World J Gastroenterol. 2012 Dec 21;18(47):6865-73. doi: 10.3748/wjg.v18.i47.6865.
NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily. It was originally considered to be essential in the generation and maintenance of dopaminergic neurons, and associated with neurological disorders such as Parkinson's disease. Recently, NR4A2 has been found to play a critical role in some inflammatory diseases and cancer. NR4A2 can be efficiently trans-activated by some proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and vascular endothelial growth factor (VEGF). The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells. NR4A2 can trans-activate Foxp3, a hallmark specifically expressed in regulatory T (Treg) cells, and plays a critical role in the differentiation, maintenance, and function of Treg cells. NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions. High density of Foxp3(+) Treg cells is significantly associated with gastrointestinal inflammation, tumor immune escape, and disease progression. NR4A2 is produced at high levels in CD133(+) colorectal carcinoma (CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E(2) in a cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent manner in CRC cells. The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer. NR4A2 trans-activates osteopontin, a direct target of the Wnt/β-catenin pathway associated with CRC invasion, metastasis, and poor prognosis. Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation, migration and in vivo angiogenesis. Taken together, NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer, especially CRC, and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.
NR4A2 是一种转录因子，属于甾体孤儿核受体超家族。它最初被认为是多巴胺能神经元生成和维持所必需的，与帕金森病等神经退行性疾病有关。最近，NR4A2 被发现与一些炎症性疾病和癌症有关。NR4A2 可以被一些促炎细胞因子（如肿瘤坏死因子-α、白细胞介素-1β 和血管内皮生长因子）有效地转录激活。核因子-κB 信号通路是免疫细胞中诱导型 NR4A 表达的主要调节因子。NR4A2 可以转录激活 Foxp3，Foxp3 是调节性 T（Treg）细胞中特有的标志物，在 Treg 细胞的分化、维持和功能中发挥关键作用。T 淋巴细胞中的 NR4A2 对于 Treg 细胞的诱导以及在生理和病理条件下抑制 Th1 的异常诱导至关重要。高密度的 Foxp3(+)Treg 细胞与胃肠道炎症、肿瘤免疫逃逸和疾病进展显著相关。NR4A2 在 CD133(+)结直肠癌（CRC）细胞中高表达，并在 CRC 细胞中以环磷酸腺苷（cAMP）/蛋白激酶 A（PKA）依赖的方式被环加氧酶-2 衍生的前列腺素 E2 显著上调。cAMP/PKA 信号通路是与炎症和癌症相关的 NR4A2 的共同通路。NR4A2 转录激活骨桥蛋白，骨桥蛋白是与 CRC 侵袭、转移和预后不良相关的 Wnt/β-catenin 通路的直接靶点。内源性 NR4A2 表达的敲低可减弱 VEGF 诱导的内皮细胞增殖、迁移和体内血管生成。综上所述，NR4A2 作为一种将胃肠道炎症与癌症（特别是 CRC）联系起来的重要核因子，应作为炎症相关胃肠道癌症的候选治疗靶点。
