Study On The Correlation Between MiRNAs In Advanced Lung Adenocarcinoma And The Efficacy Of Platinum-containing Dual-drug Chemotherapy

Objective: Lung cancer is the most common carcinoma with highest morbidity and mortality in China,80% of which is non-small cell lung cancer(NSCLC).Platinum still plays a cornerstone role in the treatment of advanced NSCLC.Growing evidence has demonstrated that mi RNAs can modulate the sensitivity of platinum and that mi RNAs can be used as potential biomarkers for prediction of platinum-based chemotherapy response in patients with lung adenocarcinoma.However,the relevant studies of these mi RNAs were almost all conducted in in vitro.The purpose of this study was to evaluate whether platinum-resistance-related mi RNAs,alone or in combination,could be used as biomarkers to predict the efficacy of platinum-based chemotherapy in patients with advanced lung adenocarcinoma.Besides,we also try to explore the potential drug resistance pathways.Methods: According to results of our previous research and other references,eight mi RNAs which were most likely related to the efficacy of platinum were screened,and the expression of these mi RNAs in 111 cases of advanced lung adenocarcinoma tumor tissues was determined.Univariate,multivariate Cox regression analysis,KaplanMeier survival analysis,chi-square test,univariate and multivariate Logistic regression analysis were used to explore which mi RNA expression was correlated with the response of patients with advanced lung adenocarcinoma to platinum-based chemotherapy.The most significant OR values were obtained by multivariate Logistic regression analysis over multiple cycles and the cut-off values of mi RNAs were obtained meantime.The mi RNAs chemo-sensitivity index(CI)prediction model was established by Logistic regression analysis of the train set,and then the predictive efficacy of this model was verified in the test set(31 patients with advanced lung adenocarcinoma).In addition,we also predicted the target genes of mi RNAs and analyzed their related signaling pathways through bioinformatics analysis.Results: This study found that lower expression levels of six mi RNAs(mi RNA-21,mi RNA-27 b,mi RNA-100,mi RNA-125 b,mi RNA-181 b,mi RNA-224)were significantly associated with longer PFS in patients with advanced lung adenocarcinoma(P<0.05)by univariate,multivariate Cox regression analysis and Kaplan-Meier survival analysis.Further chi-square test,univariate and multivariate Logistic regression analysis found that the low expression of three mi RNAs(mi RNA-21,mi RNA-125 b,mi RNA-224)was independently associated with chemotherapy sensitivity in patients with lung adenocarcinoma.To better predict the response of patients with lung adenocarcinoma to platinum,we further established a CI predictive model that included these three mi RNAs,CI =(1.364 × mi R-21)+(1.323 × mi R-125b)+(1.131 × mi R-224).The higher the value of CI suggested that the tumor was more likely to be resistant to platinum,and its predictive performance was verified in the test group(n=31).Potential target genes and pathways associated with three mi RNAs(mi RNA-21,mi RNA-125 b,mi RNA-224)were predicted and the MAPK,PI3K-Akt,c GMP-PKG and Ras signaling pathways were most probably associated with platinum resistance.CONCLUSIONS: The expression of mi RNA-21,mi RNA-125 b,and mi RNA-224 in advanced lung adenocarcinoma tissues is significantly associated with the efficacy of platinum-based chemotherapy,and the CI prediction model with mi RNAs we established can be used as an independent predictor of the efficacy of platinum-based chemotherapy in patients with advanced lung adenocarcinoma.