Hippo in Gastric Cancer: From Signalling to Therapy
Abstract
:Simple Summary
Abstract
1. The Hippo Pathway
1.1. Overview
1.2. Regulation Mechanisms
1.2.1. YAP/TAZ Effectors Regulation
1.2.2. Hippo Kinase Core and Upstream Partners Regulation
1.2.3. Hippo Pathway Crosstalk with/and Regulation by Other Signalling Pathways
- ○
- AKT/p73 related pathway
- ○
- JNK/AP1/c-Jun/p73 pathway
- ○
- Src/c-Abl/p73 pathway
- ○
- Wnt/β-catenin pathway
- ○
- TGFβ/BMP/Smad pathway
- ○
- PI3K/AKT/mTOR pathway
- ○
- Pax8/TFF-1 pathway
- ○
- EGFR/RAF/MEK/ERK pathway
- ○
- AMPK pathway
- ○
- EMT/ZEB1/SNAIL/SLUG pathway
1.3. Hippo and Cancer
2. Hippo Pathway in Gastric Carcinogenesis
2.1. Hippo Pathway in Helicobacter-Mediated Gastric Carcinogenesis
2.2. Hippo Pathway in GC and CSCs
2.3. Hippo Pathway in GC Resistance to Therapy
3. Anti-GC Strategies Involving the Hippo Pathway
3.1. Downstream Strategies: Targetting Oncogenic YAP/TAZ-TEAD Signaling
3.2. Upstream Strategies: Hippo Kinases and/or Side-Pathways Stimulation
4. Hippo Pathway-Aiming Strategies, Not Tested in GC
4.1. Downstream Strategies: Targetting Oncogenic YAP/TAZ-TEAD Signaling
4.2. Upstream Strategies: Hippo Kinases and/or Side-Pathways Stimulation
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Expression Levels of YAP/TAZ | Regulation | Reference |
---|---|---|
Overexpression of YAP | Increase in pro-proliferation and pro-survival genes | [106] |
Upregulated through RUNX3 inactivation in GC | [31] | |
Induced by METTL3 found highly expressed in GC | [139] | |
Regulation by fixation of lncRNA RP11-323N12.5 on its promoter | [145] | |
Induced by HER4 and increases EMT, GC cells proliferation, and HER2-therapy resistance | [151] | |
Overactivation of YAP | Activated by PAR1 through inhibition of LATS Upregulation of stem-like properties | [126] |
Interacts with AMOTL1 to promote its nuclear translocation and activity | [140] | |
Activation through MAPK-c-Jun pathway | [141] | |
Inhibition is decreased through PP2A- inhibition of MST1/2 | [142] | |
Overexpression of TAZ | Co-localisation with ZEB1 EMT transcription factor CSC tumorigenic properties | [107] |
Upregulation by MiR-125a-5p, leading to stimulation of genes involved in cell survival, EMT, invasion, and tumour growth | [87] | |
Highly expressed in SRCC poorly undifferentiated GC | [153] | |
YAP/TAZ overexpression in CSCs and residual cells after chemotherapy-treatment | Overexpression of associated target genes | [125] |
Strategies | Molecules | Mechanism | Reference |
---|---|---|---|
Targeting oncogenic YAP/TAZ-TEAD signalling | RUNX3 | YAP-TEAD interaction competitor | [31,151,152] |
VGLL4 | YAP-TEAD interaction competitor | [30,113,153] | |
Super-TDU | YAP-TEAD interaction competitor | [113] | |
Verteporfin | YAP-TEAD interaction competitor Targets FAT1 and Survivin Induces 14-3-3 proteins PDT and induces cell death through singlet oxygen production | [121,149,154,155,156,157,158] | |
Peptide 17 | YAP-TEAD interaction inhibitor, Targets N6-methyladenosine (m6A)’s methyltransferase 3 | [135,159,160] | |
WZ35, a Curcumin analogue | Cell death through increase in cellular ROS level | [161,162] | |
Hippo kinases and/or side-pathways stimulation | Dobutamine | Recruits YAP to the cytoplasm through PKA signalling | [163] |
Compound F10 | MST1/2 activation through cytoskeletal alteration | [164] | |
Statins (Lovastatin, Fluvastatin, Simvastatin) | Modulates actin dynamics and activate Hippo kinases Inhibit β-catenin expression and YAP activity | [165,166,167] | |
Metformin | Induces AMPK, which stabilizes AMOTL1 and induces Hippo kinases | [67,168] | |
Pazopanib | Promotes effectors degradation by the ubiquitin-proteasome system | [165] | |
SHAP | Alters STRN3-PP2Aa interaction and restores MST1/2 activity | [142] | |
Leukaemia Inhibitory Factor | Induces LATS1/2 phosphorylation by MST1/2 and through Scribble activation in some cases | [42,43] |
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Seeneevassen, L.; Dubus, P.; Gronnier, C.; Varon, C. Hippo in Gastric Cancer: From Signalling to Therapy. Cancers 2022, 14, 2282. https://doi.org/10.3390/cancers14092282
Seeneevassen L, Dubus P, Gronnier C, Varon C. Hippo in Gastric Cancer: From Signalling to Therapy. Cancers. 2022; 14(9):2282. https://doi.org/10.3390/cancers14092282
Chicago/Turabian StyleSeeneevassen, Lornella, Pierre Dubus, Caroline Gronnier, and Christine Varon. 2022. "Hippo in Gastric Cancer: From Signalling to Therapy" Cancers 14, no. 9: 2282. https://doi.org/10.3390/cancers14092282