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. 2021 Jun 20;13(12):3076. doi: 10.3390/cancers13123076

Table 2.

EVs as biomarkers for detection of HCC.

Biomarkers/
Diagnostic Model		 Biomarker
Type		 Expression Level in HCC EV isolation Method 1 Number of Patients Sen/Spe
(%)		 AUROC Study Type Restricts HCC to Early-Stage? Ref.
Amount of total EVs – ↑ Ultracentrifugation 28 TNM stage I HCC vs. 40 cirrhosis 63/89 0.83 Case-control Yes [12]
Amount of AnnexinV+ EpCAM+ ASGPR1+ EV – ↑ Ultracentrifugation 86 HCC vs. 49 cirrhosis 81/47 0.73 Case-control No [13]
FIBG Protein –
(↑in iCCA)		 Filtration and Ultracentrifugation 29 HCC vs. 12 iCCA 83/90 0.89 Case-control No [113]
SMAD3 Protein ↑ ExoQuick™ Exosome Precipitation Solution 29 HCC vs. 37 HD + benign hepatoma –/– 0.70 Case-control No [99]
A panel combining miR-122, miR-148a, and AFP miRNA +
AFP		 ↑ Ultracentrifugation, filtration, and precipitation 50 HCC vs. 40 cirrhosis 86/88 0.93 Case-control No [114]
A panel combining miR-10b-5p, miR-221-3p, miR-223-3p, and miR-21-5p miRNA ↑ ExoEnrich™ instant exosome isolation kit and immunoaffinity capture (anti-ASGR2) 38 HCC vs. 35 CH + 25 cirrhosis 59/95 0.80 Case-control No [115]
miR-18a, miR-101, miR-106b, miR-122, miR-195, miR-221, miR-222, miR-224 miRNA ↑(18a, 221, 222, 224)
↓(101, 106b, 122, 195)		 Ultracentrifugation 20 HCC vs. 20 cirrhosis vs. 20 CH B –/– – Case-control No [116]
LINC00853 lncRNA ↑ ExoQuick™ Exosome Precipitation Solution 32 early-stage HCC (single, <2 cm) vs. 28 CH + 35 cirrhosis 94/85 0.96 Case-control Yes [117]
Lnc85 lncRNA ↑ Ribo™ Exosome Isolation Reagent 122 HCC vs. 43 cirrhosis 80/74 0.89 Case-control No [118]
RN7SL1 S fragment lncRNA ↑ Ultracentrifugation and Filtration 25 HCC vs. 25 healthy donors –/– 0.75 Case-control No [119]
A risk score panel combining AFP and
ENSG00000248932.1, ENST00000440688.1, ENST00000457302.2 		lncRNA +
AFP		 ↑ ExoQuick™ Exosome Precipitation Solution Training set: 20 HCC vs. 20 CH
Validation set: 180 HCC vs. 180 CH		 –/– 0.97
0.87		 Case-control No [120]
A panel combining circ_0004001,
circ_0004123, and circ_0075792 		circRNA ↑ Ultracentrifugation 71 HCC vs. 40 HD 91/78 0.89 Case-control No [121]
A panel combining 8 long RNAs – ↑ exoRNeasy Maxi Kit Training set: 44 HCC vs. 78 HD
1st Validation set: 27 HCC vs. 53 HD
2nd Validation set: 33 HCC vs. 33 HD + 6 hepatic benign disorders 		84/94
89/91
–/–		 0.95
0.96
0.96		 Case-control No [122]
LDHC mRNA ↑ exoRNeasy Midi Kit 50 TNM stage I/II HCC vs. 100 HD 88/93 0.95 Case-control Yes [123]
A panel combining AFP, GPC3, ALB, APOH, FABP1, FGB, FGG, AHSG, RBP4,TF mRNA ↑ EV Click Chip (immunoaffinity + microfluidic device) 36 BCLC stage 0-A HCC vs. 26 cirrhosis 84/88 0.93 Case-control Yes [38]

1 ExoEnrich™ instant exosome isolation kit is produced by ExoCan Healthcare Technologies Private Limited, India; ExoQuick™ Exosome Precipitation Solution is produced by System Biosciences, USA; exoRNeasy Midi/Maxi Kit is produced by Qiagen, Germany; Ribo™ Exosome Isolation Reagent is produced by RiboBio, China. AFP, alpha-fetoprotein; AHSG, alpha 2-HS glycoprotein; ALB, albumin; APOH, apolipoprotein H; ASGPR1, asialoglycoprotein receptor 1; ASGR 2, asialoglycoprotein receptor 2; AUROC, area under the receiver operating characteristic; BCLC, Barcelona Clinic liver cancer; CH, chronic hepatitis; CH B, chronic hepatitis B; circRNA, circular RNA; FABP1, fatty acid binding protein 1; EpCAM, epithelial cell adhesion molecule; EVs, extracellular vesicles; FIBG, fibrinogen gamma chain; FGB, fibrinogen beta chain; FGG, fibrinogen gamma cha; GPC3, glypican 3; HCC, hepatocellular carcinoma; HD, healthy donors; iCCA, intrahepatic cholangiocarcinoma; LDHC, actate dehydrogenase C; lncRNA, long non-coding RNA; miRNA, microRNA; RBP4, retinol binding protein 4; RN7SL1, RNA component of signal recognition particle 7SL1; SMAD3, SMAD family member 3; TF, transferrin.