Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Center for Medical Research (ZMF), Medical University of Graz, Graz, Austria.
Cancer Res. 2017 May 1;77(9):2375-2386. doi: 10.1158/0008-5472.CAN-16-2320. Epub 2017 Mar 1.
Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. .
核孤儿受体 NR4A1 在侵袭性淋巴瘤中发挥重要的肿瘤抑制功能。在这项研究中，我们研究了相关的 NR4A 家族成员 NR4A3 对淋巴瘤发生的假设贡献。在侵袭性淋巴瘤患者中，NR4A3 的低表达与预后不良相关。在淋巴瘤细胞系中外源性表达或药理学激活 NR4A3 可导致凋亡细胞的比例显著增加。在淋巴瘤的 NSG 异种移植小鼠模型（稳定转导的 SuDHL4 细胞）中，与载体对照和未诱导的形成大肿瘤的细胞相比，NR4A3 的表达可阻断肿瘤生长。过表达 NR4A3 或 NR4A1 的四种不同侵袭性淋巴瘤细胞系的转录分析表明，凋亡是通过诱导 BAK、PUMA、BIK、BIM、BID 和 Trail 相似地驱动的。总的来说，我们的结果表明，NR4A3 在侵袭性淋巴瘤中具有与 NR4A1 相似的强大肿瘤抑制功能。
