The RNA editing enzyme ADAR modulated by the rs1127317 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma.
Life Sci
; 296: 120408, 2022 May 01.
Article
em En
| MEDLINE
| ID: mdl-35202641
ABSTRACT
AIMS:
The adenosine-to-inosine (A-to-I) RNA editing controlled by the editing genes are known to diversify transcripts in human. Aberrant A-to-I editing due to dysregulation of the editing genes are involved in cancer development. However, it is still largely unclear how single nucleotide polymorphisms (SNPs) in the A-to-I editing genes confer to recurrence and/or drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small-cell lung cancer (NSCLC). MATERIALS ANDMETHODS:
In this study, we systematically evaluated and validated the role of twenty-eight potential functional genetic variants in four A-to-I editing genes (ADAR, ADARB1, ADARB2 and AIMP2) in prognosis of NSCLC patients receiving EGFR-TKIs. KEYFINDINGS:
We identified the ADAR rs1127309, rs1127317, and rs2229857 SNPs markedly contributing to prognosis of patients treated with EGFR-TKIs. Interestingly, SNP rs1127317 locating in the ADAR 3'-untranslated region regulates gene expression in an allele-specific manner via modulating binding of miR-454-5p in cells. In support of this, patients with the rs1127317 C allele correlated with elevated ADAR expression in tumors showed profoundly shorten survival after EGFR-TKIs therapy compared to the A allele carriers. Silencing of ADAR notably enhanced gefitinib sensitivities of NSCLC cells.SIGNIFICANCE:
Our findings highlight the importance of the A-to-I RNA editing in drug resistance and nominate ADAR as a potential therapeutic target for unresectable NSCLC.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Adenosina Desaminase
/
Proteínas de Ligação a RNA
/
Inibidores de Proteínas Quinases
/
Adenocarcinoma de Pulmão
/
Neoplasias Pulmonares
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Life Sci
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China