation.…”