1、REVIEWOpen AccessLong non-coding RNAs towards precisionmedicine in gastric cancer:early diagnosis,treatment,and drug resistanceLi Yuan1,Zhi-Yuan Xu2,Shan-Ming Ruan1,Shaowei Mo1,Jiang-Jiang Qin2,3*and Xiang-Dong Cheng2*AbstractGastric cancer is a deadly disease and remains the third leading cause of
2、cancer-related death worldwide.The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%,whereas that ofpatients with distant metastasis is less than 5%.Surgical resection is the best option for early-stage gastric cancer,while chemotherapy is mainly use
3、d in the middle and advanced stages of this disease,despite the frequentlyreported treatment failure due to chemotherapy resistance.Therefore,there is an unmet medical need foridentifying new biomarkers for the early diagnosis and proper management of patients,to achieve the bestresponse to treatmen
4、t.Long non-coding RNAs(lncRNAs)in body fluids have attracted widespread attention asbiomarkers for early screening,diagnosis,treatment,prognosis,and responses to drugs due to the high specificityand sensitivity.In the present review,we focus on the clinical potential of lncRNAs as biomarkers in liqu
5、id biopsiesin the diagnosis and prognosis of gastric cancer.We also comprehensively discuss the roles of lncRNAs and theirmolecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastriccancer precision medicine.Keywords:LncRNA,Gastric cancer,Preci
6、sion medicine,Early diagnosis,Cancer treatment,ChemoresistanceBackgroundGastric cancer is one of the most common malignanciesworldwide,with more than one million new cases everyyear,and remains the third leading cause of cancer-related deaths 1,2.The clinical stage at the time ofdiagnosis directly d
7、etermines the prognosis of patientswith this disease.The patients with localized,early-stagegastric cancer usually have a high 5-year overall survival(OS)rate(60%),whereas the 5-year OS rates for gas-tric cancer patients with local and distant metastasisdramatically decrease to 30 and 5%,respectivel
8、y 2.Un-fortunately,due to the occult and atypical nature of earlyclinical symptoms of gastric cancer,more than 60%ofpatients have local or distant metastases at the time ofdiagnosis 2.For patients with early gastric cancer,sur-gical resection is the best treatment option;for patientswho cannot under
9、go surgical resection or patients withadvanced metastases,chemotherapy is the most import-ant treatment 3,4.However,poor or even no responseto chemotherapy is often observed in gastric cancer pa-tients because of the intrinsic or acquired resistance,which becomes the most common cause of treatmentfa
10、ilure 5.Therefore,the low rate of early diagnosis andchemotherapy resistance constitute the main contribu-tions to the poor prognosis of gastric cancer.To date,the biomarkers commonly used in earlyscreening for gastric cancer include carcinoembryonic The Author(s).2020 Open Access This article is li
11、censed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you giveappropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate i
12、fchanges were made.The images or other third party material in this article are included in the articles Creative Commonslicence,unless indicated otherwise in a credit line to the material.If material is not included in the articles Creative Commonslicence and your intended use is not permitted by s
13、tatutory regulation or exceeds the permitted use,you will need to obtainpermission directly from the copyright holder.To view a copy of this licence,visit http:/creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver(http:/creativecommons.org/publicdomain/zero/1.0/)
14、applies to thedata made available in this article,unless otherwise stated in a credit line to the data.*Correspondence:;Li Yuan and Zhi-Yuan Xu contributed equally to this work.2Institute of Cancer and Basic Medicine,Chinese Academy of Sciences,Cancer Hospital of the University of Chinese Academy of
15、 Sciences,ZhejiangCancer Hospital,Banshan Road 1#,Gongshu District,Hangzhou 310022,ChinaFull list of author information is available at the end of the articleYuan et al.Molecular Cancer (2020)19:96 https:/doi.org/10.1186/s12943-020-01219-0antigen(CEA),alpha-fetoprotein(AFP),carbohydrateantigen 199(C
16、A199),CA724,CA125,etc.6,7.However,the sensitivities and positive rates of these bio-markers are poor;their sensitivities in the diagnosis ofgastric cancer are from 4.7 to 33.3%,and the positiverates of CEA,CA199,and CA724 only range from 21.1to 30%79.The diagnosis of gastric cancer still de-pends on
17、 upper gastrointestinal endoscopy,but its clin-ical application is limited because of the invasivenessand high cost 10.Therefore,there is an urgent needforminimal-invasiveornon-invasivedetectionap-proaches,as well as highly specific biomarkers,to im-provegastriccancerearlydiagnosisandsurvivaloutcome
18、s.Long non-coding RNAs(lncRNAs)have attracted in-creasing attention as cancer biomarkers for early screen-ing,diagnosis,prognosis,andresponsestodrugtreatment 1113.A recent study has shown that theexpression of lncRNA MNX1-AS1(MNX1 antisenseRNA 1)is significantly increased in gastric cancer tissuesan
19、d associated with the poor prognosis of gastric cancerpatients 14.LncRNA SNHG11(small nucleolar RNAhost gene 11)has been reported as a potential biomarkerfor early detection of colon cancer and a new thera-peutic target of this disease 15.A stroma-relatedlncRNA panel has been found to predict recurr
20、ence andadjuvant chemotherapy benefit in patients with early-stage colon cancer 16.LncRNAs are involved in theacquired resistance to chemotherapy 17,18,and target-ing lncRNA can reverse drug resistance and enhance thesensitivity of cancer cells to chemotherapy 19.Giventhe importance of lncRNAs in ca
21、ncer,a better under-standing of their roles in the early diagnosis,treatment,prognosis,and drug resistance of gastric cancer mayprovide new insights for precise treatment and individu-alized management of patients with this disease.The regulation of lncRNA expression and the roles oflncRNAs in gastr
22、ic cancer progression and metastasishave been extensively discussed in several recent reviews2024.In the present review,we focus on the clinicalevidence of lncRNAs as biomarkers in liquid biopsies inthe early diagnosis and prognosis of gastric cancer.Wealso comprehensively discuss the roles of lncRN
23、As andtheir molecular mechanisms in gastric cancer chemore-sistance,as well as their potential as therapeutic targetsfor gastric cancer precise medicine.An overview of lncRNAsThe Encyclopedia of DNA Elements(ENCODE)projecthas revealed that only about 1.2%of human transcripts(RNAs)encode proteins and
24、 more than 98%of humantranscriptsarenon-protein-coding RNAs(ncRNAs),such as lncRNAs,circular RNAs(circRNAs),micro-RNAs(miRNAs),and small nucleolar RNAs(snoRNAs)25.LncRNAs are the transcripts of more than 200 nu-cleotides,accounting for 80 to 90%of all ncRNAs andare characterized by low expression le
25、vels,poor interspe-cies conservation,and high expression coefficient ofvariance 26,27.According to their genomic localization and evolution-ary lineage,lncRNAs can be divided into intergeniclncRNAs,intronic lncRNAs,exonic lncRNAs,senselncRNAs,and antisense lncRNAs.Intergenic lncRNAs(also called linc
26、RNAs)are transcribed from genomic re-gions between coding genes,while intronic lncRNAsoverlap entirely with introns of protein-coding genesand exonic lncRNAs overlap entirely or partially withexons of protein-coding genes 28,29.The transcrip-tional orientation of lncRNAs can be in sense or anti-sens
27、ewhencomparedwiththetranscriptionalorientation of the protein-coding genes 30.Besides,lncRNAs can be classified into nuclear lncRNAs andcytoplasmiclncRNAsbasedonthesubcellularlocalization,which is critical for their functions.MostlncRNAs are located in the nucleus and only about 15%are in the cytopl
28、asm 31.Nuclear lncRNAs mainly regu-late the transcription or mRNA processing,e.g.lncRNAXIST(X inactive specific transcript),MALAT1(metasta-sis associated lung adenocarcinoma transcript 1),andNEAT1(nuclear paraspeckle assembly transcript 1)functioningastranscriptionregulators3234.Cytoplasmic lncRNAs
29、are more often involved in post-transcriptional regulation,such as playing the role ofmiRNA sponges.Du et al.have demonstrated thatcytoplasmic localization is an important factor in deter-mining the sponge efficacy of lncRNA TUG1(taurineup-regulated 1)35.Cytoplasmic lncRNA PVT1(plas-macytoma variant
30、 translocation 1)has been found to actas a competitive endogenous RNA(ceRNA)againstmiR-214-3p and promote the progression of colon can-cer 36.LncRNAs were initially considered as“junk”or“gen-omic dark matter”without function.With the deepeningof research in recent years,lncRNAs have been found topar
31、ticipate widely in various physiological and patho-logical processes of organisms.In the human body,lncRNAs not only regulate the physiological processessuch as cell proliferation,differentiation,and apoptosisbut also participate in regulating various pathologicalprocesses of the body,such as cancer
32、,cardiovascular dis-eases,autoimmune diseases,diabetes,and more 3740.The specific function of lncRNAs is to regulate gene ex-pression at the pre-transcriptional,transcriptional,andpost-transcriptional levels.At the pre-transcriptionallevel,lncRNA regulates gene expression by gene modifi-cation,histo
33、ne modification,and chromatin remodeling,without changing the DNA sequences of the organisms41,42.During transcription,lncRNA interacts withYuan et al.Molecular Cancer (2020)19:96 Page 2 of 22transcription factors to regulate gene transcription 43.At the post-transcriptional level,lncRNA acts as a p
34、re-cursor of some miRNAs to regulate gene expression,oras a ceRNA to regulate the translation of the corre-sponding mRNA 44.However,due to the large numberof lncRNAs,the functions of most lncRNAs are still un-clear and require further comprehensive research.LncRNAs as liquid biopsy biomarkers of gas
35、tric cancerThe development of liquid biopsies has opened a newera for precision medical treatment of human cancer.Because of their minimal-invasive or non-invasive char-acteristics and high public acceptance,liquid biopsiescan be conducted more frequently for early screening,diagnosis,and prognosis
36、of cancer.Besides,liquid biop-sies can be collected at specific time intervals to monitorresponses to treatment,drug resistance,recurrence,andmetastasis of cancer.Added benefits are that,unlike tis-sue biopsies obtained from only one tumor area,liquidbiopsies may better reflect the genetic character
37、istics ofall tumor subclones in patients 45.LncRNAs arewidely distributed in peripheral plasma/serum,saliva,gastric juice,urine,semen,and other liquids and playimportant roles in various aspects of human physio-logical and pathological processes 4650.Based on theaforementioned benefits,a comprehensi
38、ve understand-ing of the current research status of lncRNAs is criticalfor the further development of them as cancer bio-markers in liquid biopsies.Accumulating evidence suggests the usefulness oflncRNAs as liquid biopsy biomarkers for human cancer.LncRNAs in peripheral blood plasma/serum have beend
39、emonstrated as biomarkers for various types of humancancer,such as lung,breast,and colon cancer 5153.LncRNAs in saliva have been mainly used as biomarkersfor head and neck cancer,such as oral,pharyngeal,andlaryngeal cancer 54,55.LncRNAs in gastric juice andurine have also been reported as biomarkers
40、 of gastriccancer and urinary system cancer,respectively 49.Ofnote,the urinary level of lncRNA PCA3(prostate cancerassociated 3)has been used as a biomarker for the diag-nosis of prostate cancer in clinical applications 56,57.Although there is no report on lncRNAs in semen,re-cent studies have shown
41、 that miRNAs in semen may beused as biomarkers for prostate cancer 58.To date,al-most all attention has been paid to the lncRNAs inplasma/serum and gastric juice but not in other liquidbiopsies as biomarkers of gastric cancer,which has beencomprehensively discussed in this section.LncRNAs in plasma/
42、serum as diagnostic and prognosticbiomarkers of gastric cancerThe development of a disease often leads to changes inthe plasma/serum composition,which can be detectedto reflect the status of the disease 59.LncRNAs,whichare freely circulating in the plasma/serum or packagedin exosomes,have all of the
43、 characteristics of ideal bio-markers because they are stable over long periods atroom temperature,during repeated freeze-thaw cycles,or at different pH values 60.More importantly,theplasma/serum levels of lncRNAs are mostly the same asthose in the primary tumor tissues,thus preciselyreflecting the
44、characteristics of the tumors 61,62.Inaddition,the collection of plasma/serum samples at dif-ferent time points is relatively convenient for monitoringthe progress of the disease 6366.LncRNAs in plasma/serum as diagnostic biomarkers ofgastric cancerA large number of circulating lncRNAs have been re-
45、ported as biomarkers for the diagnosis of gastric cancer(as summarized in Table 1),which have obvious advan-tages over the diagnostic biomarkers in clinical applica-tions.Xian et al.have found that lncRNA HULC(hepatocellular carcinoma upregulated long noncodingRNA)and ZNFX1-AS1(ZNFX1 antisense RNA 1
46、)candistinguish gastric cancer patients from healthy controlsand have proposed them as biomarkers for diagnosinggastric cancer 77.The receiver operator characteristiccurve(ROC)analysis has shown that the area undercurve(AUC)values for HULC and ZNFX1-AS1 are 0.65and 0.85,respectively,which are higher
47、 than those oftraditional serum biomarkers,including CEA(0.62),CA199(0.56),CY211(0.59),and neuron-specific eno-lase(NSE,0.56)77.Jin et al.have further confirmedthat HULC is more sensitive and specific than CEA andCA724 as a diagnostic marker of gastric cancer 82.Yang et al.have found that the AUC va
48、lues of lncRNAPANDAR(promoter of CDKN1A antisense DNA dam-age activated RNA),FOXD2-AS1(FOXD2 adjacent op-positestrandRNA1),andSMARCC2(SWI/SNFrelated,matrix associated,actin dependent regulator ofchromatin subfamily c member 2)as diagnostic bio-markers of gastric cancer are 0.77,0.7,and 0.75,respect-
49、ively,which are similar to the AUC value of combinedCEA,AFP,CA125,CA153,and CA199 97.Feng et al.have also demonstrated that lncRNA B3GALT5-AS1(B3GALT5 antisense RNA 1)is better than CEA andCA199 as a diagnostic biomarker of gastric cancer 87.Zhou et al.have recently reported that lncRNA C5orf66-AS1(C5orf66 antisense RNA 1)can be utilized for thediagnosis of gastric cancer with the AUC value of 0.68867.More importantly,lncRNA C5orf66-AS1 has fur-ther been shown to predict early gastric cancer with theAUC value of 0.789 67.Circulating lncRNAs have better biomarker valueswhen combined,bining lnc