Favorable prognostic significance of high-level retinoic acid receptor β expression in neuroblastoma mediated by effects on cell cycle regulation

Abstract

We have previously shown that ectopic overexpression of retinoic acid receptor (RAR) subtypes α, β and γ in human neuroblastoma cells had different effects on growth and retinoid sensitivity. Only overexpressed RARβ induced profound growth inhibition in the absence of additional retinoid, and increased retinoid sensitivity. In this study, we measured mRNA expression levels of RARα, β, and γ in 50 primary neuroblastoma tumor samples, and found a strong correlation between favorable patient prognosis and high-level RARβ expression. Human neuroblastoma cells transfected with a vector expressing RARβ demonstrated irreversible growth arrest following a 1 week exposure to all-trans-retinoic acid, whereas control cells continued to proliferate. In the absence of additional retinoid, RARβ transfectants demonstrated a higher proportion of cells in the G₀/G₁ phase of the cell cycle, increased p21^WAF1/CIP1 expression and specific binding to a retinoic acid response element. These were changes which we also observed in control neuroblastoma cells following retinoid treatment. Our data indicate that RARβ is an important factor mediating the growth inhibitory effects of retinoids in neuroblastoma cells. The favorable effect of high-level RARβ expression on prognosis in primary tumor tissue may occur through RARβ effects on p21 expression and consequent G₀/G₁ cell cycle arrest.