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

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


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.

Keywords: Apoptosis; Chemo-resistance; Colorectal carcinoma; Inflammation; NR4A2; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / drug therapy*
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / mortality
  • Adenoma / pathology
  • Adenoma / surgery
  • Adenomatous Polyposis Coli / drug therapy*
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / metabolism
  • Adenomatous Polyposis Coli / mortality
  • Adenomatous Polyposis Coli / pathology
  • Adenomatous Polyposis Coli / surgery
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Chemotherapy, Adjuvant
  • Chi-Square Distribution
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / surgery
  • Dinoprostone / metabolism
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Fluorouracil / administration & dosage
  • HCT116 Cells
  • Humans
  • Intestinal Polyps / drug therapy*
  • Intestinal Polyps / genetics
  • Intestinal Polyps / metabolism
  • Intestinal Polyps / mortality
  • Intestinal Polyps / pathology
  • Intestinal Polyps / surgery
  • Kaplan-Meier Estimate
  • Leucovorin / administration & dosage
  • Multivariate Analysis
  • Neoplasm Staging
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • Organoplatinum Compounds / administration & dosage
  • Proportional Hazards Models
  • Time Factors
  • Transfection
  • Treatment Outcome
  • Up-Regulation


  • Biomarkers, Tumor
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Organoplatinum Compounds
  • Dinoprostone
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol