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首页> 外文期刊>Cancer: A Journal of the American Cancer Society >Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy
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Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

机译：胃癌细胞中孤儿核受体NR4A2的表达赋予化学抗药性，并预示胃癌化疗患者的术后生存不利

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BACKGROUND NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score ≥ 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P =.011), especially for those who received 5-fluorouracil-based chemotherapy (P =.016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumorode/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLUSIONS High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-3445.
机译：背景技术NR4A2是多巴胺能神经元产生中必不可少的孤儿核受体，最近已与炎症和癌症联系在一起。本研究试图确定NR4A2在胃癌（GC）的化学耐药性和术后预后中的作用。方法将NR4A2转染GC细胞，研究其对5-氟尿嘧啶化学耐药性及裸鼠致瘤性的作用。本研究还研究了前列腺素E2（PGE2）诱导的NR4A2表达及其对化学耐药性的影响。免疫组化检查了I期至III期GC患者的手术标本中NR4A2的表达。 245名患者的中位随访时间为76个月。结果NR4A2的异位表达显着增加了化学耐药性并减弱了5-氟尿嘧啶诱导的细胞凋亡。用PGE2短暂处理GC细胞可通过蛋白激酶A途径显着上调NR4A2表达，并增加化学抗性。 NR4A2的异位表达显着增加了致瘤性。在临床样品中，NR4A2在邻近粘膜的淋巴细胞和上皮细胞质中优先表达。癌细胞中NR4A2的高表达（免疫反应评分≥3）显着预示了I至III期GC患者的疾病特异性生存不良（P = .011），特别是对于接受了基于5氟尿嘧啶的化疗的患者（P = .016）。在没有化疗的患者中未发现这种作用。在多变量Cox分析中，年龄，TNM（肿瘤/淋巴结/转移）阶段和高NR4A2表达显着预测了术后生存不良。结论GC细胞中较高的NR4A2表达赋予化学抗性，减弱5-氟尿嘧啶诱导的细胞凋亡，并预测不良的存活率，尤其是对于那些接受化学疗法的患者。 NR4A2可能作为GC患者的预后和预测因素以及治疗目标。癌症2013; 119：3436-3445。

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