核孤儿受体 NR4A2 赋予结直肠癌患者对术后化疗的耐药性，并预测其预后不良。

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

机构信息

Department of Epidemiology, Second Military Medical University, Shanghai, China.

出版信息

Eur J Cancer. 2013 Nov;49(16):3420-30. doi: 10.1016/j.ejca.2013.06.001. Epub 2013 Jun 25.

DOI:10.1016/j.ejca.2013.06.001

PMID:23809767

Abstract

BACKGROUND

NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown.

METHODS

NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months.

RESULTS

Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020).

CONCLUSION

High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

摘要

背景

NR4A2 是一种在神经元生成中必不可少的孤儿核受体，最近与结直肠癌（CRC）的炎症和代谢途径有关。然而，NR4A2 对 CRC 的化疗耐药性和术后预后的影响尚不清楚。

方法

将 NR4A2 转染到 CRC 细胞中，以研究其对 5-氟尿嘧啶和奥沙利铂的化疗耐药性以及化疗诱导的细胞凋亡的影响。我们还研究了前列腺素 E2（PGE2）诱导的 NR4A2 表达及其对化疗耐药性的影响。使用组织微阵列对 51 个腺瘤、14 个家族性腺瘤性息肉病伴 CRC、17 个 IV 期 CRC 伴相邻黏膜和 682 个 I-III 期 CRC 标本进行了 NR4A2 表达的免疫组织化学检查。对 I-III 期 CRC 患者的中位随访时间为 53 个月。

结果

NR4A2 的异位表达增加了化疗耐药性，并减弱了化疗诱导的细胞凋亡。短暂的 PGE2 处理通过蛋白激酶 A 途径显著上调了 NR4A2 的表达，并增加了化疗耐药性。上皮细胞中 NR4A2 的表达从腺瘤、相邻黏膜到 CRC 依次增加（P(trend)<0.001）。在多变量 Cox 回归分析中，癌症细胞核中高 NR4A2 表达（免疫反应性评分≥4）显著预测 CRC 患者的疾病特异性生存率（DSS）较短（风险比[HR]=1.88，P=0.024）。高 NR4A2 表达特异性预测了结肠癌患者的 DSS 较短（二分法，HR=2.55，对数秩检验 P=0.011），特别是那些接受术后 5-氟尿嘧啶/亚叶酸钙加奥沙利铂（FOLFOX）化疗的患者（3 分范围，HR=1.86，对数秩检验 P=0.020）。