levoleucovorin and Intestinal-Polyps

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.. 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.. 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).. 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.

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Chemotherapy, Adjuvant; Chi-Square Distribution; Colorectal Neoplasms; Dinoprostone; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fluorouracil; HCT116 Cells; Humans; Intestinal Polyps; Kaplan-Meier Estimate; Leucovorin; Multivariate Analysis; Neoplasm Staging; Nuclear Receptor Subfamily 4, Group A, Member 2; Organoplatinum Compounds; Proportional Hazards Models; Time Factors; Transfection; Treatment Outcome; Up-Regulation

Topics: Adult; Anemia, Hypochromic; Arthroplasty, Replacement, Hip; Chronic Disease; Colitis; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Ferric Compounds; Folic Acid; Humans; Intestinal Polyps; Leucovorin; Malabsorption Syndromes; Male; Methotrexate; Osteoarthritis, Hip; Preoperative Care; Recombinant Proteins; Rectal Diseases; Remission Induction; Spondylitis, Ankylosing; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Child; Colonoscopy; Cyclophosphamide; Doxorubicin; Gastrointestinal Hemorrhage; Humans; Hydrocortisone; Immunophenotyping; Intestinal Mucosa; Intestinal Polyps; Leucovorin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Methotrexate; Methylprednisolone; Rectum; Vincristine