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Abstract
BackgroundImmunohistochemical detection of cold shock proteins is predictive for deleterious outcome in various malignant diseases. We recently described active secretion of a family member, denoted Y-box (YB) protein-1. We tested the clinical and diagnostic value of YB-1 protein fragment p18 (YB-1/p18) detection in blood for malignant diseases.MethodsWe used a novel monoclonal anti-YB-1 antibody to detect YB-1/p18 by immunoblotting in plasma samples of healthy volunteers (n = 33), patients with non-cancerous, mostly inflammatory diseases (n = 60), hepatocellular carcinoma (HCC; n = 25) and advanced solid tumors (n = 20). YB-1/p18 was then tested in 111 patients with chronic liver diseases, alongside established tumor markers and various diagnostic measures, during evaluation for potential liver transplantation.ResultsWe developed a novel immunoblot to detect the 18 kD fragment of secreted YB-1 in human plasma (YB-1/p18) that contains the cold-shock domains (CSD) 1-3 of the full-length protein. YB-1/p18 was detected in 11/25 HCC and 16/20 advanced carcinomas compared to 0/33 healthy volunteers and 10/60 patients with non-cancerous diseases. In 111 patients with chronic liver disease, YB-1/p18 was detected in 20 samples. Its occurrence was not associated with advanced Child stages of liver cirrhosis or liver function. In this cohort, YB-1/p18 was not a good marker for HCC, but proved most powerful in detecting malignancies other than HCC (60% positive) with a lower rate of false-positive results compared to established tumor markers. Alpha-fetoprotein (AFP) was most sensitive in detecting HCC, but simultaneous assessment of AFP, CA19-9 and YB-1/p18 improved overall identification of HCC patients.ConclusionsPlasma YB-1/p18 can identify patients with malignancies, independent of acute inflammation, renal impairment or liver dysfunction. The detection of YB-1/p18 in human plasma may have potential as a tumor marker for screening of high-risk populations, e.g. before organ transplantation, and should therefore be evaluated in larger prospective studies.
Highlights
Immunohistochemical detection of cold shock proteins is predictive for deleterious outcome in various malignant diseases
Study populations In this survey, five independent cohorts were tested for the diagnostic value of YB-1/p18 in human plasma: (i) healthy volunteers (n = 33), (ii) patients with chronic renal disorders and/or acute infections (n = 60), (iii) patients with solid tumors with hepatic metastases (n = 20), (iv) patients with known and histologically proven non-metastasizing hepatocellular carcinoma (n = 25), and (v) patients with chronic liver diseases (n = 111)
YB-1 protein complexes are present in plasma samples To address whether YB-1 protein and fragments thereof are present in plasma samples of healthy volunteers, immunoblotting was performed
Summary
Immunohistochemical detection of cold shock proteins is predictive for deleterious outcome in various malignant diseases. A pivotal role for cold shock proteins has been originally described in breast cancer, as these proteins relate to cell transformation and confer aggressive tumor growth [1,2]. The overexpression of one prototypic member of this correlation of upregulated, mostly nuclear YB-1 expression with poor outcome, e.g. early relapses and tumor growth, suggesting high YB-1 expression is an independent negative prognostic marker for many solid tumors. Transcription rates of proliferation-associated genes are upregulated by YB-1, e.g. DNA-polymerase-a [10], epidermal growth-factor receptor [11], plateletderived growth factor [12] and matrix metalloproteinase-2 [13]. YB-1 facilitates wt-p53 binding to DNA motifs, not of mutated p53, and represses cell death-associated fas gene transcription [14]. Adenocarcinoma, hepatoma, fibrosarcoma, and colon cancer cells die with YB-1 knock-down [17,18]
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