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Suppressing Cx32 gap-junction communication preserves differentiation but triggers a wound-healing, highly migratory phenotype marked by TGFβ-SMAD signalling, ECM remodelling, and mesenchymal and cell-cycle marker induction. In muscle-invasive bladder cancer, non-membrane Cx32 defines a Ki67-high, vimentin-positive, TGFβ-activated luminal subset, predicting more invasive biology and EMT potential.",{"@graph":14,"@context":72},[15,34,55],{"@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/research-report/","Research & 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role does Connexin 32 (Cx32) play in differentiated urothelium?","Question",{"text":62,"@type":63},"Cx32 is expressed in differentiated human urothelium and predominantly localises to the basolateral borders of superficial urothelial cells.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"What happens when Cx32 gap-junction communication is suppressed?",{"text":67,"@type":63},"Differentiation is not affected, but cells switch to a highly migratory wound-healing phenotype with TGFβ-SMAD signalling, ECM remodelling, and induction of mesenchymal and cell-cycle markers.",{"name":69,"@type":60,"acceptedAnswer":70},"How does Cx32 relate to luminal muscle-invasive bladder cancer biology?",{"text":71,"@type":63},"Immunohistological classification shows Cx32 expression is informative, and non-membrane localised Cx32 defines a Ki67-high, vimentin-expressing, TGFβ-activated luminal subset linked to more invasive biology and potential 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\nJennifer Hinley1 , Simon C Baker1 , Andrew S Mason1 , Grigorios Kyriazis2 , Omar Masood3, Jennifer Southgate1   \nThe molecular programming of epithelial wound repair provides the origin for the signalling pathways that drive the growth and spread of carcinoma cells. Urothelium is the mitotically quiescent, barrierforming transitional epithelium of the urinary tract, characterised by uniquely specialised superficial cells and a remarkable regenerative capacity in response to damage. Connexin 32 (Cx32) was expressed by differentiated human urothelium where it predominantly localised to the basolateral borders of superficial urothelial cells. Suppression of Cx32 gap junction intercellular communication did not affect differentiation but instigated the switch to a highly migratory, wound healing phenotype marked by TGFβ-SMAD signalling, ECM-remodelling, and induction of mesenchymal and cellcycle markers. Immunohistological classification of muscle-invasive bladder cancers revealed Cx32 expression to be informative in luminal tumour biology, with non-membrane localised Cx32 defining a Ki67-high, vimentin-expressing, and TGFβ-activated subset of luminal tumours. Our findings identify Cx32 cell–cell communication as suppressing migratory and proliferative behaviours in normal urothelial differentiation and suggest that Cx32 assessment, within the context of luminal muscle-invasive bladder cancer, can predict more invasive biology. This reveals the potential for differentiated cancers to exhibit EMT.  \nDOI 10.26508/lsa.202503427 | Received 19 June 2025 | Revised 29 January 2026 | Accepted 30 January 2026 | Published online 17 February 2026  \nIntroduction  \nMost bladder cancers arise by neoplastic transformation of urothelium, the transitional epithelium that lines the urinary tracts, including the bladder and ureters. Urothelium functions as astable, low-turnover but self-repairing barrier evolved to protect the underlying tissues from exposure to pathogens and excreted urinary toxins. A dearth of targeted therapies for bladder cancer fuelled international interest in transcriptomic-based classification studies. By consensus, this has led to muscle-invasive bladder cancers (MIBCs) being broadly classified into “basal” and “luminal”subtypes, based on pathways driven, respectively, by P63 or PPARγ  \nsignalling (Choi et al, 2014; Dadhania et al, 2016; Kamoun et al, 2020) . Basal cancers show loss of urothelial identity by reverting toa more primitive basal/squamous epithelial form, with corresponding changes in cytokeratin expression, such as KRT5, KRT6A, and KRT14 gain and reflected in therapeutically relevant biology, such as autocrine-stimulated EGFR-driven growth ( Rebouissou et al, 2014) . By contrast, luminal MIBCs retain a similar profile of gene expression to normal differentiated urothelium, including KRT20 and uroplakins, and underpinning transcriptional regulators GATA3 and FOXA1 (Choi et al, 2014), with mutations and amplifications in PPARG contributing significantly to this subtype ( Bitonet al, 2014; Rochel et al, 2019) . While this suggests that luminal cancers retain dependency on urothelial differentiation programming, the underpinning biology is less clear.  \nHuman urothelium has evolved features that make it an exceptional urinary barrier. It has long been recognised as the least permeable mammalian epithelial barrier ( Hicks et al, 1974; Negrete et al, 1996), since attributed to the superficial membraneembedded uroplakin plaques that restrict transcellular solute permeability (Liang et al, 2001) and the highly developed tight junctions that limit paracellular permeability between adjacent superficial cells (Varley et al, 2006; Smith et al, 2015) . In habit, urothelium is recognised as a stable, low turnover epithelium that balances mitotic quiescence with an exceptional capacity for selfregeneration a","cbCaiauvOVQBAL8C","https://ap.wps.com/l/cbCaiauvOVQBAL8C","pdf",10586519,21,"English","# Introduction\n## Bladder cancer subtypes and differentiation programming\n## Urothelium barrier features and regeneration\n## Gap junctions and connexin biology","[{\"question\":\"What role does Connexin 32 (Cx32) play in differentiated urothelium?\",\"answer\":\"Cx32 is expressed in differentiated human urothelium and predominantly localises to the basolateral borders of superficial urothelial cells.\"},{\"question\":\"What happens when Cx32 gap-junction communication is suppressed?\",\"answer\":\"Differentiation is not affected, but cells switch to a highly migratory wound-healing phenotype with TGFβ-SMAD signalling, ECM remodelling, and induction of mesenchymal and cell-cycle markers.\"},{\"question\":\"How does Cx32 relate to luminal muscle-invasive bladder cancer biology?\",\"answer\":\"Immunohistological classification shows Cx32 expression is informative, and non-membrane localised Cx32 defines a Ki67-high, vimentin-expressing, TGFβ-activated luminal subset linked to more invasive biology and potential EMT.\"}]","Connexin 32 constrains a mesenchymal-like switch in differentiated urothelium and luminal cancers | PDF",1790092492,53]