RESUMEN

Lung cancer is one of the leading causes of cancer-associated mortality. Non-small cell lung carcinoma (NSCLC) accounts for 70-85% of the total cases of lung cancer. Radioresistance frequently develops in NSCLC in the middle and later stages of radiotherapy. We investigated the role of miR-219a-5p in radioresistance of NSCLC. miR-219a-5p expression in serum and lung tissue of lung cancer patients was lower than that in control. Compared with radiosensitive (RS) NSCLC patients, miR-219a-5p expression was decreased in serum and lung tissue in radioresistant patients. miR-219a-5p expression level was negatively associated with radioresistance in NSCLC cell lines. Up-regulation of miR-219a-5p increased radiosensitivity in radioresistant NSCLC cells in vitro and in vivo. Down-regulation of miR-219a-5p decreased radiosensitivity in radiosensitive A549 and H358 cells. miR-219a-5p could directly bind in the 3'UTR of CD164 and negatively regulated CD164 expression. CD164 expression was higher in radioresistant NSCLC tissues than RS tissues. Up-regulation of CD164 significantly inhibited miR-219a-5p-induced regulation of RS in radioresistant A549 and H358 cells. Down-regulation of CD164 significantly inhibited the effect of anti-miR-219a-5p on radiosensitive A549 and H358 cells. miR-219a-5p or down-regulation of CD164 could increase apoptosis and γ-H2A histone family member X (γ-H2AX) expression in radioresistant cells in vitro and in vivo. Up-regulation of CD164 could inhibit the effect of miR-219a-5p on apoptosis and γ-H2AX expression. Our results indicated that miR-219a-5p could inhibit CD164, promote DNA damage and apoptosis and enhance irradiation-induced cytotoxicity. The data highlight miR-219a-5p/CD164 pathway in the regulation of radiosensitivity in NSCLC and provide novel targets for potential intervention.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , MicroARNs/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Tolerancia a Radiación/genética , Células A549 , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Regulación hacia Abajo , Endolina/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Ratones , MicroARNs/agonistas , MicroARNs/antagonistas & inhibidores , MicroARNs/sangre , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/prevención & control , Fotones/uso terapéutico , Neumonectomía , Radioterapia Adyuvante/métodos , Tasa de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto