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Article: FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways
Title | FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways |
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Authors | |
Issue Date | 7-Dec-2023 |
Publisher | Lippincott, Williams & Wilkins |
Citation | Hepatology Communications, 2023, v. 7, n. 12 How to Cite? |
Abstract | Background:Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive. Methods:CRISPR-Cas9 system was used to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using in vitro experiments. Results:We found that FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. FAT4-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of FAT4-KO cells identified PAK6-mediated WNT/β-catenin signaling to promote tumor growth. Suppression of PAK6 led to β-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed FAT4-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on β-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/β-catenin signaling, suggesting the shifting of β-catenin-dependent to β-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival. Conclusions:Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment. |
Persistent Identifier | http://hdl.handle.net/10722/339466 |
ISSN | 2023 Impact Factor: 5.6 2023 SCImago Journal Rankings: 2.217 |
DC Field | Value | Language |
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dc.contributor.author | Huang, Fung-Yu | - |
dc.contributor.author | Wong, Danny Ka-Ho | - |
dc.contributor.author | Mak, Lung-Yi | - |
dc.contributor.author | Cheung, Tan-To | - |
dc.contributor.author | Zhang, Sai-Sai | - |
dc.contributor.author | Chau, Hau-Tak | - |
dc.contributor.author | Hui, Rex Wan-Hin | - |
dc.contributor.author | Seto, Wai-Kay | - |
dc.contributor.author | Yuen, Man-Fung | - |
dc.date.accessioned | 2024-03-11T10:36:51Z | - |
dc.date.available | 2024-03-11T10:36:51Z | - |
dc.date.issued | 2023-12-07 | - |
dc.identifier.citation | Hepatology Communications, 2023, v. 7, n. 12 | - |
dc.identifier.issn | 2471-254X | - |
dc.identifier.uri | http://hdl.handle.net/10722/339466 | - |
dc.description.abstract | <h3>Background: </h3><p>Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive.</p><h3>Methods: </h3><p>CRISPR-Cas9 system was used to knockout FAT4 (<em>FAT4</em>-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using <em>in vitro</em> experiments.</p><h3>Results: </h3><p>We found that <em>FAT4</em>-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. <em>FAT4</em>-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of <em>FAT4</em>-KO cells identified PAK6-mediated WNT/β-catenin signaling to promote tumor growth. Suppression of PAK6 led to β-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed <em>FAT4</em>-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on β-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/β-catenin signaling, suggesting the shifting of β-catenin-dependent to β-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival.</p><h3>Conclusions: </h3><p>Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment.</p> | - |
dc.language | eng | - |
dc.publisher | Lippincott, Williams & Wilkins | - |
dc.relation.ispartof | Hepatology Communications | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways | - |
dc.type | Article | - |
dc.identifier.doi | 10.1097/HC9.0000000000000338 | - |
dc.identifier.volume | 7 | - |
dc.identifier.issue | 12 | - |
dc.identifier.eissn | 2471-254X | - |
dc.identifier.issnl | 2471-254X | - |