RESUMEN
BACKGROUND: Emerging evidence suggests that stemness in cancer cells is a cause of drug resistance or metastasis and is an important therapeutic target. PR [positive regulatory domain I-binding factor 1 (PRDI-BF1) and retinoblastoma protein-interacting zinc finger gene (RIZ1)] domain containing 14 (PRDM14), that regulates pluripotency in primordial germ cell, has reported the overexpression and function of stemness in various malignancies, suggesting it as the possible therapeutic target. However, to our knowledge, there have been no reports on the expression and function of PRDM14 in colorectal cancer (CRC). Therefore, we investigated the expression and the role of PRDM14 in CRC. METHODS: We performed immunohistochemistry evaluations and assessed PRDM14 expression on 414 primary CRC specimens. Colon cancer cell lines were subjected to functional and stemness assays in vitro and in vivo. RESULTS: We found that PRDM14 positive staining exhibited heterogeneity in the CRC primary tumor, especially at the tumor invasion front. The aberrant expression of PRDM14 at the invasion front was associated with lymph node metastasis and disease stage in patients with CRC. Furthermore, the multivariate analysis revealed high PRDM14 expression as an independent prognostic factor in the patients with Stage III CRC. Overexpression of PRDM14 enhanced the invasive, drug-resistant and stem-like properties in colon cancer cells in vitro and tumorigenicity in vivo. CONCLUSION: Our findings suggest that PRDM14 is involved in progression and chemoresistance of CRC, and is a potential prognostic biomarker and therapeutic target in the CRC patients.
Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenoma/genética , Adenoma/metabolismo , Adenoma/patología , Anciano , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/genética , Femenino , Fluorouracilo/farmacología , Humanos , Inmunohistoquímica , Irinotecán/farmacología , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Trasplante de Neoplasias , Oxaliplatino/farmacología , Pronóstico , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/metabolismo , Carga TumoralRESUMEN
For several years we have screened natural products having aldose reductase (AR) inhibitory activity. 3,3',4-Tri-O-methylellagic acid 4'-sulfate potassium salt (2) was isolated from a Mexican herb "Sinfito" (Potentilla candicans) as a potent AR inhibitory active constituent. 2 was more potent (IC50 = 8.0 x 10(-8)M) than ellagic acid, which is one of the natural inhibitors of AR. So we examined the synthesis of ellagic acid derivatives and found that the sulfate group is one of the important function.