Current perspectives on exosomes in the diagnosis and treatment of hepatocellular carcinoma (review)

Figures & data

Figure 1. Functions of exosomes in hepatocellular carcinoma development. Exosomes, which harbor proteins, mRNAs, microRNAs, long non-coding RNAs, circular RNAs, and DNAs, are involved in tumor microenvironment regulation, intercellular communication, immune modulation, cell differentiation, drug-resistance, and angiogenesis

Table 1. Overview of the roles of exosomal contents in HCC.

Types of exosomal contents	Functions in tumor	Mechanism	References
Exosomal proteins
SMAD	Detaching HCC cells and facilitating their adhesion	SMAD3/ROS signaling pathway	^Citation93
Caveolin	HCC motility and malignant progression	-	^Citation94
MET caveolins S100	Enhancing the migratory and invasive abilities of non-motile cell lines	PI3K-AKT-mTOR, RAS-RAF-MEK-ERK	^Citation95
ITGαvβ5	HCC metastasis	Specifically bind to Kupffer cells	^Citation96
OXL4	Promoting migration and angiogenesis	Activate FAK/Src pathway	^Citation97
SDF-1α	Promoting the migration and invasion	MMPs secretions to facilitate lymph node metastasis	^Citation98
IL-6 IL-8	Promoting cells migration and increasing tube formation	NF-κB signaling pathway	^Citation99
Golgim1	Accelerating cell proliferation and migration	GSK-3β/MMPs signaling axis	^Citation100
VASN	Promoting proliferation and Migration of recipient HUVECs	-	^Citation101
HMGB1	Higher infiltration	Activating TLR-MAPK pathway	^Citation102
AFP GGT	Inducing EMT	-	^Citation103
Exosomal miRNA
miR-320a	Suppressing HCC cells proliferation, migration and metastasis	MAPK pathway	^Citation51
miR-200b-3p	Decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues	Enhancing endothelial ERG expression	^Citation104
miR-451a	Inhibiting hepatocellular tumorigenesis	Targeting LPIN1 to regulate tumor cells apoptosis and angiogenesis	^Citation105
miR-744	Downregulated miR-744 promotes HepG2 cells proliferation and inhibits the chemosensitivity of HepG2 cells to sorafenib	PAX2 is identified as the functional target of miR-744	^Citation106
miR-92a-3p	Promoting metastasis	Targeting PTEN and regulating its downstream Akt/Snail signaling to promote EMT	^Citation52
miR-224	Tumor promotor Increasing in cells proliferation	Targeting glycine N-methyltransferase	^Citation107
miR-21	Promoting cancer progression	Targeting PTEN, leading to activation of PDK1/AKT signaling	^Citation108
miR-10b	Promoting HCC cells proliferation, migration, and invasion	Activating HIF-1α and HIF-2α	^Citation53
miR-665	Promoting HCC cells proliferation	Activating MAPK/ERK pathway	^Citation109
miR-150-3p	The loss of antitumoral miR-150-3p in CAFs-derived exosomes greatly promotes HCC progression	-	^Citation110
miR-9-3p	Overexpression of miR-9-3p reduces HCC cell viability and proliferation	Regulating HBGF-5 expression Reducing ERK1/2 expression	^Citation111
miR-103	Increasing vascular permeability and promoting tumor metastasis	Inhibiting the expression of VE-Cadherin (VE-Cad), p120-catenin (p120) and zonula occludens 1	^Citation112
miR-490	Inhibiting HCC cell metastasis	Inhibiting the ERK1/2 pathway	^Citation113
miR146a	Anti-HCC function	Promoting M2-polarization and suppresseing the function of T-cells	^Citation114
miR-155	Stimulating the proliferation of HCC cells	Bounding to 3ʹ-UTR of PTEN leads to the reduction of relevant targets in recipient liver cells	^Citation22
miR-93	Increasing proliferation and invasion ability of HCC cells	TP53INP1, TIMP2 and CDKN1A are direct targets of miR-93	^Citation115
miR-92b	Enhancing the migration ability of liver cancer cells	Suppressing CD69 on NK cells	^Citation116
miR-1247-3p	Activated CAFs further promote cancer progression via secreting pro-inflammatory cytokines	Activating β1-integrin-NF-κB signaling pathway in fibroblasts	^Citation41
miR-32-5p	Multidrug resistance via modulating angiogenesis and EMT	Activating the PI3K/Akt pathway	^Citation65
miR-145	Suppressing tumorigenesis and metastasis	GSK-3β/MMPs signaling axis	^Citation100
miR-1273 f	Directly replicating the effects of hypoxic exosomes within HCC cells	Activating the Wnt/β-catenin signaling	^Citation117
miRNA-25-5p	Increasingly recognized as key instigators of cancer progression by facilitating cell-cell communication	-	^Citation118
Exosomal lncRNA
TUC339	Regulating macrophage activation	Regulating macrophage M1/M2 polarization	^Citation119
lncRNA H19	Accelerating the proliferation and motility while hampering the apoptosis of HCC cells	H19/miR-520a-3p signaling	^Citation120
lnc-FAM72D-3	Functions as an oncogene in HCC	-	^Citation121
lnc-EPC1-4	Functions as a tumor suppressor gene	-	^Citation121
lncRNA MALAT1	Increasing hepatic cell invasion and migration	Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling	^Citation122
ATB	Promoting invasion and metastasis	Upregulation of TGF-β signaling pathway	^Citation123
Exosomal circular RNA
circRNA Cdr1as	Greatly accelerating HCC cells to proliferate and migrate	Sponging miR-1270	^Citation124
circPTGR1	Promotes metastasis	-	^Citation32
circRNA-100,338	Enhancing the metastatic ability of HCC cells	Affect proangiogenic activity by regulating angiogenesis	^Citation35
circUHRF1	Driving resistance to anti-PD1 immunotherapy in HCC patients	Expression of TIM-3 via degradation of miR-449 c-5p	^Citation67
circ-1441443	Suppressing the malignant biological behaviors	Via BAK1 upregulation	^Citation125
circFBLIM1	Facilitatign HCC progression and glycolysis	MiR-338/LRP6 axis	^Citation126Citation127Citation128Citation129Citation130

Abbreviation: AFP (alpha-fetoprotein), GGT (gamma-glutamyl transpeptidase), HCC(Hepatocellular Carcinoma), EMT (epithelial-stromal transformation), CAFs (cancer-related fibroblasts).

Figure 2. Roles of RNAs from hepatocellular carcinoma (HCC)-derived exosomes. Exosomes mediate the transport of various RNAs. Exosomes-associated miRNAs, such as miR-221, miR-222, and miR-224 can be potential diagnostic biomarkers for HCC. miR-155, lncR-HULC, and circR-DB promote HCC progression and invasion, whereas miR-194 and miR-424-5p suppress HCC growth and invasion. Exosome-associated RNAs, such as miR-1247-3p, which are transferred from the donor cells, can regulate stromal cells, such as cancer-related fibroblasts. The secretion of cytokines, such as chemokine and interleukins from the exosomes promotes HCC growth and invasion, including angiogenesis. miR-32-5p, lncRNA-RoR, and lncRNA-VLDLR are involved in the development of drug-resistance.131132133134135

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