Table 1.
Role of GPCRs in HCC.
| 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) |