Increased retinoic acid receptor gamma expression suppresses the malignant phenotype and alters the differentiation potential of human neuroblastoma cells.
Increased retinoic acid receptor gamma expression suppresses the malignant phenotype and alters the differentiation potential of human neuroblastoma cells.
复制标题
视黄酸受体γ表达增加可抑制恶性表型并改变人神经母细胞瘤细胞的分化潜力。
作者：
G. Marshall;B. Cheung;K. Stacey;M. Camacho;A. Simpson;E. Kwan;Stewart A. Smith;M. Haber;Norris
在体外用类维生素A、全反式视黄酸（aRA）处理的人神经母细胞瘤（NB）肿瘤细胞系形成神经突并经历生长停滞。类维生素A通过涉及核类维生素A受体的信号通路发挥其不同的形态学作用。维甲酸受体（RAR）功能缺陷导致了几种人类和实验性肿瘤的恶性表型。来自基因破坏研究的相当多的证据现在表明，RAR之一，RAR γ，可能直接介导一些类维生素A对胚胎和恶性细胞的影响。我们首先检查了原发性NB肿瘤组织的内源性RAR γ表达与肿瘤临床分期之间的相关性，其次检查了RAR γ基因的外源性过表达对人NB肿瘤细胞系的影响。32例原发性NB肿瘤组织样本中RAR γ mRNA表达在临床定位肿瘤中显著高于晚期或播散性肿瘤。用过表达人RAR γ cDNA的哺乳动物表达载体（pREP 4）稳定转染人NB肿瘤细胞系BE（2）-C。与对照细胞相比，两个选择的过表达RAR γ的克隆（BE/G1和2）表现出降低的生长速率。BE/G1细胞的致瘤性受到抑制，BE/G2细胞的肿瘤形成延迟。ARA引起BE/G克隆的生长抑制，但不引起神经炎分化，而9-顺式维甲酸引起生长停滞和神经炎分化。总之，这些结果表明，减少内源性RAR γ表达可能有助于人类NB的恶性表型。在NB细胞中，用于神经炎分化的类维生素A信号传导途径可能不同于引起生长抑制的信号传导途径。
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.