6533b7dcfe1ef96bd1271fea

RESEARCH PRODUCT

Retinoic-Acid-Induced Downregulation of the 67 KDa Laminin Receptor Correlates with Reduced Biological Aggressiveness of Human Neuroblastoma Cells

subject

description

Neuroblastoma is a common tumor of the childhood arising from embryonal sympathetic neural cell precursors. Despite of the improved therapeutic strategies, the survival rate of high-risk neuroblastoma patients is poor. Although complete clinical remissions can be achieved, relapse is relatively frequent, indicating a role for the persistence of the minimal residual disease (for review, Maris, 2010). Treatments with derivatives of retinoic acid (RA), the biologically active form of vitamin A, produce significant improvements on the therapy of high-risk neuroblastoma patients, when used together with intensive multimodal therapies (Reynolds et al., 2003, for review). Despite some controversy on dosage and treatment schedules (Matthay & Reynolds, 2000; Reynolds et al., 2003), treatment with 13cis-RA (isotretinoin) has been reported to produce a modest but significant increase in the event-free survival of high-risk neuroblastoma patients (Matthay et al., 2009; Matthay et al., 1999). RA and its derivatives, the retinoids, are differentiating agents that induce growth arrest, differentiation and/or apoptosis of neuroblastoma cells in vitro (Lovat et al., 1997; Pahlman et al., 1984; Sidell, 1982; Thiele et al., 1985). However the molecular bases of RA therapeutic actions in neuroblastoma have not been established yet. With the aim of identifying possible molecular targets for RA treatment, we have analyzed RA-induced gene expression changes in SH-SY5Y cultured human neuroblastoma cells (Lopez-Carballo et al., 2002), by means of Ordered Differential Display RT-PCR (Matz et al., 1997). Among more than 60 genes identified, we could found LAMR1 (also called RPSA), encoding the precursor for the 67-KDa Laminin Receptor (67LR) (Wewer et al., 1986; Yow et al., 1988), whose mRNA levels were remarkably reduced after RA treatment. The 67LR is a multifunctional protein which is involved in cell adhesion, required for maintaining of cell viability (Scheiman et al., 2010; Susantad & Smith, 2008), acts as receptor for infectious agents like viruses and prions (Vana et al., 2009) and mediates the actions of the green tea polyphenol epigallocatechin-3-gallate (Umeda et al., 2008). Expression of 67LR has been