A miR‐15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum‐based chemotherapy

Abstract

Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.

ERCC1 polymorphism and its expression associated with ischemic stroke in Chinese population

“…In addition, Yu et al predicted the ERCC1 mRNA secondary structure between two genotypes of rs3212986 by bioinformatics software and found that ERCC1 rs3212986 genetic variation may affect DNA repair capacity by altering the folded stem-loop structure consisting of six repeats of “GCT”, which could impact the 18-base sequence in the 3′-UTR of ERCC1 ( 25 ). Furthermore, ERCC1 mRNA expression may be regulated by miRNAs, which could also be affected by the rs3212986 polymorphism in the target complementary sequence ( 16 , 26 ). There were some candidate miRNAs in the ERCC1 3′-UTR region identified by online websites (miRNASNP-v3, miRBase, and TargetScan Release 7.2), including 4 miRNAs of target gain (hsa-miR-3185, hsa-miR-7-5p, hsa-miR-10522-5p, and hsa-miR-6077) and 2 miRNAs of target loss (hsa-miR-6828-5p and hsa-miR-671-5p) in 3'-UTR of ERCC1 .…”

“…It was suggested that A allele of the ERCC1 rs3212986 polymorphism might be a risk factor for ischemic stroke. The ERCC1 rs3212986 polymorphism, located on the 3'-UTR of the ERCC1 gene, has been widely studied in previous studies (16,22,23) and might be involved in the potential pathophysiological mechanism in ischemic stroke. ERCC1 rs3212986 polymorphism might affect the DNA repair capacity and interfere with the NER pathway by regulating ERCC1 transcription and translation and/or altering ERCC1 biological activity (24,25).…”

“…Genome-wide association studies have been conducted to confirm the relationship between genetic polymorphisms and susceptibility to ischemic stroke (14,15). Recently, several common and putatively functional single nucleotide polymorphisms (SNPs) of ERCC1 have been identified, of which ERCC1 C118T (rs11615) at exon 4 without amino acid change and ERCC1 C8092A (rs3212986) located at the 3'-untranslated region (3'-UTR) were likely to have some effects on ERCC1 mRNA expression, which played an important role in cancer susceptibility, clinical phenotype diversity, and therapy (16)(17)(18). As everyone knows, the 3'-UTR of a gene is strongly related to regulating transcription and translation.…”