RESUMEN
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.
Asunto(s)
Adenoma/tratamiento farmacológico , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Pólipos Intestinales/tratamiento farmacológico , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adenoma/mortalidad , Adenoma/patología , Adenoma/cirugía , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/metabolismo , Poliposis Adenomatosa del Colon/mortalidad , Poliposis Adenomatosa del Colon/patología , Poliposis Adenomatosa del Colon/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Dinoprostona/metabolismo , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Fluorouracilo/administración & dosificación , Células HCT116 , Humanos , Pólipos Intestinales/genética , Pólipos Intestinales/metabolismo , Pólipos Intestinales/mortalidad , Pólipos Intestinales/patología , Pólipos Intestinales/cirugía , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Análisis Multivariante , Estadificación de Neoplasias , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Compuestos Organoplatinos/administración & dosificación , Modelos de Riesgos Proporcionales , Factores de Tiempo , Transfección , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
BACKGROUND: Risk factors for clear cell renal cell carcinoma (ccRCC) differ among populations and remain controversial. We carried out a hospital-based case-control study to examine the effects of health status, lifestyle, and some genetic polymorphisms on ccRCC risk in Chinese subjects. METHODS: Between 2007 and 2009, 250 newly diagnosed, histologically confirmed ccRCC cases and 299 sex-, age-matched healthy controls provided complete information including consumption of tea and alcohol, smoking, occupational exposure, body mass index (BMI), hypertension, diabetes, and urolithiasis by face-to-face interview in Shanghai. Genetic polymorphisms of cytochrome P450 mono-oxygenase (CYP1A1: 6235T>C, 4889A>G, and 4887C>A), glutathione S-transferase (GSTP1: 342A>G), and N-acetyltransferase (NAT2: 481C>T, 590G>A, and 857G>A) were identified by PCR-RFLP and DNA sequencing. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were derived through multivariate logistic regression. RESULTS: Green tea intake (≥500 ml/d) was inversely associated with ccRCC risk, with an AOR of 0.34 (95% CI 0.21-0.55). BMI (≥25 kg/m(2)), hypertension, and urolithiasis were independently associated with an increased risk of ccRCC, with AOR (95% CI) of 2.10 (1.32-3.34), 2.49 (1.57-3.93), and 3.33 (1.12-9.89), respectively. No association was observed between smoking, alcohol consumption, or occupational exposure with ccRCC risk. The polymorphisms and their interactions with the environmental exposures were mostly not associated with ccRCC risk. CONCLUSION: BMI (≥25 kg/m(2)), hypertension, and urolithiasis are independently associated with an increased risk, whereas green tea intake (≥500 ml/d) is independently associated with a decreased risk of ccRCC. The polymorphisms of the xenobiotic-metabolizing enzymes are weakly associated with ccRCC risk in Chinese subjects.