Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction of Hepatocellular Carcinoma (HCC)
2. Canonical and Non-Canonical Pathways of Wnt Signaling
3. The Role of Wnt/β-Catenin Signaling Pathway in HCC
3.1. Mutation and Expression Status of the Wnt/β-Catenin Pathway and Its Clinical Significance
3.2. Regulation of Wnt/β-Catenin Pathway in HCC
3.2.1. Epigenetic Regulation of Wnt/β-Catenin
3.2.2. Non-Coding RNAs in Regulation of Wnt/β-Catenin
3.2.3. Other Molecules Involved in the Regulation of Wnt/β-Catenin
4. Wnt/β-Catenin Signaling in Cancer Metabolism
4.1. The Role of Wnt/β-Catenin in Aerobic Glycolysis
4.2. The Role of Wnt/β-Catenin in Glutaminolysis
4.3. The Role of Wnt/β-Catenin in Fatty Acid Metabolism
4.4. The Roles of Growth Factors and Oncogenic Factors in Regulation of Wnt/β-Catenin-Induced Cellular Metabolism
5. The Role of β-Catenin in Cancer Stemness and Drug Resistance in HCC
5.1. The Role of Wnt/β-Catenin in the Regulation of Cancer Stemness
5.2. The Role of Wnt/β-Catenin in Drug Resistance
6. Therapeutic Implications of Targeting the Wnt/β-Catenin Pathway in HCC
6.1. Targeting the Interaction between Wnt Ligands and Their Receptors
6.2. Targeting the β-Catenin Destruction Complex
6.3. Targeting β-Catenin/LEF-TCF Signaling
6.4. Targeting Other Components in the Wnt/β-Catenin Signaling Pathway
7. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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LncRNA | miRNA | Targets | Ref. |
---|---|---|---|
LINC00346 | miR-542-3p | FZD7, WDR18 | [54] |
LINC00355 | miR-217-5p | GSK3β, c-myc, CCND1 | [46] |
LINC00355:8 | miR-6777-3p | Wnt10b | [55] |
LINC00662 | miR-15a, miR-16, miR-107 | Wnt3a | [48] |
LINC01278 | miR-1258 | TCF-4, Smad2/3 | [47] |
ANRIL | miR-191, miR-122-5p | CCND1, p53, p21, MMP-2, MMP-9, Vimentin | [56,57] |
DGCR5 | miR-346 | KLF14 | [58] |
DSCR8 | miR-485-5p | FZD7 | [59] |
DLGAP1-AS1 | miR-26a-5p, miR-26b-5p | IL-6, JAK2, STAT3 | [60] |
FEZF1-AS1 | miR-107 | Wnt3a, ICAM1, Vimentin | [49] |
HOTAIR | miR-34a | Akt | [61] |
MIR194-2HG | miR-1207-5p | TCF19 | [62] |
NEAT1 | miR-384 | Wnt | [63] |
NR2F1-AS1 | miR-363 | ABCC1 | [64] |
PRR34-AS1 | miR-296-5p | E2F2, SOX12 | [65] |
RUNX1-IT1 | miR-632 | GSK3β | [66] |
SNHG5 | miR-26a-5p | GSK3β | [67] |
SUMO1P3 | miR-320a | C-myc, CCND1 | [68] |
SOX9-AS1 | miR-5590-3p | SOX9 | [69] |
Clinical | ||||
---|---|---|---|---|
Agents | Targets/Mechanisms | Phase | Clinical Trial no. | Ref. |
CGX1321 | PORCN inhibitor | I | NCT03507998 | [177] |
CGX1321 (With pembrolizumab) | PORCN inhibitor | I | NCT02675946 | [178] |
OMP-54F28 (with sorafenib) | FZD8 decoy receptor | I | NCT02069145 | [179] |
DKN-01 | DDK1 | I/II | NCT03645980 | [180] |
Preclinical | ||||
Agents/Molecules | Roles/Mechanisms | Ref. | ||
Anti-Wnt1 mAb | Inhibit Wnt signaling and Wnt related ligands | [181] | ||
Anti-Wnt2 mAb | Blockade of Wnt binding to FZD receptors Inhibit Wnt signaling and Wnt related ligands | [181,182] | ||
Bcl9/9L | Inactivate Wnt signaling | [183] | ||
BrMC | Inhibit CD133+ liver CSCs proliferation Decrease β-catenin expression | [184] | ||
CGK062 | Enhance proteasomal degradation of β-catenin Induce β-catenin phosphorylation | [185] | ||
CGP049090 | Blockade of β-catenin/TCF/LEF interaction Decrease Wnt-target genes expression | [186,187] | ||
Curcumin | Inhibit GPC3/TPA-induced Wnt activation | [188] | ||
Epigallocatechin-3-gallate | Inhibit Wnt via suppressing c-myc while activating SFRP1 | [189] | ||
FH-535 | Inhibit the activation of β-catenin regulated genes | [176] | ||
FH-535 (Combined with sorafenib) | Inhibit Wnt-target genes Suppress the recruitment of β-catenin | [190] | ||
IC-2 | Wnt/β-catenin signaling | [191] | ||
ICG-001 | Disrupt the binding of β-catenin-CREB | [192] | ||
LncRNA-RUNX1 | Increase GSK3β expression for β-catenin phosphorylation | [193] | ||
LncRNA-Mir22HG | Inactivate β-catenin via downregulation of miRNA-10a-5p | [194] | ||
miRNA-885-5p | Decrease CTNNB1 expression level | [195] | ||
miRNA-122 | Decrease MDR1 expression level and inhibit Wnt/β-catenin | [196] | ||
miRNA-1246 | Target the Wnt/β-catenin degradation complex, GSK-3β and AXIN2 | [197] | ||
NVP-TNKS656 | Tankyrase inhibitor | [198,199] | ||
OMP-18R5 | Blockade of Wnt binding to FZD receptors | [182,200] | ||
Ornithine aminotransferase (OAT) | Inactivators Decrease L-Gln and AFP serum levels | [201] | ||
PKF115-854 | Blockade of β-catenin/TCF/LEF interaction Decrease Wnt-target genes expression | [186,187] | ||
PKF118-310 | Blockade of β-catenin/TCF/LEF interaction Decrease Wnt-target genes expression | [202] | ||
Pimozide | Antipsychotic drug Inhibit the degradation complex and Wnt signaling | [203] | ||
PMED-1 | Blockade of β-catenin/CBP interaction | [204] | ||
Pyrvinium pamoate | Increase GSK3b expression for β-catenin phosphorylation | [205] | ||
SFRP1 | Wnt antagonists Blockade of Wnt signaling | [206] | ||
sFZD7 (Or combined with doxorubicin) | Blockade of FZD/DVL interaction Decrease Wnt-target genes expression | [207] | ||
Sorafenib | Decrease TCF/LEF, β-catenin and Wnt-target genes mRNA levels | [208] | ||
WIF1 | Wnt antagonists Blockade of Wnt signaling | [206] |
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Leung, R.W.H.; Lee, T.K.W. Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers 2022, 14, 5468. https://doi.org/10.3390/cancers14215468
Leung RWH, Lee TKW. Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers. 2022; 14(21):5468. https://doi.org/10.3390/cancers14215468
Chicago/Turabian StyleLeung, Rainbow Wing Hei, and Terence Kin Wah Lee. 2022. "Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma" Cancers 14, no. 21: 5468. https://doi.org/10.3390/cancers14215468
APA StyleLeung, R. W. H., & Lee, T. K. W. (2022). Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers, 14(21), 5468. https://doi.org/10.3390/cancers14215468