Exosomal noncoding RNAs in cholangiocarcinoma: Laboratory noise or hope?

Table 1 Potential clinical application of selected extracellular vesicle-derived microRNAs as biomarkers in cholangiocarcinoma

microRNA	Expression	Type of EVs	EV source	Major finding	Potential application	Ref.
miR-205	↑	Exosomes	Human CCA cell lines	Downregulation of miR-205-5p decreased migration and invasion in CCA cell lines	Therapy monitoring/therapeutic target	[47]
Members of miR-200 family
miR-200c-3p, miR-200b-3p, miR-200a-3p, miR-429 and miR-141-3p	↑	Exosomes	Human CCA cell lines	Supported the role of exosomal miR-200 family in CCA progression	Prognostic value	[47]
miR-200c-3p, miR-200a/c-3p	↑	Exosomes	Peripheral blood samples (36 patients)	(a) miR-200c-3p emerged as a potential diagnostic biomarker; and (b) miR-200a/c-3p emerged as a potential diagnostic and prognostic biomarker	Early diagnostic and prognostic value	[48]
miR-199 family	↓	Exosomes	Human CCA cell lines	Supported the role of miR-199 family in CCA carcinogenesis	-	[47]
miR-214	↓	Exosomes	Human CCA cell lines	Supported the role of miR-214 in CCA carcinogenesis	-	[47]
5 miR-based panel (miR-191, miR-486-3p, miR-1274b, miR-16 and miR-484)	↑	EVs	Bile samples (46 CCA vs 50 control patients with PSC, biliary obstruction and bile leak)	(a) The panel displayed a 67% sensitivity and 96% specificity for CCA diagnosis; and (b) tool for differential diagnosis between biliary obstruction of nonmalignant etiologies and CAA	Diagnostic value	[49]
miR-30e	↓	EVs	Nonmalignant human cell vs CCA cell lines	Encapsulation of miR-30e in EVs could suppress CCA cell invasion and migration by inhibiting EMT	EVs may be used as vehicles for delivery of therapeutic agents	[50]
miR-195	↓	EVs	Human liver stellate cell line	Coculture of CCA and stellate cell lines resulted in downregulation of miR-195. EV-mediated miR-195 transfer targeted tumor cells and inhibited proliferation in a rat model.	EVs may be used as vehicles for delivery of therapeutic agents	[52]
miR-604	↑	EVs	Serum	Displayed 0.944 diagnostic capacity for CCA	Diagnostic value	[53]
miR-551B	↑	EVs	Serum	Displayed 0.909 diagnostic capacity for CCA	Diagnostic value	[53]
miR-96-5p, miR-151a-5p, miR-191-5p and miR-4732-3p	↑	Exosomes	Blood	Stage II CCA patients displayed the highest levels	Diagnostic value in early CCA stages	[58]
miR-9-5p	↑	Exosomes	Human ICC samples	Significant association with malignancy promotion via ↑IL-6 expression in vCAFs	Prognostic value	[59]

EV: Extracellular vesicle; CCA: Cholangiocarcinoma; ICC: Intrahepatic cholangiocarcinoma; PSC: Primary sclerosing cholangitis; EMT: epithelial-mesenchymal transition; vCAF: Vascular cancer-associated fibroblast.

Table 2 Potential clinical application of selected extracellular vesicle-derived long noncoding RNAs as biomarkers in cholangiocarcinoma

lncRNA	Expression	Type of EVs	EV source	Major finding	Potential application	Ref.
ENST00000517758.1 and ENST00000588480.1	↑	Exosomes	Bile samples of CCA (n = 35) and biliary obstruction patients (n = 56)	(a) ENST00000588480.1 expression may contribute to tumorigenesis and CCA progression (via p53 signaling pathway); and (b) Combined ENST00000588480.1 and ENST00000517758.1 exhibited higher sensitivity than CA19-9 (82.9% vs 74.3%)	Diagnostic value; Prognostic value/Therapeutic target	[63]
MALAT-1	↑	EVs	Serum	Upregulated in EVs from CCA vs PSC patients	Diagnostic value	[53]

lncRNA: Long noncoding RNA; EV: Extracellular vesicle; CCA: Cholangiocarcinoma; PSC: Primary sclerosing cholangitis.