Ke Ning, Claassen Gisela, Yu De-Hua, Albers Aaron, Fan Wufang, Tan Philip, Grifman Mirta, Hu Xiuyuan, Defife Kristin, Nguy Vivian, Meyhack Bernd, Brachat Arndt, Wong-Staal Flossie, Li Qi-Xiang
Immusol, Inc., San Diego, California 92121, USA.
Cancer Res. 2004 Nov 15;64(22):8208-12. doi: 10.1158/0008-5472.CAN-04-2134.
HeLaHF cells are transformation revertants of cervical cancer HeLa cells and have lost anchorage-independent growth potential and tumorigenicity. Activation of tumor suppressor(s) was implicated previously in this transformation reversion. In this study, expression profiling analysis was carried out to identify potential oncogenes that are down-regulated in HeLaHF cells. We found that all three members of the NR4A1/Nur77/NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2, and NR4A3) were down-regulated in the HeLaHF revertant. Small interfering RNA-mediated down-regulation of NR4A2 in HeLa cells, either transiently or stably, resulted in reduced anchorage-independent growth that was largely attributable to increased anoikis. Furthermore, down-regulation of NR4A2 as well as NR4A1 promoted intrinsic apoptosis. These phenotypes were also observed in several other experimental cancer cells, suggesting the observed apoptosis suppression is a more general property of NR4A2 and NR4A1. These phenotypes also suggest that the Nur77/NGFIB subfamily of orphan receptors exhibit certain oncogenic functionalities with regards to cell proliferation and apoptosis and could therefore be evaluated as potential cancer therapeutic targets.
HeLaHF细胞是宫颈癌HeLa细胞的转化回复突变体，已丧失不依赖贴壁生长的潜力和致瘤性。先前认为肿瘤抑制因子的激活与这种转化回复有关。在本研究中，进行了表达谱分析以鉴定在HeLaHF细胞中下调的潜在癌基因。我们发现NR4A1/Nur77/NGFIB孤儿核激素受体亚家族的所有三个成员（NR4A1、NR4A2和NR4A3）在HeLaHF回复突变体中均下调。在HeLa细胞中，通过小干扰RNA介导的NR4A2瞬时或稳定下调，导致不依赖贴壁生长减少，这在很大程度上归因于失巢凋亡增加。此外，NR4A2以及NR4A1的下调促进了内源性凋亡。在其他几种实验性癌细胞中也观察到了这些表型，表明观察到的凋亡抑制是NR4A2和NR4A1更普遍的特性。这些表型还表明，孤儿受体的Nur77/NGFIB亚家族在细胞增殖和凋亡方面表现出某些致癌功能，因此可作为潜在的癌症治疗靶点进行评估。
