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  • Kshirsagar et al previously reported an association between


    Kshirsagar et al. previously reported an association between CHK2thr68 expression and the presence of the chromatin remodeling factor Rsf-1 in solid HGSC specimens [22]. Rsf-1 expression was previously analyzed in our effusion series and was found to be related to poor survival [23]. Analysis of the association between this protein and CHK2thr68 in our cohort (101 cases with both analyses) did not show any significant association. However, inverse association was observed between Rsf-1 nuclear staining intensity and CHK1ser296 expression (p = 0.047; data not shown). The biological significance of this finding is unclear at present. Ganzinelli and co-workers analyzed 158 ovarian carcinomas of various histotype for mRNA expression of various genes involved in DNA repair and damage, including CHK1. No association with OS or PFS was observed [13]. Ehlén et al. analyzed 2 cohorts of ovarian carcinoma patients. CHK1 mRNA expression, analyzed in a series of 267 serous and endometrioid carcinomas, was significantly related to shorter relapse-free survival (RFS) in univariate, but not in multivariate analysis, and was unrelated to OS. In a second series of 154 tumors, CHK1 protein expression by IHC was significantly related to OS in univariate, but not in multivariate analysis. CHK2 mRNA expression was associated with poor RFS in both univariate and multivariate analysis, whereas CHK2 protein expression was significantly related to shorter OS only in univariate analysis. p-CHK2thr68 protein expression in cohort 2 was associated with shorter OS in univariate, but not in multivariate analysis, whereas p-CHK1ser345 expression was unrelated to OS [14]. Alkema et al. analyzed 125 ovarian carcinomas for protein expression of several DDR-related proteins, including CHK2 and p-CHK2thr68. CHK2 and p-CHK2thr68 expression was unrelated to OS or PFS, though CHK2 expression was significantly associated with better response to platinum-based chemotherapy [15]. Ocaña et al. recently identified CHK1 as part of a gene panel associated with poor PFS in an in silico analysis of public databases [16]. The strength of the present study is the analysis of a large series of specimens with full clinical data and uniform histology, the majority at advanced stage. We additionally focused on effusions, specimens which cannot be surgically eradicated and are a chemoresistant niche enriched in cancer stem Amyloid β-peptide (10-35), amide [24]. The cohort analyzed consists almost entirely of patients with FIGO stage III–IV disease, and the data presented therefore pertain to a patient population with generally aggressive disease and poor outcome, which may benefit from new treatment modalities. One weakness of our study is the absence of data regarding BRCA status, which primarily owes to the fact that this is a relatively old cohort. Our data nevertheless suggest that CHK proteins are informative of the clinical course of metastatic HGSC. CHK1 and CHK2 may be therapeutic targets in HGSC. The following are the supplementary data related to this article.
    A family of proteins called Y-box proteins has emerged as multifunctional regulators of transcription and translation . They are evolutionarily conserved from bacteria to vertebrates , , . These proteins are capable of binding one or more types of nucleic acids—single-stranded DNA or RNA or double-stranded DNA , . Diverse biological roles proposed for Y-box proteins include positive or negative modulation of transcription , , , masking of mRNA translation , , participation in eukaryotic redox signaling pathway , cell proliferation , storage and translation of mRNA in germ cells as well as in the upregulation of the multidrug resistance gene, mdr1 . These proteins also function as RNA chaperones that couple transcription to translation of mRNA , . Several studies have shown a high degree of sequence conservation especially in the nucleic acid binding domain, usually referred to as `cold shock domain or CSD,' highlighting the importance of the metabolic processes regulated by Y-box proteins , , , , . A direct role for YB-1 in cell division and cell proliferation has been suggested, based on the following observations. (i) YB-1 is known to activate several cell proliferation-related genes such as proliferating cell nuclear antigen (PCNA), DNA polymerase, thymidine kinase , epidermal growth factor receptor, and growth hormone receptor genes , (ii) YB-1 is expressed at higher levels in actively proliferating cells compared to quiescent cells , , and (iii) YB-1 is over-expressed in regenerating liver and in liver cancers whereas in normal adult liver it is barely detectable , . However, direct evidence is lacking. DT40 cells have been reported to undergo homologous recombination at an exceptionally high frequency , . This property has earlier been exploited for targeted disruption of a number of genes , , , . To gain a better insight into the function of YB-1, we disrupted one allele of the Chk-YB-1b gene and analyzed the resulting phenotype of the heterozygous DT40 cells (DT40-YB-1b). Compared to wild-type DT40 cells, DT40-YB-1b cells have an increased cell size, increased genomic DNA content (4), and grow slowly (doubling time of approximately 35–40h compared to 12–13h for wild-type cells), resembling phenotypic abnormalities typical of cells with a defect in G2/M. We have shown further that a fraction of these mutant cells undergo apoptosis. Thus, our results provide, for the first time, direct evidence for the crucial role of YB-1 in cell growth.