Functional validation of miRNAs targeting genes of DNA double-strand break repair to radiosensitize non-small lung cancer cells.
Biochim Biophys Acta Gene Regul Mech
; 1861(12): 1102-1118, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-30389599
ABSTRACT
DNA-Double strand breaks (DSBs) generated by radiation therapy represent the most efficient lesions to kill tumor cells, however, the inherent DSB repair efficiency of tumor cells can cause cellular radioresistance and impact on therapeutic outcome. Genes of DSB repair represent a target for cancer therapy since their down-regulation can impair the repair process making the cells more sensitive to radiation. In this study, we analyzed the combination of ionizing radiation (IR) along with microRNA-mediated targeting of genes involved in DSB repair to sensitize human non-small cell lung cancer (NSCLC) cells. MicroRNAs are natural occurring modulators of gene expression and therefore represent an attractive strategy to affect the expression of DSB repair genes. As possible IR-sensitizing targets genes we selected genes of homologous recombination (HR) and non-homologous end joining (NHEJ) pathway (i.e. RAD51, BRCA2, PRKDC, XRCC5, LIG1). We examined these genes to determine whether they may be real targets of selected miRNAs by functional and biological validation. The in vivo effectiveness of miRNA treatments has been examined in cells over-expressing miRNAs and treated with IR. Taken together, our results show that hsa-miR-96-5p and hsa-miR-874-3p can directly regulate the expression of target genes. When these miRNAs are combined with IR can decrease the survival of NSCLC cells to a higher extent than that exerted by radiation alone, and similarly to radiation combined with specific chemical inhibitors of HR and NHEJ repair pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Carcinoma Pulmonar de Células não Pequenas
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MicroRNAs
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Rad51 Recombinase
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Proteína Quinase Ativada por DNA
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DNA Ligase Dependente de ATP
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Raios gama
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Gene Regul Mech
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Itália