Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside
Abstract
:1. Introduction
2. Kinase Cascade of the Hippo Pathway
3. Hippo Pathway and GC
3.1. Functional Roles of Dysregulated Hippo Signaling in GC
3.2. The Upstream Regulatory Mechanisms on Hippo Signaling in GC
3.3. Downstream Effectors of Hippo Pathway in GC and Crosstalks between Signalings
3.4. Therapeutic Potential of Targeting the Hippo Signaling in GC
4. Hippo Pathway and Other Digestive Malignancies
5. Clinical Significance of Hippo Signatures in GI Cancers
6. Therapeutic Strategies for Directly Targeting the Hippo Pathway
7. Conclusions
8. Discussion
9. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Regulators | Targets | Regulatory Mechanisms | References |
---|---|---|---|
FBXW5 | LATS1 | FBXW5 inactivates the Hippo pathway by enhancing LATS1 ubiquitination and degradation, which promotes GC cell invasion, metastasis, and drug resistance. | [34] |
circLARP4 | circLARP4 increases miR-424 level, which in turn inhibits LATS1 translation. | [51] | |
WBP2 | LATS2 | WBP2 directly interacts with LATS2 promoter to inhibit LATS2 and activate the YAP1-TEAD transcriptional activity. | [35] |
lncRNAs | Both MYLK-AS1 and LATS2-AS1-001 bind with EZH2 to induce LATS2 activation. | [44,50] | |
LIF | LATS1/2 | Activates LATS1/2 to suppress the malignant properties of CSCs. | [37] |
PAR1 | YAP1 | PAR1 activates YAP1 in a Rho-dependent manner. | [38] |
IRF3 | IRF3 strengthens the interaction between YAP1 and TEAD4 for YAP1 activation. | [39] | |
AMOTL1 | AMOTL1 associates with YAP1 to prevent the ubiquitin-mediated YAP1 degradation, thus promoting its nuclear translocation and subsequent tumorigenic roles. | [40] | |
MST4 | MST4 phosphorylates YAP1 at Thr83 to impede its interaction with importin α for YAP1 inactivation. | [42] | |
Netrin-1 | Netrin-1 phosphorylates YAP1 via its receptor neogenin. | [43] | |
RP11-323N12.5 | LncRNA RP11-323N12.5 binds with c-MYC to transactivate YAP1. | [45] | |
METTL3 | METTL3 regulates the m6A modification of YAP1 for its activation. | [56] | |
NUSAP1 | NUSAP1 stabilizes YAP1 protein through direct binding. | [62] | |
KRT17 | KRT17 loss stimulates RhoA-dependent F-actin polymerization and induces YAP1 signaling activation and nuclear localization. | [30] | |
microRNA-141 | TAZ | microRNA-141 directly downregulates TAZ. | [47] |
RUNX3 | TEAD | RUNX3 interacts with TEAD to abrogate the DNA binding ability of TEAD, thus limiting the oncogenic property of the TEAD-YAP1 complex in GC. | [41] |
H. Pylori | Hippo components | Controls the expression of MST1, LATS2, YAP1, and TAZ to promote EMT and other tumorigenic properties. | - |
Downstream Targets of YAP1 in GC | Regulatory Mechanisms | References | |
YAP1 | MYC | Upon YAP1 activation, activated YAP1 transcriptionally modulates MYC by binding to MYC enhancer and sequesters p72 to hinder miRNAs-mediated MYC suppression. | [16] |
IL-1ß | YAP1-TEAD complex binds onto IL-1ß promoter to transcriptionally upregulate IL-1ß production, thus resulting in GC cell proliferation. | [54] | |
SLC35B4 | YAP1-TEAD complex induces SLC35B4 transactivation via binding to the promoter region of SLC35B4. | [58] | |
SOX9 | YAP1 binds to peroxisome proliferator-activated receptors (PPARs) to induce transcriptional regulation of SOX9, which further leads to enhanced cancer stemness and tumorigenicity. | [31,59] | |
ARHGAP29 | YAP1 transcriptionally upregulates ARHGAP29 to suppress the RhoA-LIMK-cofilin pathway for F-actin destabilization. The YAP1-ARHGAP29 signaling is essential for GC metastasis. | [60] |
Members | Cancer Type | Expression | Function | Mechanisms | Reference |
---|---|---|---|---|---|
MST1/2 | CRC | Downregulated | Tumor suppressor | Depletion of Mst1/2 driven CRC. | [72] |
HCC | Mst1/2 kinases are canonical YAP/TAZ regulators. | [73] | |||
LATS1/2 | CRC | Downregulated | Tumor suppressor | LATS1/2 can inhibit CRC growth and metastasis via downregulating Gli1 expression and MT2A-mediated absence of YAP1 nuclear localization. | [72,74,75] |
HCC | Depletion of LAST1/2 lead to hyperactivation of YAP/TAZ. | [74] | |||
YAP1/YAZ | CRC | Upregulated | Oncogene | The expression of YAP1 is driven via aberrant Wnt/β-catenin signaling in human CRC cells. | [75,76,77,78] |
HCC | YAP1/TAZ activates mTORC1 in HCC cells. The interaction of RBM3 -YAP1 is important for HCC proliferation, and USP10 was reported to inhibit YAP1/TAZ ubiquitinating. Overexpression of miR-375 and miR-590-5P inhibited cell proliferation and invasion by downregulating YAP1 activity. | [79,80,81,82] | |||
EC | Gli1 upregulated YAP1 with LATS1 independent mode. Simultaneously, YAP1 increased Gli1 expression by direct regulation PI3K/AKT pathway. | [83] | |||
PDAC | YAP1/TAZ acts as an essential downstream in the oncogenic transition of both KRAS and MAPK pathways. KRAS-mutation promotes PDAC initiation in transgenic models by activating YAP1/TAZ to upregulate JAK-STAT3 signaling activation. | [84,85] |
ClinicalTrials.gov Identifier | Official Title | Condition or Disease | Intervention/Treatment | Phase | Status |
---|---|---|---|---|---|
NCT00944463 | Trial of Simvastatin and Gemcitabine in pancreatic cancer patients | PDAC | Drug: Gemcitabine + simvastatin Drug: Gemcitabine+Placebo | 2 | Completed |
NCT01813994 | Role of Statin on gastric inflammation in patients at high risk of gastric cancer | Early GC or gastric adenoma | Drug: Arm1: Statin Drug: Arm2: Placebo | Not applicable | Completed |
NCT02968810 | Simvastatin in preventing liver cancer in patients with liver cirrhosis | Cirrhosis | Other: Placebo Administration Other: Questionnaire Administration Drug: Simvastatin | 2 | Active, not recruiting |
NCT04947020 | dataBase for analysis of rectal cancer oncological results (BARO) | Rectal cancer | Drug: Metformin | Not applicable | Recruiting |
NCT01099085 | Trial of XP (Capecitabine/CDDP) Simvastatin in advanced gastric cancer patients | GC | Drug: Simvastatin Drug: Placebo | 3 | Completed |
NCT02569645 | Rosuvastatin in the treatment of rectal cancer | Rectal cancer | Drug: Rosuvastatin | 2 | Completed |
NCT01075555 | Sorafenib Tosylate with or without pravastatin in treating patients with liver cancer and cirrhosis | Liver cancer | Drug: Pravastatin sodium Drug: Sorafenib tosylate | 3 | Completed |
NCT02026583 | A Single Arm, Phase II study of Simvastatin Plus XELOX and Bevacizumab as first-line chemotherapy in metastatic CRC Patients | CRC | Drug: Simvastatin | 2 | Completed |
NCT01281761 | Simvastatin + Cetuximab/Irinotecan in K-ras mutated CRC | Metastatic CRC | Drug: Cetuximab/irinotecan/simvastatin | 2 | Completed |
NCT00313859 | Phase II Study of Simvastatin Plus Irinotecan, Fluorouracil, and Leucovorin (FOLFIRI) for metastatic CRC | Metastasis CRC | Drug: Simvastatin | 2 | Completed |
NCT03889795 | Phase IB Metformin, Digoxin, Simvastatin in solid tumors | Advanced PDAC | Drug: Metformin Drug: Simvastatin Drug: Digoxin | 1 | Recruiting |
NCT05368805 | Fruquintinib DDI study with P-gp and BCRP substrates | Metastatic CRC | Drug: Fruquintinib Drug: Dabigatran Etexilate Drug: Rosuvastatin | 1 | Active, not recruiting |
NCT04767984 | Testing Atorvastatin to lower colon cancer Risk in longstanding ulcerative colitis | CRC and ulcerative colitis | Drug: Atorvastatin Calcium | 2 | Recruiting |
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Liu, X.; Wang, Y.; Chen, B.; Chan, W.N.; Mui, C.W.; Cheung, A.H.K.; Zhang, J.; Wong, K.Y.; Yu, J.; Kang, W.; et al. Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022, 10, 2512. https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102512
Liu X, Wang Y, Chen B, Chan WN, Mui CW, Cheung AHK, Zhang J, Wong KY, Yu J, Kang W, et al. Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines. 2022; 10(10):2512. https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102512
Chicago/Turabian StyleLiu, Xiaoli, Yifei Wang, Bonan Chen, Wai Nok Chan, Chun Wai Mui, Alvin H.K. Cheung, Jinglin Zhang, Kit Yee Wong, Jun Yu, Wei Kang, and et al. 2022. "Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside" Biomedicines 10, no. 10: 2512. https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102512