| Background:Lung cancer is one of the malignant tumors with the highest mortality rate in the world.Patients with non-small small cell lung cancer(NSCLC)account for 85%of lung cancer,which is a serious threat to human life and health.According to the report of the National Cancer Registration Center,lung cancer is the most common malignant tumor in China,with about 787000 cases and 631000 deaths in 2015,which is the highest prevalence and mortality rate of cancer.In Recent years,it has been found that long non-coding RNA(lncRNA)plays an important role in the diagnosis,treatment and prognosis of NSCLC with the development of molecular biology and genomics.A large number of clinical studies have demonstrated the important value of lncRNA as a prognostic marker in NSCLC,and many anticancer drugs can regulate the regulation of lncRNA.Dysregulation of lncRNA is also associated with acquired resistance to multiple drugs.Traditional Chinese medicine(TCM)has unique advantages in the treatment of NSCLC.A large number of mechanism studies and clinical studies have proved that TCM could significantly improve the prognosis of patients.Combined with Western medicine,TCM can not only improve the efficacy,but also significantly reduce the frequency of adverse reactions,improve the life quality and prolong the survival of patients.A variety of traditional Chinese medicine components have been proved to be able to regulate the regulation of some lncRNA in cancer patients,thereby regulating the development of tumors.Therefore,we systematically review the clinical value of abnormal regulation of lncRNA for the prognosis of NSCLC,and explore the combination of traditional Chinese medicine components that can regulate prognosis-related lncRNA and the combination of traditional Chinese medicine components combined with western medicine to improve the prognosis of patients.It is very necessary for the treatment of NSCLC.Objective:To systematically evaluate the clinical value of abnormal regulation of lncRNA in the prognosis of NSCLC,and to excavate the combination of traditional Chinese medicine components and the combination of traditional Chinese medicine components combined with Western medicine that can improve the prognosis of NSCLC patients by regulating the level of lncRNA.Materials:(1)To carry out systematic review and meta-analysis,that is,to search the clinical research literature of lncRNA expression in NSCLC from seven databases,and to carry out systematic review and meta-analysis on the role of abnormal expression of lncRNA in the prognostic value of NSCLC.(2)According to the results of systematic review and meta-analysis,the lncRNAs included in the study were analyzed by bioinformatics,the competitive endogenous RNA(ceRNA)network of these lncRNAs was constructed,and the traditional Chinese medicine components and Western medicine that could act on the ceRNA network were screened.To explore the combination of traditional Chinese medicine components and the combination of traditional Chinese medicine components combined with western medicine that can improve the prognosis of patients by regulating the expression of lncRNA.Methods:(1)In this systematic review,7 literature databases at home and abroad were searched:CNKI,Wanfang,CBM,PubMed,Web of Science,EBSCO Medline and the Cochrane library.Two researchers screened the literature,evaluated the quality and extracted the data,and used R software to merge and analyze the data.To analyze the prognostic value of abnormally expressed lncRNA in the clinicopathological changes and survival of NSCLC patients.(2)The valuable lncRNAs for NSCLC prognosis verified by clinical trials in the systematic review were input into the LncACTdb database one by one,and the ceRNA network of these lncRNAs was constructed and visualized by Cytoscape3.7.2 software.TCMSP database and Drugbank database were used to search the components of Chinese medicine and western medicine that could act on the ceRNA network,and the best combination of Chinese medicine components was screened out by greedy algorithm.Results:(1)a total of 7742 original articles were retrieved,and 48 articles were included for systematic review and meta-analysis.Of the 48 articles,38 articles studied lncRNAs highly expressed in NSCLC,including 4126 cases.At the same time,there were 10 articles that studied lncRNAs with low expression in NSCLC,including 1085 cases.Overexpression of lncRNA was associated with tumor size in NSCLC(tumor size ≤3 cm:OR=0.52,95%CI=0.43-0.64;Tumor size>3 cm:OR=1.92,95%CI=1.57-2.34,P<0.01,I2=52%),pathological type(LSCC:OR=0.78,95%CI=0.65-0.95;LAD:OR=1.30,95%CI=1.081.57,P=<0.01,I2=11%),TNM stage(TNM stage Ⅰ/Ⅱ:OR=0.41,95%CI=0.29-0.57;TNM stage Ⅲ/Ⅳ:OR=2.44,95%CI=1.73-3.44,P<0.01,I2=70%),lymph node metastasis(lymph node metastasis negative OR=0.49,95%CI=0.34-0.71);Positive lymph node metastasis(OR=2.04,95%CI=1.40-2.96,P<0.01,I2=81%),pathological differentiation(low/moderate pathological differentiation OR=0.61,95%CI=0.38-0.99;High pathological differentiation(OR=1.63,95%CI=1.01-2.64,P=0.04,I2=56%),distal metastasis(OR=0.37,95%CI=0.26-0.53;Distal metastasis positive OR=2.72,95%CI=1.90-3.90,P<0.01,I2=43%)The association of these pathological features was statistically significant.Five studies that only studied TNM Ⅲa stage were included in this meta-analysis,and the results of pooled analysis were OR=4.07,95%CI=2.63-6.28,P<0.01,12=0%.The correlation between TNM Ⅲa stage and high expression of lncRNA was statistically significant,suggesting that TNM Ⅲa stage of NSCLC was associated with high expression of lncRNA.The correlation between lncRNA overexpression and NSCLC overall survival was statistically significant(HR=1.79,95%CI=1.59-2.02,P<0.01,I2=89%).Five articles on the correlation between lncRNA overexpression and NSCLC disease-free survival were pooled using a fixed-effect model.Results showed HR=3.04(95%CI=2.22-4.17),P<0.01,I2=0%,Two articles on the correlation between highly expressed IncRNA and progressionfree survival of NSCLC were pooled using a fixed-effect model,and the pooled results showed HR=2.18(95%CI=1.76-2.69),P<0.01,I2=8%,one article(2017,Li,HOXA-AS2)reported the correlation between high expression of lncRNA and relapse-free survival of NSCLC,and data analysis showed HR=6.74(9 5%CI=2.54-17.84),P<0.01.It is suggested that the correlation between highly expressed lncRNA and overall survival,disease-free survival,progression-free survival and relapse-free survival of NSCLC is statistically significant.Low expression of lncRNA was not significantly associated with pathological features and overall survival in NSCLC.(2)In LncACTdb 2.0 database,43 lncRNAs identified by meta-analysis were input into the ceRNA network in which 12 lncRNAs were retrieved.The 12 lncRNAs were LINC01234,XIST,SNHG16,LINC00668,HOTTIP,ZEB1-AS1,H19,HOXA-AS2,PVT1,HOTAIR,TUSC7,and GAS6-AS1.Through TCSMP database search,a total of 3662 TCM components were obtained,which acted on 19 mRNAs,and these 19 mRNAs were associated with 7 IncRNAs by ceRNA.Among these traditional Chinese medicine ingredients,Quercetin,luteolin,resveratrol,puerarin,triptolide,fisetin,Scutellaria baicalensis and baicalein are all proved to have anticancer pharmacological effects by experiments,and their effects on improving the prognosis of NSCLC are worthy of further study.In addition,336 kinds of western medicines and small molecules were obtained by searching Drugbank database,which acted on 48 mRNAs and 10 lncRNAs.Among the top 25 western medicines that regulate lncRNA most,20 western medicines are EGFR targeting drugs,and 3 western medicines act on VEGFA targets,which further proves that the therapeutic effects of clinical EGFR targeting drugs and angiogenesis inhibitors on NSCLC are closely related to the abnormal expression of lncRNA.(3)The components of Chinese medicine calculated by greedy algorithm were(-)epigallocatechin-3-gallate(MOL006821)and 17-beta-estradiol(17-beta-estradiol,MOL006821).MOL010919),indicating that the combined use of the two traditional Chinese medicine components can regulate all seven abnormal expression lncRNAs.The combination of the traditional Chinese medicine component and the western medicine is(-)epigallocatechin-3-gallate,MOL006821),17-beta-estradiol(MOL010919),Genistein(DB04522)and Dexfosfoserine(DB01645).(-)-Epigallocatechin-3-gallate may have a potential regulatory effect on XIST,PVT1,HOTAIR,H19,SNHG16 and LINC00668,and 17-β-estradiol may have a potential regulatory effect on XIST,PVT1,HOTAIR,H19 and HOXA-AS2.Genistein may have a potential regulatory effect on GAS6-AS1,Right phosphoserine may have a potential regulatory effect on HOTTIP.Conclusion:(1)The results of systematic review and meta-analysis show that the high expression of lncRNA may have good prognostic value for the pathological characteristics and survival time of NSCLC patients.In particular,the high expression of linc01234,ZEB1-AS1,linc00152,PVT1 and BANCR may be more accurate in predicting the prognosis of patients if combined with TNM staging.However,the prognostic value of low expression of lncRNA in NSCLC patients may need further exploration and clinical studies to further confirm.(2)Traditional Chinese medicine components such as quercetin,luteolin,resveratrol,puerarin,triptolide,fisetin,wogonin and baicalein may regulate the expression of lncRNA in tumors through the regulation of ceRNA network,thus achieving anti-tumor effect.EGFR targeted inhibitors and anti-angiogenesis drugs may have regulatory effects on H19,PVT1 and HOTAIR,three prognosis-related lncRNAs,in the treatment of NSCLC.(3)The combination of(-)-epigallocatechin-3-gallate and 17-β-estradiol can regulate seven related lncRNAs simultaneously,which provides a feasible scheme for screening the combination of traditional Chinese medicine components in NSCLC.Finally,the traditional Chinese medicine components of(-)-epigallocatechin-3-gallate,17-beta-estradiol,genistein and dextro-phosphoserine are combined with western medicines,can simultaneously regulate 9 NSCLC prognosis-related lncRNAs,and the combination conforms to the treatment principle of eliminating pathogenic factors and strengthening body resistance of traditional Chinese medicine for NSCLC,and provides a new research direction for screening effective drugs for improving the prognosis of non-small cell lung cancer in vivo and in vitro experiments in the future. |
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