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

作者：Han Yifang; Cai Hui; Ma Liye; Ding Yibo; Tan Xiaojie; Liu Yan; Su Tong; Yu Yongwei; Chang Wenjun; Zhang Hongwei; Fu Chuangang; Cao Guangwen^*

来源：European Journal of Cancer, 2013, 49(16): 3420-3430.

DOI：10.1016/j.ejca.2013.06.001

• NR4A2
• Chemo-resistance
• Apoptosis
• Prognosis
• Inflammation
• Colorectal carcinoma

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 (PGE(2))-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.

• 出版日期2013-11
• 单位中国人民解放军第二军医大学