Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma
Abstract
:1. Introduction
2. Structure and Signal Transduction of G Protein-Coupled Receptors (GPCRs)
2.1. Structure and Classification of GPCRs
2.2. Signal Transduction of GPCRs
3. Role of GPCRs in the Occurrence and Development of Hepatocellular Carcinoma (HCC)
3.1. Chemokine Receptors
3.1.1. CCRn
3.1.2. CXCRn
3.1.3. CX3CRn
3.1.4. CXRn
3.2. E-Prostanoid Receptors
3.3. Lysophosphatidic Acid Receptors
3.4. Adrenergic Receptors
3.5. Angiotensin II Receptors
3.6. Smoothened (Smo) Receptors
3.7. Orphan GPCRs
4. GPCR-Based Treatments in HCC
5. Conclusions
Acknowledgments
Conflicts of Interest
Abbreviations
GPCRs | G protein-coupled receptors |
HCC | hepatocellular carcinoma |
GRKs | G protein receptor kinases |
AC | adenylyl cyclases |
GABAB | γ-aminobutyric acid type B |
GDP | guanosine diphosphate |
GTP | guanosine triphosphate |
DCs | dendritic cells |
IL-12 | interleukin-12 |
IFN-γ | interferon-γ |
3‘-UTR | 3'-untranslated region |
p-JNK | phosphorylase c-jun N-terminal kinase |
PLC | phospholipase C |
TGF-β | transforming growth factor-β |
MAPK | mitogen-activated protein kinase |
DEN | N-nitrosodiethylamine |
HBs | hepatitis B virus surface |
MMPs | matrix metalloproteinases |
RNAi | RNA interference |
EMT | epithelial-mesenchymal transition |
EGFR | epidermal growth factor receptor |
PDGFR | platelet-derived growth factor receptor |
IGF1R | insulin-like growth factor 1 receptor |
siRNAs | small interfering RNAs |
RTKs | receptor tyrosine kinases |
VEGF | vascular endothelial growth factor |
PGE2 | prostaglandin E2 |
PKA | protein kinase A |
YB-1 | Y-box-binding protein 1 |
LPA | lysophosphatidic acid |
Edg | endothelial differentiation gene |
PTFs | peritumoral tissue fibroblasts |
PI3K | phosphoinositide 3-kinase |
PKCδ | protein kinase Cδ |
HIF-1 | hypoxia-inducible factor-1 |
ETAR | endothelin type A receptor |
ARs | adrenergic receptors |
SNS | sympathetic nervous system |
cAMP | cyclic 3′,5′-adenosine monophsphate |
CREB | cAMP response element binding protein |
Ang II | angiotensin II |
AT1 | angiotensin II type 1 |
Ang-2 | angiopoietin-2 |
Hh | hedgehog |
Ptc | patched |
oGPCRs | orphan GPCRs |
TAMs | tumor associated macrophages |
Met-RANTES | methionylated RANTES |
Shh | sonic hedgehog |
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GPCRs | Protein Expression | Cognate Ligands | Role in HCC | Biological Model |
---|---|---|---|---|
CCR1 | Up | CCL2, CCL3, CCL5 | Increased migration [21], increased angiogenesis [19,20], increased invasion [15] | HCC patients, DEN-induced mice model, myelo-ablated syngeneic HBs antigen transgenic mice, CCR1-deficient mice, human HCC cell line (HCCLM3) |
CCR2 | Up | CCL2 | Increased metastasis [22], increased angiogenesis [23] | HCC patients, CD11b/Gr1mid cells, transgenic CD11b-diphtheria toxin receptor mouse model, CCR2- deficient mice |
CCR5 | Up | CCL3 | Alter tumor microenvironment: increased IL-6 and TNF-α [24] | HCC patients, Mdr2-knockout mice |
CCR6 | Up | CCL20 | Increased migration [25], increased invasion, migration and angiogenesis [26] | HCC patients, Tregs cell, human HCC cell line (HepG2, MCF-7) |
CCR7 | Up | CCL21, CCL19 | Increased angiogenesis [27], alter tumor microenvironment: increased IL-10 and TGF-β1, decreased level of IL-12 and IFN-γ [28] | HCC patients, DEN-induced mice model |
CCR9 | Up | CCL25 | Increased proliferation [29] | HCC patients, human HCC cell lines (HepG2, Huh7, Hepan3B) |
CXCR2 | Up | CXCL5 | Increased EMT [16], increased migration and invasion [16,17,30], increased angiogenesis [31] | HCC patients, xenograft mouse models, orthotropic nude mice, human HCC cell lines (MHCC97-L, MHCC97-H, HCCLM3, HepG2, Huh7) |
CXCR3 | Up | CXCL9, CXCL10 | Increased invasion and migration [32] | HCC patients, metastasis mice model, human HCC cell lines (Hep3B, PLC/PRF/5, Huh7) |
CXCR4 | Up | CXCL12 | Increased invasion and migration [33,35,36,38], increased EMT [34,36,37,38] | HCC patients, human HCC cell lines (Huh7, Hep3B, MHCC97, SMMC7721), hepatic stellate cell (LX-2) |
CXCR6 | Up | CXCL16 | Increased invasion, alter tumor microenvironment: increased proinflammatory cytokine production such as IL-17, IL-6, and IL-8 [43] | HCC patients, xenograft mouse models, human HCC cell lines (Hep3B, HepG2, Huh7, PLC/PRF/5, SK-HEP-1, MHCC97L, MHCC97H, HCCLM3), human liver cell line (L-02) |
CXCR7 | Up | CXCL12 | Increased proliferation, migration and invasion [39,40,41], increased angiogenesis and EMT [42] | HCC patients, DEN-induced mice model, human micro-vascular endothelial cell line (HMEC-1) |
CX3CR1 | Down | CX3CL1 | Immunoprevention [44,45] | HCC patients |
XCR1 | Down | XCL1 | Suppresses liver cancer growth and tumorigenesis, increased metastasis [18] | human HCC cell lines (Huh-7, HepG2, Hep3B, SMMC7721, HCLM3, HCCLM6, MHCC-97L, MHCC-97H) |
EP1 | Up | PGE2 | Increased invasion [47], increased migration [48], increased apoptosis [49] | HCC patients, human HCC cell lines (Huh-7, Hep3B, HEK293 cells) |
EP2 | Up | PGE2 | Decrease apoptosis [50,51] | Human HCC cell lines (SMMC-7721, HepG2) |
EP4 | Up | PGE2 | Increased proliferation and invasion [46] | Human HCC cell line (Huh-7) |
LPAR1 | Up | LPA | Increased invasion and migration [55], increased proliferation [56] | HCC patients, human HCC cell lines (SK-Hep1, HepG2 and HuH-7) |
LPAR3 | Up | LPA | Increased invasion and migration [56] | HCC patients, human HCC cell lines (SK-Hep1, HepG2 and HuH-7) |
LPAR6 | Up | LPA | Increased proliferation, invasion and migration [53,56] | HCC patients, subcutaneous implantation HCC female CD-1 nude athymic mice, human HCC cell lines (HepG2, HuH-7 PLC/PRF/5, and HLE) |
α1-AR | Down | Catecholamines | Increased ALT, alter tumor microenvironment: decrease energy expenditure, low levels of thyroid hormones, induce hepatocyte injury [59] | HCC patients |
β1-AR | Up | Catecholamines | Increased proliferation [60] | HCC patients |
β2-AR | Up | Catecholamines | Increased proliferation, invasion and migration [61,62,63] | HCC patients, DEN-induced HCC mice model, xenograft male nude mice model, human HCC cell lines (SMMC-7721, HepG2, MHCC-97L) human normal liver cell line (L-02) |
AT1R | Up | Ang II | Increased angiogenesis [67] | human HCC cell lines (MHCC97-L, Bel-7402) |
AT2R | Up or down | Ang II | Increased proliferation [68], increased angiogenesis [69,70,71] | Intrahepatic tumor mice model, wild-type and AT2-deleted mice, human HCC cell lines (SMMC-7721, Bel7402, HepG2), human fetal liver cell line (L-02) |
Smo | Up | Sonic hedgehog | Increased invasion and migration [77,78,79,80] | HCC patients, normal human hepatic cell (L-02), human liver cancer cell lines (PLC/PRF/5, Hep3B, SK-HEP-1, Huh7, Bel-7402, and SMMC-7721) |
GPR49 | Up | Unknown | Increased proliferation [81] | HCC patients, human HCC cell lines (PLC/PRF/5 and HepG2) |
GPR137 | Up | Unknown | Increased proliferation, decreased apoptosis [82] | Human HCC cell lines (HepG2, Bel7402, Bel7404, SK-HEP-1, Hep3B, SMMC-7721), human embryonic kidney cell line (HEK293T) |
GPR37 | Up | Unknown | Increased proliferation, decreased apoptosis [83] | HCC patients, human HCC cell line (Huh-7) |
Antagonists | Targeted-GPCR | Mechanism | Biological Model | Reference |
---|---|---|---|---|
RDC018 | CCR2 | Inhibits the recruitment of inflammatory monocytes, infiltration, and M2-polarisation of tumor-associated macrophages resulting in reversal of the immunosuppression status of the tumor microenvironment and activation of an antitumorous CD8+ T cell response. | HCC patients, orthotopic HCC model, murine HCC cell line (Hepa1-6, LPC-H12, and H22), human HCC cell lines (Hep3B, HepG2, BEL-7404, SMMC-7721, Huh-7, PVTT-1, MHCC-97L, MHCC-97H, and MHCC-LM3), human liver cell lines (HL-7702 and L-02) | [84] |
Maraviroc | CCR5 | Inhibits hepatic stellate cells activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. | Choline-containing diet male C57BL/6 mice | [24,85] |
Met-RANTEs | CCR1, CCR5 | Reduced inflammation by reducing periductal accumulation of CD24+ oval cells and abrogation of fibrosis. | Wild-type C57Bl/6J, CCR5-deficient mice, double mutant Mdr2:CCR5 and Mdr2:CCR1 DKO mice | [24] |
AMD3100 | CXCR4 | In combination with sorafenib treatment block CXCR4/SDF1α, prevents the infiltration of tumor-associated macrophages. enhanced antiangiogenic effect and suppress local and distant tumor growth in HCC. | Orthotopically implanted HCC Male C3H/HeNCrNarl mice, murine HCC cell line(HCA-1), human HCC cell line(JHH-7) | [86,87] |
CCX771 | CXCR7 | Inhibited CXCR7-induced phosphorylation of ERK1/2 signaling and secretion of the proangiogenic factors VEGF-A. | HCC patients, hepatic cell lines (L-02 and QSG7701), human HCC cell lines (QGY7703, HepG2, Hep3B, MHCC97L, MHCC97H, HCCLM3, HCCLM6) | [40] |
ONO-8711 | EP1 | Decreased EGFR phosphorylation and tumor cell invasion. | HCC patients, human HCC cell lines (Hep3B, Huh7, and HepG2) | [88,89] |
AH6809 | EP1 | Combination of EP1 receptor antagonist and COX inhibitors produced a significantly greater cell growth inhibition than the single agent alone. | HCC patients with hepatitis virus-associated chronic liver disease, human HCC cell lines (HuH-6 and Huh7) | [90] |
AH23848 | EP4 | Inhibition of HSC-derived PGE2 could inhibit HSC-induced MDSC accumulation and HCC growth. | Adult male BALB/c mice injected intra-hepatically with cell suspension, mouse hepatoma cell line (H22) | [91] |
Propranolol | β2-AR | Enhanced autophagy, HIF-1α destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. | Human patients, DEN-induced HCC mouse model, human HCC cell line (SMMC-7721) | [63] |
BQ123 | ETAR | Blockade of ETAR inhibits HCC cell migration and invasion via blocking ERK1/2 and Akt signaling pathways and lowering MMP-3 expression. | Human liver cell line (L-02), human HCC cell lines (MHCC97-L, Bel-7402, SMMC-7721, and HepG2) | [92] |
GDC-0449 (vismodegib) | Smo | Blockade of Smo and Shh signaling pathway result in a successful mitigation of ML-1 growth. | Implantation of mice hepatoma ML-1 cells C57BL/6 mice model | [93] |
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Peng, W.-T.; Sun, W.-Y.; Li, X.-R.; Sun, J.-C.; Du, J.-J.; Wei, W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2018, 19, 1366. https://doi.org/10.3390/ijms19051366
Peng W-T, Sun W-Y, Li X-R, Sun J-C, Du J-J, Wei W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2018; 19(5):1366. https://doi.org/10.3390/ijms19051366
Chicago/Turabian StylePeng, Wen-Ting, Wu-Yi Sun, Xin-Ran Li, Jia-Chang Sun, Jia-Jia Du, and Wei Wei. 2018. "Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma" International Journal of Molecular Sciences 19, no. 5: 1366. https://doi.org/10.3390/ijms19051366