Abstract
Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.
Highlights
Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for 8-10% of childhood cancers in the USA and Europe [1], with an incidence of 10.5 per million children and affecting males slightly more often than females (1.2:1.0) [2]
High levels of DDX39A and PBX1 were found in all tumor samples while high mobility group A (HMGA) proteins showed poor (HMGA1) or no (HMGA2) endogenous expression in tumor cells (Table 4)
We found that cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids
Summary
Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for 8-10% of childhood cancers in the USA and Europe [1], with an incidence of 10.5 per million children and affecting males slightly more often than females (1.2:1.0) [2]. Biomarkers of neuroblastoma cell response to retinoids surgery, radiotherapy, high-dose chemotherapy with autologous stem cell transplantation, biologics and immunotherapy is administered to these patients. Differentiation therapy with retinoids in patients with minimal residual disease was proven to be effective, since such a treatment was reported to prevent tumor relapse after myeloablative therapy. Retinoids as differentiation inducers represent an important part of high-risk NBL treatment, their toxicity and acquired resistance to retinoids limit their use in clinical practice [5]. Identifying molecular markers that can predict the therapeutic response to retinoids is an important aspect for their use in clinical practice [6]
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