Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy

Abstract

Purpose: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP.Experimental Design: Eight SNPs (rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsamir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs.Results: We found that the microRNA-499 rs3746444T>C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02-1.49; P ¼ 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01-1.71; P ¼ 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12-1.86; P ¼ 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance.Conclusion: Our findings suggested that the rs3746444T>C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis.

Associations between genetic variants located in mature microRNAs and risk of lung cancer

“…A recent meta-analysis showed that miR-499 rs3746444 polymorphism contributed to increased risk of many cancers (GG versus AA: OR = 1.24, 95% CI: 1.01-1.52; G versus A: OR = 1.11, 95% CI: 1.01–1.23) [32]. This is consistent with our results, which revealed that rs3746444 in mir-499 was significantly associated with increased risk of lung cancer, and the carriers of minor allele C have higher expression levels of mir-499 than those of major allele T. Very recently, Qiu et al [37] also reported that rs3746444 could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy. Furthermore, the in silico functional analysis of rs3746444 and rs4919510 was conducted by miRVaS: a tool to predict the impact of genetic variants on miRNAs [38].…”

GLNMDA: a novel method for miRNA-disease association prediction based on global linear neighborhoods

“…For instance, the hsa-let-7 family which regulates the cell cycle and the hsa-mir-200 family that induces cell death and cell proliferation were all differentially expressed in LN tumor samples[50]. Among the five unconfirmed miRNAs, hsa-miR-499 has been found that the rs3746444T> C polymorphism in its mature sequence could contribute to poor prognosis by modulating cancer-related gene expression and thus involve in the tumorigenesis of LN[51]. Besides, studies have shown that miR-103 was able to promote proliferation of small cell lung cancer cells through targeting MED26 mRNA 3ʹ-UTR[52].…”

miRNA-486 and miRNA-499 in human plasma evaluate the clinical stages of lung cancer and play a role as a tumor suppressor in lung tumorigeneisis not pathogenesis

“…We got the similar data that the expression of miR-499 don't have any statistical significance on clinicopathologic features in SCLC and NSCLC, but I/II stage with III/IV stage and differentiation degree in NSCLC. miR-499 could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which maybe a useful biomarker to predict lung cancer patients' prognosis (Qiu et al, 2015).…”

“…miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo (Peng et al, 2013). miR-499 could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy (Qiu et al, 2015). It may influence the expression of a series cancer-related genes that might be annotated to immunity and defense, cell growth, tumor invasion and metastasis, cancer stem cell, and cell death, although no available evidences supported any genes to be known or predicted target genes of miR-499.…”