Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review

Table 1 Diagnostic efficiencies of circulating miRNAs in gastric cancer

Circulating miRNA	Species	Samples	Sensitivity	Specificity	AUC	Population
miR-1, miR-20a, miR-27a, miR-34a and miR-423-5p[28]	Human	Serum	80% of miR-1 + miR-20a + miR-27a + miR-34a + miR-423-5p	81% of miR-1 + miR-20a + miR-27a + miR-34a + miR-423-5p	0.879 of miR-1 + miR-20a + miR-27a + miR-34a + miR-423-5p	82 GC patients and 63 healthy controls
miR-16, miR-25, miR-92a, miR-451 and miR-486-5p[52]	Human	Plasma	84.1% of miR-16 + miR-25 + miR-92a + miR-451 + miR-486-5p	90.8% of miR-16 + miR-25 + miR-92a + miR-451 + miR-486-5p	0.89 of miR-16 + miR-25 + miR-92a + miR-451 + miR-486-5p	106 non-cardiac early GC patients and 160 healthy controls
miR-223, miR-16 and miR-100[45]	Human	Serum	81% of miR-223, 79% of miR-16 and 71% of miR-100	78% of miR-223, 78% of miR-16 and 58% of miR-100	0.85 of miR-223, 0.9 of miR-16 and 0.71 of miR-100	50 GC patients and 47 healthy controls
miR-18a[114]	Human	Plasma	84.6%	69.2%	0.8059	104 GC patients and 65 healthy controls
miR-18a[115]	Human	Plasma	80.5%	84.6%	0.907	82 GC patients and 65 healthy controls
miR-106a and miR-17[90]	Human	Whole blood	62.96% of miR-106a + miR-17, 48.15% of miR-106a and 51.85% of miR-17	80.49% of miR-106a + miR-17, 90.24% of miR-106a and 92.68% of miR-17	0.741 of miR-106a + miR-17, 0.684 of miR-106a and 0.74 of miR-17	90 GC patients and 27 healthy controls
The ratio of miR-106a/let-7a[90]	Human	Serum	85.5%	80%	0.879	69 GC patients and 30 healthy controls
miR-103, miR-107, miR-194 and miR-210[101]	Mouse	Serum	81.8% of miR-103, 90.9% of miR-107, 90.9% of miR-194 and 72.7% of miR-210 only for early-stage DGC	95.7% of miR-103, 95.7% of miR-107, 95.7% of miR-194 and 87.0% of miR-210 only for early-stage DGC	0.881 of miR-103, 0.909 of miR-107, 0.925 of miR-194 and 0.846 of miR-210 only for early-stage DGC	5 advanced-stage DGC patients, 6 early-stage DGC patients and 18 healthy controls
miR-223, miR-21 and miR-218[118]	Human	Plasma	84.29% of miR-223 + miR-21 + miR-218, 84.29% of miR-223, 74.29% of miR-21 and 94.29% of miR-218	92.86% of miR-223 + miR-21 + miR-218, 88.57% of miR-223, 75.71% of miR-21 and 44.29% of miR-218	0.9531 of miR-223 + miR-21 + miR-218, 0.9089 of miR-223, 0.7944 of miR-21 and 0.7432 of miR-218	60 GC patients and 60 healthy controls
miR-21[121]	Human	Plasma	66.5%	83.1%	0.80	251 GC patients and 184 controls
miR-21 and miR-106b[133]	Human	Serum	69% of miR-21 + miR-106b, 58.6% of miR-21 and 75.8% of miR-106b	69.4% of miR-21 + miR-106b, 86.1% of miR-21 and 51.4% of miR-106b	0.72 of miR-21 and 0.7 of miR-106b	87 non-cardiac early GC patients and 114 healthy controls
miR-17 and miR-106b[91]	Human	Serum	83.3% of miR-17 + miR-106b, 80.6% of miR-17 and 75.0% of miR-106b	87.5% of miR-17 + miR-106b, 87.5% of miR-17 and 92.5% of miR-106b	0.913 of miR-17 + miR-106b, 0.879 of miR-17 and 0.856 of miR-106b	40 GC patients, 32 BGD patients and 36 healthy controls
miR-106b, miR-20a and miR-221[172]	Human	Plasma	Null	Null	0.773 of miR-106b, 0.8593 of miR-20a and 0.7960 of miR-221	60 GC patients and 60 healthy controls
miR-122 and miR-192[174]	Human	Plasma	Null	Null	0.808 of miR-122 for discriminating GC/DM from GC/NDM and 0.815 of miR-122 for discriminating GC/DM patients from healthy controls; 0.732 of miR-192 for discriminating GC/DM from GC/NDM and 0.818 of miR-192 for discriminating GC/DM patients from healthy controls	36 GC/DM patients, 36 GC/NDM patients and 36 healthy controls
miR-195-5p[175]	Human	Plasma	Null	Null	Null	20 GC patients and 190 healthy controls
miR-196a[173]	Human	Serum	Null	Null	Null	20 Pre- and post-operative GC patients
miRNA-199a-3p[87]	Human	Plasma	74%	75%	0.818	80 early GC patients, 20 patients with gastric precancerous
						diseases and 70 healthy controls
miR-200c[42]	Human	Whole blood	65.4%	100%	0.715	52 GC patients and 15 healthy controls
miR-221, miR-376c and miR-744[138]	Human	Serum	82.4% of miR-221 + miR-376c + miR-744	58.8% of miR-221 + miR-376c + miR-744	0.7 of miR-221, 0.74 of miR-744 and 0.71 of miR-376c	38 advanced GC patients, 30 early GC patients, 46 DYS patients and 128 healthy controls
			73.3% of miR-221 + miR-376c + miR-744 for early GC detection
miR-375[155]	Human	Serum	80%	85%	0.835	20 DGAC patients and 20 healthy controls
miR-378[81]	Human	Serum	87.5%	70.73%	0.861	40 GC patients and 41 healthy controls
miR-421[74]	Human	Whole blood	94.12%	62.5%	0.773	40 GC patients and 17 healthy controls
miR-421[75]	Human	Whole blood	95.5%	89.1%	0.821	90 GC patients and 90 healthy controls

When a combination of circulating miRNAs is characterized, a (+) is included between the listed circulating miRNAs. AUC: Area under the curve; GC: Gastric cancer; DGC: Diffuse-type gastric cancer; DYS: Dysplasia; BGD: Benign gastric disease; DGAC: Distal gastric adenocarcinoma; GC/DM: Gastric cancer with distant metastasis; GC/NDM: Gastric cancer with no distant metastasis.

Table 2 Expression levels of circulating miRNAs in gastric cancer tissues and their targeted genes

Circulating miRNA	Expression in the circulation	Expression in tissue	Validated target genes
miR-1	Up-regulation	Down-regulation	MET, Coronin1C, API-5, Slug, PIK3CA, NRF2, CCND2, CXCR4, SDF-1α, TAGLN2
miR-17-5p	Up-regulation	Up-regulation	YES1, STAT3, SMAD7, SOCS6, Beclin1, P21, P130, PCAF, TP53INP1, VDUP1, HBP1, AIB1,
miR-16	Up-regulation	Inconsistent direction of expression	ABCF2, ABHD10, ACP2, ACTR1A, ACVR2A, ADSS, ALG3, ANAPC16, ARHGDIA, ARL2, ASXL2, ATG9A, AURKB, BCL2, BMI1, BRCA1, C14orf109, C17orf80, C2orf43, C2orf74, C4orf27, C9orf114, C9orf167, C9orf89, CA12, CACNA2D1, CADM1, CAPRIN1, CARD8, CCDC109A, CCDC111, CCDC76, CCND1, CCND3, CCNE1, CCNT2, CDC14B, CDK5RAP1, CDK6, CENPJ, CEP63, CFL2, CHORDC1, CHUK, CREBL2, CRHBP, CSHL1, DNAJB4, ECHDC1, EGFR, EIF4E, EPT1, FAM122C, FAM69A, FGF2, FNDC3B, GALNT7, GFM1, GFPT1, GNL3L, GOLGA5, GOLPH3L, GPAM, GSTM4, GTF2H1, H3F3B, HACE1, HARS, HARS2, HBXIP, HDHD2
			HERC6, HMGA1, HMOX1, HRSP12, HSDL2, HSP90B1, HSPA1A, IFRD1, IFRD2, IGF2R, IPO4, ITGA2, JUN, KCNN4, KPNA3, LAMC1, LAMTOR2, LAMTOR3, LUZP1, LYPLA2, MCL1, MLLT11, MMS19, MRPL20, MSH2, MYB, NAA15, NAA25, NAPG, NIPAL2, NOB1, NOTCH2, NPR3, NT5DC1, OMA1, OSGEPL1, PAFAH1B2, PANX1, PDCD4, PDCD6IP, PHKB, PHLDB2, PISD, PLK1, PMS1, PNN, PNPLA6, PPIF, PPM1D, PPP2R5C, PRIM1, PSAT1, PTCD3, PTGS2, PURA, PWWP2A, RAB21, RAB30, RAB9B, RAD51C, RARS, RFT1, RHOT1, RNASEL, RTN4, SEC24A, SERPINE2, SHOC2, SKAP2, SLC12A2, SLC16A3, SLC25A22, SLC35A1, SLC35B3, SLC38A1, SLC38A5, SLC7A1, SPTLC1, SQSTM1, SRPR, SRPRB, TIA1, TMEM109, TMEM43, TNFSF9, TOMM34, TP53, TPI1, TPM3, TPPP3, TXN2, UBE2S, UBE2V1, UBE4A, UGDH, UGP2, UTP15, VEGFA, VPS45, VTI1B, WIPF1, WNT3A, WT1, YIF1B, ZNF384, ZNF559, ZNF622, NFKB1, ZYX
miR-17	Inconsistent direction of expression	Up-regulation	APP, BCL2, BCL2L11, BMPR2, CCL1, CCND1, CCND2, CDKN1A, DNAJC27, E2F1, E2F3, FBXO31, GPR137B, ICAM1, JAK1, MAP3K12, MAPK9, MEF2D, MUC17, MYC, NCOA3, NPAT, OBFC2A, PKD2, PTEN, PTPRO, RB1, RBL1, RBL2, RUNX1, SELE, SMAD4, TGFBR2, THBS1, TNFSF12, VEGFA, WEE1, YES1, ZNFX1, PTEN
miR-18a	Up-regulation	Up-regulation	CCNL1, CSRNP3, CTGF, ESR1, HSF2, NCOA3, NR3C1, PTEN, SMAD4, SPPL3, TGFBR2, THRA, TNFSF11, TSC22D3, ATM
miR-20a	Up-regulation	Up-regulation	APP, BCL2, BMPR2, BNIP2, CCND1, CCND2, CDKN1A, E2F1, E2F3, HIF1A, MAP3K12, MAPK9, MEF2D, MUC17, MYC, NRAS, PTEN, RB1, RBL1, RBL2, RUNX1, SMAD4, TGFBR2, THBS1, VEGFA, WEE1, EGLN3, IRF2, KIT
miR-21	Up-regulation	Up-regulation	ANKRD46, APAF1, BASP1, BCL2, BMPR2, BTG2, CCR1, CDC25A, CDK2AP1, DAXX, DERL1, E2F1, E2F2, EGFR, EIF2S1, EIF4A2, ERBB2, FMOD, HNRNPK, ICAM1, IL1BISCU, JAG1, JMY, LRRFIP1, MARCKS, MEF2C, MSH2, MSH6, MTAP, MYC, NCAPG, NCOA3, NFIB, PCBP1, PDCD4, PDHA2, PLAT, PLOD3, PPIF, PTEN, PTX3, RASA1, RASGRP1, RECK, REST, RHOB, RPS7, RTN4, SERPINB5, SOX5, SPATS2L, SPRY2, TGFBI, TGFBR2, TGFBR3, TGIF1, TIAM1, TIMP3, TM9SF3, TNFAIP3, TOPORS, TP53BP2, TP63, TPM1, WFS1, WIBG, ANP32A, CCL20, DOCK4, DOCK5, DOCK7, DUSP10, NFKB1, PIAS3, PPARA, SMARCA4, SP1, DAPK1, EZH2, MAP2K3, MAPK8, PLXNB1, POU4F2, PTEN, SRGAP1, ING4, XBP1, ACVR2B, WNK1
miR-25	Up-regulation	Up-regulation	BCL2L11, CDKN1C, KAT2B, KLF4, PRMT5, TP53, CCL26, CDH1, WDR4
miR-27a	Up-regulation	Up-regulation	FOXO1, HIPK2, MYT1, PHB, SP1, SP3, SP4, SPRY2, THRB, ZBTB10, APC, FBXW7, IGF1, MMP13, PAX3, WEE1
miR-34a	Up-regulation	Inconsistent direction of expression	AXIN2, BCL2, BIRC3, CCND1, CCND3, CCNE2, CD44, CDC25A, CDC25C, CDK4, CDK6, CEBPB, DLL1, E2F1, E2F3, E2F5, EMP1, FOXP1, GRM7, HMGA2, HNF4A, IFNB1, JAG1, MAGEA12, MAGEA2, MAGEA3, MAGEA6, MAP2K1, MAP3K9, MDM4, MET, MYB, MYC, MYCN, NOTCH1, NOTCH2, PEA15, SIRT1, SPI1, TNFRSF6B, VAMP2, VEGFA, WNT1, YY1, ZAP70, EPHA5, FOSL1, IMPA1, IMPDH2, MET, NANOG, PDGFRA, SOX2, STX1A, SYT1, ULBP2
miR-92a	Up-regulation	Up-regulation	ARID4B, BMPR2, CPEB2, ESR2, HIPK3, ITGA5, KAT2B, MYLIP, SMAD4, TGFBR2, THBS1, TP63, BCL2L11, CDH1, KLF2
miR-100	Up-regulation	Up-regulation	ATM, EGR2, FGFR3, ID1, MMP13, PLK1, IGF1R
miR-103	Up-regulation	Inconsistent direction of expression	CCNE1, CDK2, CREB1, DICER1, GPD1, CAV1
miR-106a	Up-regulation	Up-regulation	APP, ARID4B, CDKN1A, E2F1, HIPK3, IL10, MYLIP, RB1, RUNX1, VEGFA, FAS
miR-106b	Up-regulation	Up-regulation	APP, CCND1, CCND2, CDKN1A, E2F1, E2F3, ITCH, KAT2B, MAPK9, PTEN, RB1, RBL1, RBL2, TCEAL1, VEGFA, WEE1, EOMES
miR-107	Up-regulation	Inconsistent direction of expression	ARNT, BACE1, CCNE1, CDCA4, CDK6, CRKL, DICER1, FBXW7, GRN, HIF1A, MYB, NFIA, PLAG1, RAB1B, VEGFA
miR-146a	Up-regulation	Down-regulation	BRCA1, BRCA2, CCNA2, CD40LG, CDKN1A, CDKN3, CFH, CXCR4, ERBB4, FADD, FAF1, FAS, IL8, IRAK1, IRAK2, KIF22, MTA2, NFKB1, PA2G4, ROCK1, TLR2, TRAF6, EGFR, SMAD4, TLR4
miR-148a	Up-regulation	Down-regulation	CCKBR, DNMT1, DNMT3B, HLA-G, NR1I2, RPS6KA5, TGIF2
miR-192	Up-regulation	Up-regulation	ABCA8, ABCC3, ABCG2, AKAP9, ALCAM, ATP10D, ATXN7, B3GALNT1, BARD1, BCL2, BRD3, C1D, CADM1, CD164, CDC7, CDKN1B, CLIC1, CUL3, CUL5, DDOST, DDX3X, DLG5, DTL, E2F5, EGR1, ENOSF1, ENTPD3, ERCC3, ERLIN2, GOLGA6A, GRIA1, HOXA10, HRH1, HSP90B1, KIDINS220, KIF20B, LMNB2, LOXL2, MAD2L1, MAP3K1, MCM10, MFSD10, MIS12, MSN, ODC1, PANX1, PDE2A, PERP, PIK3R4, PIM1, PRPF38A, PTP4A3, RAB2A, RABGAP1, RACGAP1, RANBP3, RBL2, RRM1, SEMA4D, SEPT10, SETD4, SMARCB1, SPARC, STX7, TFG, TRAPPC2P1, WDR44, WNK1, XPA, ACVR2B, ERCC4, RB1
miR-194	Up-regulation	Down-regulation	CDH2, DNMT3A, EP300, HBEGF, IGF1R, ITGA9, PTPN12, PTPN13, RAC1, SOCS2, ACVR2B, SOX5
miR-196a	Up-regulation	Inconsistent direction of expression	Annexin A1, HOXB7, HOXB8, NME4, p-JNK, TIMP1, MMP1/9, NFKBIA, IκBα, FOXO1, p27Kip1, NTN4, HOXA5, NOBOX, HOXA9, HOX-C8, HOX-B7, BMP4
miR-199a-3p	Up-regulation	Inconsistent direction of expression	mTOR, MET, AXL, ZHX1, COX2, NLK, Aurora kinase A, c-Met, LKB1, Caveolin-2, STAT3, CD44, ZNF217, ZEB1
miR-200c	Up-regulation	Down-regulation	ADAM12-L, CYP1B1, Zeb2, Snail1, BMI-1, E2F3, HO-1, ZEB1, ZEB2, UBQLN1, USP25, HMGB1, PTEN, KRAS, VEGFR2, MUC4, MUC16, ERG, DLC1, ATRX, HFE, TUBB3, TRKB, ETS1, FLT1, FHOD1, PPM1F, BRD7, PPP2R1B
miR-210	Up-regulation	Inconsistent direction of expression	ABCB9, ACVR1B, AIFM3, APC, ATP11C, BDNF, CASP8AP2, CBX1, CDK10, CHD9, CLASP2, CPEB2, DDAH1, E2F3, EFNA3, ELK3, FAM116A, FGFRL1, GPD1L, HECTD1, HOXA1, HOXA3, HOXA9, ISCU, KIAA1161, MDGA1, MIB1, MID1IP1, MNT, MRE11A, NCAM1, NIPBL, NPTX1, P4HB, PIM1, PTAR1, PTPN1, RAD52, SEH1L, SERTAD2, SMCHD1, TNPO1, TP53I11, UBQLN1, XIST, XPA
miR-221	Up-regulation	Up-regulation	BBC3, BMF, BNIP3, CDKN1B, CDKN1C, CORO1A, DDIT4, ESR1, FOS, FOXO3, HOXB5, ICAM1, KIT, NAIP, PTEN, SELE, SSSCA1, TCEAL1, TICAM1, TNFSF10, TP53, DICER1, DIRAS3, ETS1, TIMP3
miR-223	Up-regulation	Up-regulation	CHUK, E2F1, LMO2, MEF2C, NFIA, NFIX, RHOB, STMN1, EPB41L3, FBXW7, IGF1R, SLC2A4
miR-376c	Up-regulation	Null	SMAD4, PC-TP, GRB2, TGFα, ALK5, ALK7, IGF-1R, ALK7
miR-378	Up-regulation	Down-regulation	GALNT7, MYC, NPNT, TOB2, VEGFA
miR-423-5p	Up-regulation	Up-regulation	TFF1
miR-421	Up-regulation	Up-regulation	Caspase-3, Menin, ATM, FOXO4, SERPINE 1, FXR, DPC4/Smad4
miR-451	Up-regulation	Inconsistent direction of expression	ABCB1, AKT1, BCL2, CAB39, MIF, MMP2, MMP9, SSSCA1, MYC, RAB14
miR-486-5p	Up-regulation	Inconsistent direction of expression	CD40, Pim-1, ARHGAP5
miR-744	Up-regulation	Null	Zbed4, Lrsam1, Ddx21, AW555464, c-Myc, eEF1A2, TGF-β1, Ccnb1
miR-93	Up-regulation	Up-regulation	CDKN1A, E2F1, ITGB8, KAT2B, MAPK9, TP53INP1, TUSC2, VEGFA, PTEN
miR-195-5p	Down-regulation	Null	CDK4, CDK6, CCNE1, GLUT3
Let-7a	Down-regulation	Inconsistent direction of expression	AMMECR1, APP, BCL2, CASP3, CASP8, CASP9, CCND2, DICER1, E2F1, E2F2, EGR3, EIF2C4, FOXA1, HMGA1, HMGA2, HNRPDL, HRAS, IGF2, IL6, ITGB3, KRAS, LIN28A, MEIS1, MYC, NEFM, NF2, NFKB1, NKIRAS2, NR1I2, NRAS, PRDM1, RAVER2, SLC20A1, THBS1, TRIM71, TUSC2, UHRF2, VDR, ZFP36L1, CDC34, EWSR1, IGF2BP1, MPL
miR-218	Down-regulation	Down-regulation	ACTN1, BIRC6, CDKN1B, EBP, EFNA1, IKBKB, LAMB3, LASP1, MAFG, MBNL2, MRPS27, NACC1, NFE2L1, NUP93, SP1, STAM2, VOPP1, BIRC5, GJA1, RICTOR, ROBO1
miR-375	Down-regulation	Down-regulation	ELAVL4, JAK2, MTDH, PDK1, PLAG1, RASD1, TIMM8A, YAP1, YY1AP1
miR-122	Down-regulation	Null	DLX4, Cyclin G1, MEF2D, TRAIL, PKM2, Wnt/β-catenin, AKT3, PI3K/Akt, c-Myc, CAT1, PBF, IGF1R, p53, ALDOA, ARHGAP1, BCAT2, CS, GNPDA2, IQGAP1, LAMC1, LMNB2, MTHFD2

Table 3 Diagnostic efficiencies of circulating lncRNAs in gastric cancer

Circulating lncRNA	Species	Samples	Sensitivity	Specificity	AUC	Population
FER1L4[190]	Human	Plasma	67.2%	80.3%	0.778	83 GCs (Pre- and post-operative patients)
H19[178]	Human	Plasma	74%	58%	0.64	43 GCs and 34 healthy controls
CUDR, LSINCT-5 and PTENP1[193]	Human	Serum	74.1% of CUDR + LSINCT-5 + PTENP1 for GC detection,	100% of CUDR + LSINCT-5 + PTENP1 for GC detection, 97.0% of CUDR + LSINCT-5 + PTENP1 for early GC detection	0.92 of CUDR + LSINCT-5 + PTENP1 for GC detection, 0.832 of CUDR + LSINCT-5 + PTENP1 for early GC detection	9 early-stage GCs, 64 advanced-stage GCs, 15 benign Peptic ulcer patients and 86 healthy controls
			77.8% of CUDR + LSINCT-5 + PTENP1 for early GC detection
LINC00152[189]	Human	Plasma	48.1%	85.2%	0.657	79 GCs and 81 healthy controls

When a combination of circulating lncRNAs is characterized, a (+) is included between the listed circulating lncRNAs. AUC: Area under the curve; GC: Gastric cancer.

Table 4 Expression levels of circulating lncRNAs in gastric cancer tissues and their target miRNAs

Circulating miRNA	Expression in the circulation	Expression in tissue	Validated targeted miRNAs	Putative targeted miRNAs in GC
H19	Up-regulation	Up-regulation	miR-675, let-7 and miR-200 family	miR-17-5p, miR-18a-5p, miR-18b-5p, miR-19a-3p, miR-20a-5p, miR-20b-5p, miR-106a-5p, miR-106b-5,
LINC00152	Up-regulation	Up-regulation	miR-130b-3p, miR-217	miR-18a-5p, miR-18b-5p, miR-31-5p, miR-139-5p, miR-195-5p, miR-497-5p
FER1L4	Down-regulation	Down-regulation	Null	miR-18a-5p, miR-18b-5p, miR-106a-5p, miR-133b, miR-139-5p, miR-195-5p, miR-497-5p
LSINCT-5	Down-regulation	Up-regulation	Null	Null
CUDR (UCA1)	Down-regulation	Up-regulation	miR-216b, miR-1, miR-143	Null
PTENP1	Down-regulation	Null	miR-17, miR-19b, miR-20a, miR21 and miR-26a	Null

GC: Gastric cancer.