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 a, b and g in human neuroblastoma cells had di erent e ects on growth and retinoid sensitivity. Only overexpressed RARb induced profound growth inhibition in the absence of additional retinoid, and increased retinoid sensitivity. In this study, we measured mRNA expression levels of RARa, b, and g in 50 primary neuroblastoma tumor samples, and found a strong correlation between favorable patient prognosis and high-level RARb expression. Human neuroblastoma cells transfected with a vector expressing RARb demonstrated irreversible growth arrest following a 1 week exposure to all-transretinoic acid, whereas control cells continued to proliferate. In the absence of additional retinoid, RARb transfectants demonstrated a higher proportion of cells in the G 0 /G 1 phase of the cell cycle, increased p21 WAF1/CIP1 expression and speci®c 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 RARb is an important factor mediating the growth inhibitory e ects of retinoids in neuroblastoma cells. The favorable e ect of high-level RARb expression on prognosis in primary tumor tissue may occur through RARb e ects on p21 expression and consequent G 0 /G 1 cell cycle arrest.

Retinoid therapy of high-risk neuroblastoma

“…There was no correlation seen between resistance to RA and the level of RAR or RXR expression. However, higher expression of RAR b has been associated with good outcome in neuroblastoma and overexpression of that gene by transfection appears to increase the responsiveness of some neuroblastoma cell lines to RA [7]. Thus, while alterations in RAR or RXR do not appear to be a major mechanism by which neuroblastoma achieves RA resistance, higher levels of expression for these receptors may enhance sensitivity to retinoids.…”

All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

“…Correspondingly, RARB, RARRES1 and RARRES3 mRNA levels were found to be repressed in many different tumors (Freemantle et al, 2003;Shyu et al, 2003;Sriuranpong et al, 2004). Moreover, downregulation of RARB and RARRES3 could be associated with disease progression in neuroblastoma (Cheung et al, 1998) and B-cell lymphocytic leukemia (Casanova et al, 2001), respectively. In our previous microarray analysis of 77 Wilms tumors, RARRES1 and RARRES3 were also downregulated in advanced tumors.…”

The Estrogen-responsive B Box Protein Is a Novel Regulator of the Retinoid Signal

“…BE cells cultured in T25 flasks were transfected with either ␤RARE decoy (5 M) or scrambled (5 M) oligonucleotides using 192 g/ml of SuperFect (Qiagen) for 2 h. The medium was then replaced and supplemented with 10 M aRA for 24 h. To test the efficacy of the oligonucleotide decoy at blocking responses through the ␤RARE, BE neuroblastoma cells with low level constitutive RAR␤ expression, as measured by a competitive reverse transcription (RT)-PCR (27), were used.…”