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

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• 作者：Yifang Han ; Hui Cai ; Liye Ma ; Yibo Ding ; Xiaojie Tan ; Yan Liu ; Tong Su ; Yongwei Yu ; Wenjun Chang ; Hongwei Zhang ; Chuangang Fu ; Guangwen Cao
• 关键词：NR4A2 ; Chemo-resistance ; Apoptosis ; Prognosis ; Inflammation ; Colorectal carcinoma
• 刊名：European Journal of Cancer
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：49
• 期：16
• 页码：3420-3430
• 全文大小：3497 K

文摘

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.