Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis
Abstract
Simple Summary
Abstract
1. Introduction
2. Main Actors of Liver Fibrosis
3. Liver Fibrosis and Cirrhosis
3.1. General Pan-Etiology Features
3.2. Features Linked to HCV Pathogenesis
3.2.1. Collagens and Derived Fragments
3.2.2. Enzymes of the ECM
3.2.2.1. Lysyl Oxidases
3.2.2.2. Matrix Metalloproteases (MMPs) and Their Inhibitors
3.2.2.3. A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAM and ADAM-TS)
3.2.3. Proteoglycans
3.2.3.1. Membrane-Associated PGs
3.2.3.2. Soluble Extracellular PGs
3.2.4. Matricellular Proteins
3.2.4.1. Tenascins
3.2.4.2. Osteopontin
3.2.4.3. CCN2 or CTGF
3.2.5. Adhesive Glycoproteins
3.2.5.1. Fibronectin
3.2.5.2. Laminin and Nidogen
3.2.6. Elastin
3.2.7. TGF-β and HCV Pathogenesis
4. Are HSCs Direct Targets of HCV Infection?
5. Fibrosis Reversal in the Era of DAAs in HCV-Induced Liver Fibrosis
6. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADAM | a disintegrin and metalloprotease |
ADAM-TS | ADAM with thrombospondin motifs |
ALT | alanine amino-transferase |
COX-2 | cyclo-oxygenase-2 |
CREBH | cAMP-responsive element binding protein H |
CS | chondroitin sulfate |
CTGF | connective tissue growth factor |
DAAs | direct-acting antivirals |
ECM | extracellular matrix |
ER | endoplasmic reticulum |
GAG(s) | glycosaminoglycan(s) |
GPC3 | glypican-3 |
HA | Hyaluronan or hyaluronic acid |
HBV | hepatitis B virus |
HCC | hepatocellular carcinoma |
HCV | hepatitis C virus |
HGF | hepatocyte growth factor |
HNF4α | hepatocyte nuclear factor 4α |
HPC | hepatic progenitor cells |
HSC(s) | hepatic stellate cell(s) |
HSPG(s) | heparan sulfate proteoglycan(s) |
IP-10 | interferon gamma-inducible protein 10 |
LOX | lysyl oxidase |
LOXL | LOX-like |
LTBP | large latent TGF-β-binding protein |
MMP(s) | matrix metalloprotease(s) |
NAFLD | nonalcoholic fatty liver disease |
NF-κB | nuclear factor-κB |
NK | natural killer cell |
PDGF | platelet-derived growth factor |
PG(s) | proteoglycan(s) |
SMA | smooth muscle actin |
SNP | single-nucleotide polymorphism |
SVR | sustained virological response |
TGF-β1 and -β2 | transforming growth factor-β1 and -β2 |
THBS1 | thrombospondin-1 gene |
TIMP | tissue inhibitor of MMP |
TLR | toll-like receptor |
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Virus | HBV | HCV |
---|---|---|
Viral family | Hepadnaviridae | Flaviviridae |
Genome | DNA and cccDNA | RNA |
Life cycle | Genome integration, expression of HBx protein, insertional activation of cellular oncogenes, cccDNA (minichromosome) | Exclusively cytoplasmic |
Persistence | Nucleus-located cccDNA | Chronic inflammation, oxidative stress, alterations in cellular signaling and metabolism |
HCV Proteins | ECM Proteins or Cytokines |
---|---|
Capsid core | LOX ∞ [61] Procollagen I ∞ [62] Collagen I ∞ [61] MMP-2 ∞ [58] |
MMP-9 ∞ [63] | |
COX-2 ∞ [63] | |
Syndecan-1 * [31] | |
Thrombospondin-1 ∞ [61] | |
Osteopontin * [64,65] | |
CTGF ∞ [58] | |
TGF-β1 ◊ [58,61,62,66] | |
TGF-β2 ◊ [67] | |
Endoglin ∞ [68] | |
Envelope glycoproteins E1 and/or E2 | Glypican-3 * [69] |
TGF-β1 ◊ [66] | |
Cysteine autoprotease NS2 | MICA ∞ [70] TGF-β2 ◊ [67] |
Serine protease and helicase NS3 | Procollagen I ∞ [62] MMP-9 ∞ [71] |
COX-2 ∞ [71] | |
Thrombospondin-1 [72] | |
Osteopontin * [64] | |
TGF-β1 ◊ [62,72] | |
TGF-β type I receptor * [73] | |
NS3 with its cofactor NS4A | MMP-9 ∞ [71] |
COX-2 ∞ [71] MICA ∞ [74] | |
TGF-β ◊ [72,75] | |
NS4B | MMP-2 ∞ [76] |
NS5A | MMP-2 ∞ [63] |
MMP-9 ∞ [63] | |
COX-2 ∞ [63] | |
Thrombospondin-1 ∞ [72] | |
Osteopontin * [64] | |
TGF-β1 ◊ [72,77,78] | |
RNA-dependent RNA polymerase NS5B | Osteopontin * [64] |
MICA ∞ [70] TGF-β ◊ [75] |
ECM Proteins/Cytokine | F0/F1 | F2 | F3 | F4 | HCC | References |
---|---|---|---|---|---|---|
Collagens I, III, V | F1 | [45,59,60,79,80,81,82,83] | ||||
Collagen XII | [59,84] | |||||
Collagen XIV | [59,84] | |||||
Collagen XVI | [59] | |||||
Collagen XVIII | [59] | |||||
PIIINP | F1 | [85,86,87] | ||||
MMP-2, -7, -9 | F1 | [63,82,88,89,90] | ||||
TIMP-1 | [82,86,88,91,92] | |||||
ADAM-TS1 | [93] | |||||
ADAM-TS2 | [94] | |||||
Xylosyltransferase-2 | F1 | [95,96] | ||||
Glypican-3 | [97,98,99] | |||||
Hyaluronic acid | [87,100,101] | |||||
Decorin | F1 | [92] | ||||
Biglycan | [59] | |||||
Fibromodulin | [60] | |||||
Lumican | [59,81,84,102] | |||||
Versican | F1 | [93,103] | ||||
Tenascin-C | [104,105] | |||||
Osteopontin | F1 | [82,106,107] | ||||
Fibronectin | [103,108] | |||||
Fibronectin isoforms | [108] | |||||
Elastin | [59,83,84,102] | |||||
MFAP-4 † | F1 | [84,109,110] | ||||
Fibulin-5 | [84] | |||||
TGF-β1 (protein, mRNA) | [59,100,103,111,112] | |||||
TGF-β1 (serum levels) | F1 | [87,113] | ||||
TGF-β2 | F1 | F0 | [67] | |||
Endoglin (protein, serum levels) | [100] | |||||
Endoglin (mRNA) § | [68] |
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Reungoat, E.; Grigorov, B.; Zoulim, F.; Pécheur, E.-I. Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis. Cancers 2021, 13, 2270. https://doi.org/10.3390/cancers13092270
Reungoat E, Grigorov B, Zoulim F, Pécheur E-I. Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis. Cancers. 2021; 13(9):2270. https://doi.org/10.3390/cancers13092270
Chicago/Turabian StyleReungoat, Emma, Boyan Grigorov, Fabien Zoulim, and Eve-Isabelle Pécheur. 2021. "Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis" Cancers 13, no. 9: 2270. https://doi.org/10.3390/cancers13092270
APA StyleReungoat, E., Grigorov, B., Zoulim, F., & Pécheur, E.-I. (2021). Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis. Cancers, 13(9), 2270. https://doi.org/10.3390/cancers13092270