Review
Copyright ©The Author(s) 2022.
World J Gastroenterol. Apr 21, 2022; 28(15): 1508-1525
Published online Apr 21, 2022. doi: 10.3748/wjg.v28.i15.1508
Table 1 The role of microRNAs as diagnostic and prognostic biomarkers in cholangiocarcinoma
Circulating microRNA
Biofluid
Comparison
Statistics
Discriminant specificity
Valuable considerations
Subjective rating
miR-21Increased in serum[27,28]; plasma[34]; urine[35]iCC (n = 74), HC (n = 74)[27]; CCA (n = 11), HC (n = 9)[28]. iCC (n = 25), HC (n = 7); CCA (n = 22), HC (n = 21)AUROC vs HC: Serum: 0.91[27]; serum: 0.80[28]; plasma 0.94[34]. Combined miR-21 + miR 192. Urine: 0.85[35]LOW. Also increased in HCC[36] and other malignancies[37,38]Corelates well with tumor stage and survival[39]. Most data supportUseful
miR-150-5pDecreased in serum and bile[40]CCA (n = 28), PSC (n = 30), HC (n = 50)Significantly decreased vs HC and PSC[40] association with LOW. Upregulation suppresses tumor progression in colorectal cancer[41]Appears to correlate with tumor staging. Added value of the CA19-9 combination. Contradictory findings: Report of being upregulated in iCCA (AUROC: 0.76)[27]Debatable
miR-26aIncreased in serum[29]CCA (n = 66), HC (n = 66)AUROC vs HC: 0.90[29]Moderate involved in HCC[30]Correlates well with tumor stage, metastases, differentiation, and survival. Reliable decrease following curative surgery[29]Promising
miR-30d-5pIncreased in bile[31]CCA (n = 48), benign BTD (n = 58)AUROC vs benign biliary obstruction 0.730[31]Moderate downregulated in gastric cancer[32]Increased sensitivity and specificity compared to CA19-9Debatable
miR-222; miR-483-5pIncreased in serum[33]CCA (n = 70), PSC (n = 70), HC (n = 70)AUROC vs PSC; miR-222: 0.71; miR-483-5p: 0.70 combined miR-222 and 483-5p: 0.74[33]No evidence of overlap with other cancersMight be useful for monitoring patients with PSCPromising
AUROC: Area under a receiver operating characteristic; CA19-9: Carcinoembrionic antigen 19-9; CCA: Cholangiocarcinoma; HC: Healthy controls; HCC: Hepatocellular carcinoma; iCCA: Intrahepatic cholangiocarcinoma; miRs: Micro RNAs; PSC: Primary sclerosing cholangitis.
Table 2 Proteins associated with favorable cholangiocarcinoma diagnostic potential
Protein
Comparison
SEN (%)
SPE (%)
AUC
Ref.
Tissue
CYFRA 21-1iCCA (n = 217) vs HC (n = 514) meta-analysis81.086.00.904[58]
DKK1iCCA (n = 37) vs HC (n = 50)75.7100.00.872[52]
DKK1 + CA19-9iCCA(n = 79) vs HC (n = 160)74.756.30.793[60]
IL-6CCA (n = 26), HCC (n = 26) and HC (n = 23)73.092.00.875[53]
MMP-7CCA (n = 44) vs benign BTD (n = 36)76.346.80.730[56]
CCA (n = 59) vs benign BTD (n = 128)75.078.00.840[57]
MUC5ACCCA (n = 49), benign BTD (n = 23), HC (n = 16)71.094.70.909[55]
OPNCCA (n = 107) vs HC (n = 55)87.5100.00.964[50]
S100A6CCA (n = 112) vs HC (n = 42)86.290.90.909[51]
SSP411CCA (n = 30), benign BTD (n = 13) and HC (n = 23)90.083.30.913[54]
TGF-β1CCA (n = 45), other disease conditions related inflammation (n = 25) and HC (n = 45)71.168.90.668[78]
TSP-2 + CA19-9dCCA (n = 51), pancreatic ductal adenocarcinoma (n = 52), benign pancreatic diseases (n = 27) and HC (n = 52)79.096.00.920[61]
uPARCCA (n = 118), and HC (n = 76)95.389.70.969[59]
Biomarker panel: S100A9, MUC5AC, TGF-β1, Ang-2, and CA19-9CCA (n = 40), non-CCA (n = 40) and HC (n = 40)95.090.00.975[62]
AUC: Area under the curve; BTD: Biliary tract disease; CCA: Cholangiocarcinoma; dCCA: Distal CCA; HC: Healthy controls; HCC: Hepatocellular carcinoma; iCCA: Intrahepatic cholangiocarcinoma; SEN: Sensitivity; SPE: Specificity; CYFRA 21-1: Cytokeratin 19 fragment; DKK1: Dickkopf 1; IL-6: Interleukin 6; MMP-7: Metalloproteinase 7; MUC5AC: Mucin 5AC; OPN: Osteopontin; S100A6: S100 calcium binding protein A6; SSP411: Spermatogenesis-associated protein 20; TGF-β1: Transforming growth factor-β1; TSP-2: Thrombospondin-2; uPAR: Urokinase-type plasminogen activator receptor; S100A9: S100 calcium binding protein A9; Ang-2: Angiopoietin-2.
Table 3 Proteins associated with poor outcome in cholangiocarcinoma patients
Protein
Comparison
Outcome
Ref.
Tissue
CDH17CCA (n = 180)High CDH17 was associated with a worse OS and recurrence-free survival[64]
HHLA2iCCA (n = 218) meta-analysisHigh HHLA2 expression was significantly associated with shorter OS[74]
KL-6 CCA (n = 21), cHCC-CCA (n = 12), HCC (n = 78)A key molecule for tumor cell adhesion and invasion[63]
KLK11CCA and adjacent normal tissues (n = 18)OS of CCA patients with a high expression of KLK11 was significantly shorter than those with a low expression of KLK11 (414 d vs 809 d, respectively; P = 0.048)[65]
LC3cHCC-CC (n = 40)The 5-yr OS and disease-free survival rates were 61.2% and 74.6% in high LC3 expression patients and 0% and 0% in those with low LC3 expression[70]
MMP-7Perihilar iCCA, hCCA, and eCCA (n = 66)Patients with moderate to marked expression of MMP-7 had a significantly poorer prognosis, as compared to those with negative to focal expression[72]
iCCA (n = 35)The 5-yr survival rates of MMP-7(+) and MMP-7(−) patients were 72.7% and 18.3%, respectively[73]
PD-L1 CCA (n = 2012) meta-analysisOverexpression of PD-L1 was significantly associated with worse OS[17]
S100PCCA (n = 1925) meta-analysisS100 calcium binding protein P overexpression was associated with poor OS[69]
uPaiCCA (n = 174)High uPa expression was correlated with lymphatic invasion and metastasis of CCA patients[71]
uPARCCA (n = 108) vs normal tissue (n = 108)The median OS was 890 d for patients with uPAR positive vs 1.321 d for patients with uPAR negative[59]
Biomarker panel: CEA, AFP, and Ki67iCCA (n = 92)higher AFP, CEA, and Ki67, as well as more advanced TNM staging were associated with worse OS[75]
Serum
CIAPIN1CCA (n = 159) vs HC (n = 93)Higher CIAPIN1 level was significantly associated with shorter OS time[66]
DKK1 + CA19-9iCCA (n = 79) vs HC (n = 160)DKK-1 in combination with CA19-9 showed a better diagnostic performance than CA19-9 alone; low DKK-1 and CA19-9 were associated with longer OS[60]
MUC5ACCCA (n = 49), benign BTD (n = 23), HC (n = 16)High MUC5AC level was related to a worse prognosis compared with patients with lower levels, with 3-yr survival rates of 21.5% and 59.3%, respectively[55]
OPNCCA (n = 107) vs HC (n = 55)Poor postoperative survival[50]
OPN/tumor volumeiCCA (n = 124) Low circulating OPN per tumor volume was associated with shorter OS and disease-free survival[77]
PD-L1CCA (n = 73) vs HC (n = 42)Low PD-L1 levels displayed a strong trend towards an impaired prognosis[76]
S100A6CCA (n = 112) vs HC (n = 42)S100A6 potential was like those of the clinically established biomarkers CEA and CA19-9[67]
uPARCCA (n = 168)Baseline level of uPAR was an independent predictor of survival; a high level of uPAR after 2 cycles of chemotherapy was associated with poor survival[68]
CCA (n = 117), HC (n = 76)Multivariate Cox-regression analysis revealed circulating uPAR levels as an independent prognostic marker following biliary tract cancer resection[59]
Biomarker panel: S100A9, MUC5AC, TGF-β1, Ang-2, and CA19-9CCA (n = 40), and non-CCA patients (n = 40) and HC (n = 40)TGF-β1 and Ang-2 are predictors of higher TNM stages[62]
BTD: Biliary tract disease; CCA: Cholangiocarcinoma; cHCC-CC: Combined hepatocellular carcinoma and CCA; HC: Healthy controls; HCC: Hepatocellular carcinoma; iCCA: Intrahepatic cholangiocarcinoma; OS: Overall survival; CDH17: Cadherin-17; CYFRA 21-1: Cytokeratin 19 fragment; DKK1: Dickkopf 1; IL-6: Interleukin 6; MMP-7: Metalloproteinase 7; MUC5AC: Mucin 5AC; OPN: Osteopontin; S100A6: S100 calcium binding protein A6; SSP411: Spermatogenesis-associated protein 20; TGF-β1: Transforming growth factor-β1; TSP-2: Thrombospondin-2; uPAR: Urokinase-type plasminogen activator receptor; S100A9: S100 calcium binding protein A9; Ang-2: Angiopoietin-2; PD-L1: Programmed death-ligand 1; CIAPIN1: Serum cytokine-induced apoptosis inhibitor 1; AFP: Alpha-feto protein; LC3: Microtubule-associated protein 1A/1B-light chain 3; KLK11: Kallikrein related peptidase 11; KL-6: Mucin KL-6; HHLA2: Human endogenous retrovirus-H long terminal repeat-associating protein 2.