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FAT4 loss disrupts adhesion, induces EMT, and promotes tumor initiation and growth via PAK6-mediated WNT/β-catenin signaling, followed by pathway switching toward WNT5A/ROR2 signaling.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/fat4-loss-initiates-hepatocarcinogenesis-through-the-switching-of-canonical-to-noncanonical-wnt-signaling-pathways/378543/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/fat4-loss-initiates-hepatocarcinogenesis-through-the-switching-of-canonical-to-noncanonical-wnt-signaling-pathways/378543.png","ImageObject",300,407,{"name":42,"@type":43},"kopisore","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-24","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How 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switching of canonical to noncanonical WNT signaling pathways  \nFung-Yu Huang1  Tan-To Cheung2,3  Rex Wan-Hin Hui1   \n| Danny Ka-Ho Wong1,2  | Lung-Yi Mak1,2  || Sai-Sai Zhang1  | Hau-Tak Chau 1  || Wai-Kay Seto 1,2  | Man-Fung Yuen1,2   \n1Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR 2State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR 3Department of Surgery, School of Clinical Medicine, The University of Hong Kong,  \nQueen Mary Hospital, Hong Kong SAR  \nCorrespondence  \nMan-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. Email: mfyuen@hku. hk  \nWai-Kay Seto, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. Email: wkseto@hku. hk  \n\n|  | Abstract |  |\n| --- | --- | --- |\n| | 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 |  |\n|  |  |  |\n\nAbbreviations: α-SMA, α-smooth muscle actin; 5′-aza-dC, 5-azadeoxycytidine; CCND1, Cyclin D1; COL1A1, collagen type 1; E-cad, E-cadherin; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; DEG, differential gene expressions; FAT4, FAT atypical cadherin 4; FAT4-KO, knockout FAT4; FN1, fibronectin; GO, Gene Ontology; ITGBI, integrin β1; LAMA4, laminin subunit alpha 4; MAPK, Mitogen-activated protein kinase; NCBI GEO, National Center for Biotechnology Information Gene Expression Omnibus; P13K-Akt, Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt); PAK6, p21 (RAC1)-activated kinase 6; RNA, seq, RNA-sequencing; ROR2, Receptor tyrosine kinase-like orphan receptor 2; WNT, Wingless-type; WNT5A, Wnt Family Member 5A; WT, wild-type.  \nSupplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.hepcommjournal.com.  \n-- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- -  \nThis is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.  \nCopyright © 2023 T","cbCaitrGXAUllJEh","https://ap.wps.com/l/cbCaitrGXAUllJEh","pdf",2046153,15,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Introduction\n## Chronic liver injury and HCC progression\n## EMT and myofibroblast formation\n## WNT signaling pathways","[{\"question\":\"How did the study model FAT4 loss in liver cells?\",\"answer\":\"The study used a CRISPR-Cas9 system to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line (L02).\"},{\"question\":\"What changes did FAT4 loss cause in the cellular phenotype?\",\"answer\":\"FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition (EMT), and increased extracellular matrix component expression.\"},{\"question\":\"How does FAT4 loss promote tumor initiation and growth in vivo?\",\"answer\":\"FAT4-KO was sufficient for tumor initiation in a xenograft mouse model, and RNA sequencing implicated PAK6-mediated WNT/β-catenin signaling as a driver of tumor growth.\"}]","FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways | PDF",1790231042,38]