Liver metastasis, originating either from a primary liver or other cancer types, represent a large cancer-related burden. Therefore, studies that add to better understanding of its molecular basis are needed. Herein, the role of the Wnt signaling pathway in liver metastasis is outlined. Its role in hepatocellular carcinoma (HCC) epithelial-mesenchymal transition (EMT), motility, migration, metastasis formation, and other steps of the metastatic cascade are presented. Additionally, the roles of the Wnt signaling pathway in the liver metastasis formation of colorectal, breast, gastric, lung, melanoma, pancreatic, and prostate cancer are explored.
Protein | Mechanism | Effect | Ref. |
---|---|---|---|
HGF | Activates Wnt pathway by transcriptional activation of LEF1 | Facilitates in vitro tumor migration and invasion | [47] |
CTHRC1 | Activates the PCP pathway of Wnt signaling | Promotes in vitro tumor migration and invasion and cell-matrix adhesion | [48] |
CAV1 | Induces Wnt/β-catenin pathway through nuclear accumulation of β-catenin | Enhances EMT, invasiveness, and lung metastasis in vitro and in vivo | [49] |
CLDN3 | Inactivates the Wnt/β-catenin-EMT axis through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2 | Inhibits cell motility and invasiveness in vitro and in vivo | [50] |
AEG-1 | Transcriptionally regulated by c-Myc and induces c-Myc by activating the Wnt/β-catenin pathway | Activates prosurvival and EMT–signaling pathways and induces in vivo lung metastasis | [51] |
GAL1 | Promotes β-catenin nuclear translocation, TCF4/LEF1 transcriptional activity and CCND1 and c-Myc expression | Triggers EMT in vitro | [52] |
TRIM37 | Activates the Wnt/β-catenin pathway | Promotes in vitro and in vivo cell migration and metastasis by inducing EMT | [53] |
HKDC1 | Downregulation represses β-catenin and c-Myc expression | Associated with aggressive phenotype | [54] |
FRAT1 | Knockdown suppresses Wnt/β-catenin pathway by partially suppressing the expression levels of β-catenin, CCND1, and c-Myc | Knockdown inhibits in vitro hypoxia-induced EMT, migration, and invasion | [55] |
NTR1 | NTS/NTR1 co-expression correlates with the activation of the Wnt/β-catenin signaling pathway | NTS/NTR1 co-expression enhances EMT, invasion, and in vivo metastasis formation | [56] |
CTNND1 | Acts, at least in part, by indirectly enhancing Wnt/β-catenin signaling | Promotes in vitro migration, invasion, and in vivo metastasis formation | [57] |
PRC1 | Inhibits APC stability, and promotes β-catenin release from the APC complex | Promotes in vitro migration and invasion | [58] |
CX32 | Its inhibition enhances Snail expression through activation of Wnt/β-catenin signaling | Regulates EMT, migration, and invasion in vitro and inhibits tumor metastasis in vivo | [59] |
FERMT2 | Activates Wnt/β-catenin signaling and increases β-catenin expression (especially non-phosphorylated form) | Promotes in vitro invasion and metastasis | [60] |
OCT4 | Upregulates LEF1, a key component of the WNT signaling pathway | Induces EMT in vitro | [61] |
DDX39 | Activates Wnt/β-catenin pathway by increasing β-catenin levels in the nucleus | Promotes tumor growth, migration, invasion, and in vivo metastasis | [62] |
PCL3 | Inhibits β-catenin degradation, and activates β-catenin/TCF signaling | Positively regulates the migration, invasion, and in vivo metastasis formation | [63] |
ITGB5 | Directly interacts with β-catenin and inhibits its degradation, thus leading to Wnt/β-catenin activity | Elevated ITGB5 facilitates in vitro cell migration | [64] |
JUB | Activates β-catenin in the nuclei | Induces in vitro EMT and migration | [65] |
LRP16 | Its overexpression could prevent β-catenin from entering the nucleus | Attenuates cell migration, and invasion in vitro, and metastasis in vivo | [66] |
ZIC5 | Increases the expression of β-catenin and CCND1 and promotes β-catenin to enter the nucleus | Promotes proliferation, migration, and invasion in vitro and in vivo | [67] |
SOX9 | SOX9-AS1/miR-5590-3p/SOX9 positive feedback acts through the Wnt/β-catenin pathway | Aggravates HCC progression and metastasis in vitro and in vivo | [68] |
AKIP1 | Interacts with and sustains β-catenin in the nucleus by blocking its interaction with APC; enhances phosphorylation of β-catenin | Promotes invasion and increases intrahepatic and lung metastasis in vivo | [69] |
FBXO17 | Its silencing might function through downregulating the expression of proteins in Wnt/β-catenin pathway | In vitro metastasis ability in the anti-FBXO17 group is decreased | [70] |
FOXG1 | Activates Wnt signaling through forming TCF4/β-catenin/FOXG1 complex | Promotes EMT and aggressiveness in vitro and enhances metastasis in vivo | [71] |
GATA5 | Co-localizes with β-catenin in the cytoplasm, preventing β-catenin from entering the nucleus | Inhibits in vitro cell growth, colony formation, migration, and invasion | [72] |
GRP78 | Activates the Wnt/HOXB9 pathway by chaperoning LRP6 | Promotes in vitro and in vivo invasion and metastasis | [73] |
HEG1 | Promotes β-catenin expression and maintains its stability, leading to its accumulation and nuclear translocation | Promotes EMT and in vitro and in vivo invasion and metastasis | [74] |
NDRG3 | Promotes nuclear translocation of β-catenin | Enhances metastasis and angiogenesis in vitro and in vivo | [75] |
MSI1 | Activates Wnt/β-catenin signaling pathway (downregulation reduces the expression of phospho-β-catenin and CCND1 and elevates the protein expression of DKK1 and APC) | Affects in vitro cancer cell viability, migration, and invasiveness | [76] |
p62/IMP2 | Activates Wnt/β-catenin pathway | Promotes in vitro EMT and migration | [77] |
RICH2 | Overexpression positively correlates with the expression of WNT5a and inversely correlates with β-catenin | Inhibits formation of filopodia and invasion and proliferation in vitro | [78] |
AQP9 | Overexpression reduces the levels of DVL2, GSK-3β, CCND1, and β-catenin | Overexpression suppresses in vitro migration, invasion, and EMT | [79] |
ARHGEF11 | Induces β-catenin nuclear translocation and upregulates ZEB1 | Promotes EMT and migration in vitro | [80] |
GAL3 | Activates the PI3K-Akt-GSK-3β-β-catenin signaling cascade | Regulates in vitro angiogenesis and EMT and favors tumor lung metastasis in vivo | [81] |
KIF2C | Direct target of the Wnt/β-catenin pathway that mediates the crosstalk between Wnt/β-catenin and mTORC1 signaling | Promotes migration, invasion, and metastasis both in vitro and in vivo | [82] |
KIF18B | The knockdown downregulates the expression of c-Myc, CCND1, β-catenin, and p-GSK-3β | Knockdown might suppressproliferation, migration, and invasion in vitro | [83] |
MTDH | Its overexpression induces PRMT5 translocation from the nucleus to the cytoplasm and translocation of β-catenin from the cytoplasm to the nucleus which upregulates WNT/β-catenin signaling pathway | PRMT5 and β-catenin play a pivotal role in MTDH-mediated HCC in vivo metastasis | [84] |
NRF1 | Enhances ubiquitination of β-catenin for targeting proteasomal degradation | Promotes invasion and metastasis to the lung and liver in in vivo models | [85] |
FXR | Decreases expression of β-catenin target genes and reduces nuclear translocation of β-catenin proteins in vitro and in vivo | Suppresses migration and invasion in vitro and inhibits local invasion and lung metastasis in vivo | [86] |
USP1 | Its knockout impairs expression of Wnt target genes | Frequently upregulated in liver circulating tumor cells and expression correlates with metastasis | [87] |
ATE1 | Accelerates degradation of β-catenin and inhibits Wnt signaling by regulating turnover of RGS5 | Knockdown promotes cancer growth, migration, and disease progression in vitro and in vivo | [88] |
PGC1α | Inhibits Warburg effect by PPARγ–dependent WNT/β-catenin/PDK1 axis | Suppresses in vitro and in vivo metastasis | [89] |
RAD54B | Increases nuclear β-catenin and up-regulates Wnt/β-catenin downstream target genes (c-Myc, CCND1, MMP7, CD44, VEGF, c-Jun) | Increases in vitro cell viability and motility, and in vivo intrahepatic metastasis | [90] |
ZEB1 | Could activate the Wnt/β-catenin signaling pathway by upregulating the protein expression levels of β-catenin, c-Myc, and CCND1 | Promotes in vitro cell proliferation and migration and inhibits apoptosis | [91] |
This entry is adapted from the peer-reviewed paper 10.3390/livers1040015