RESUMEN
Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.
Asunto(s)
Biomarcadores de Tumor/metabolismo , MicroARNs/metabolismo , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata/terapia , Tolerancia a Radiación/genética , Receptor alfa X Retinoide/genética , Alitretinoína/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Quimioradioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Calicreínas/sangre , Estimación de Kaplan-Meier , Masculino , Ratones , MicroARNs/agonistas , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Cultivo Primario de Células , Pronóstico , Próstata/patología , Próstata/cirugía , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Tolerancia a Radiación/efectos de los fármacos , Receptor alfa X Retinoide/agonistas , Tasa de Supervivencia , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten-/-/trp53-/- mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.