Increased retinoic acid receptor gamma expression suppresses the malignant phenotype and alters the differentiation potential of human neuroblastoma cells.
Human neuroblastoma (NB) tumor cell lines treated in vitro with the retinoid, all-trans-retinoic acid (aRA), form neurites and undergo growth arrest. Retinoids exert their diverse morphologic effects through a signalling pathway which involves the nuclear retinoid receptors. Defective retinoic acid receptor (RAR) function contributes to the malignant phenotype of several human and experimental tumors. Considerable evidence from gene disruption studies now suggests that one of the RARs, RAR gamma, may directly mediate some retinoid effects on embryonic and malignant cells. We, firstly, examined primary NB tumor tissue for a correlation between endogenous RAR gamma expression and clinical stage of the tumor and secondly, the effects of exogenous over-expression of the RAR gamma gene on a human NB tumor cell line. RAR gamma mRNA expression in 32 primary NB tumor tissue samples were significantly higher in clinically localised tumors compared with advanced or disseminated tumors. The human NB tumor cell line, BE(2)-C, was stably transfected with a mammalian expression vector (pREP4) over-expressing the human RAR gamma cDNA. Two selected clones over-expressing RAR gamma (BE/G1 and 2) exhibited a reduced growth rate compared to control cells. Tumorigenicity was inhibited for BE/G1 cells and there was a delayed onset to tumor formation for BE/G2 cells. aRA caused growth inhibition but not neuritic differentiation of the BE/G clones, while 9-cis-retinoic acid caused both growth arrest and neuritic differentiation. Taken together these results suggest that reduced endogenous RAR gamma expression may contribute to the malignant phenotype of human NB. In NB cells the retinoid signalling pathway for neuritic differentiation may be distinct from that causing growth inhibition.
Marshall
G M
GM
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Randwick, Australia.
Cheung
B
B
Stacey
K P
KP
Camacho
M L
ML
Simpson
A M
AM
Kwan
E
E
Smith
S
S
Haber
M
M
Norris
M D
MD
D000311:Adrenal Glands / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016501:Neurites / Q000648:ultrastructure; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D017931:DNA Primers; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma