Abstract
Claudins are a multigene transmembrane protein family comprising at least 27 members. In gastrointestinal tract, claudins are mainly located in the intestinal epithelia; many types of claudins form a network of strands in tight junction plaques within the intercellular space of neighboring epithelial cells and build paracellular selective channels, while others act as signaling proteins and mediates cell behaviors. Claudin dysfunction may contribute to epithelial permeation disorder and multiple intestinal diseases. Over recent years, the importance of claudins in the pathogenesis of inflammatory bowel diseases (IBD) has gained focus and is being investigated. This review analyzes the expression pattern and regulatory mechanism of claudins based on existing evidence and elucidates the fact that claudin dysregulation correlates with increased intestinal permeability, sustained activation of inflammation, epithelial-to-mesenchymal transition (EMT), and tumor progression in IBD as well as consequent colitis-associated colorectal cancer (CAC), possibly shedding new light on further etiologic research and clinical treatments.
Highlights
Claudins, a multigene transmembrane protein family comprising at least 27 members [1], reportedly contain four transmembrane (TM) helix domains, two extracellular loops (ECLs), a short N-terminus and a C-terminus [2]
Functions of Claudins in inflammatory bowel diseases (IBD) and CAC. Though it is well-acknowledged that gastrointestinal-specific claudins participate in building intestinal barriers and modulating permeability [79], there is ample evidence that claudins may act as signaling proteins and participate in inflammation, cell proliferation, differentiation, and tumorigenesis via cellular signaling pathways, including EGFR/mitogenactivated extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling, PI3K/protein kinase B (Akt) signaling, Wnt/β-catenin signaling and AMP-activated protein kinase (AMPK) signaling, etc
Though claudins participate in the pathogenesis of IBD and consequent tumorigenesis, actual prognostic or therapeutic application of claudins in IBD remains scarce
Summary
A multigene transmembrane protein family comprising at least 27 members [1], reportedly contain four transmembrane (TM) helix domains, two extracellular loops (ECLs), a short N-terminus and a C-terminus [2]. Claudins are mainly located in the intestinal epithelia; many species of claudins form a network of strands in tight junction (TJ) plaques within the intercellular space of neighboring epithelial cells and build paracellular selective channels [3,4,5], while the others act as signaling proteins and modulate cell behaviors [6]. Claudins dysfunction that occurs in enterocytes may contribute to epithelial permeation disorder and multiple intestinal diseases, including inflammatory bowel diseases (IBD) [7, 8]. As the roles of claudins have been gradually better understood in recent years, dysregulation of different claudin types may modulate barrier permeability as TJ proteins and impact tumor behaviors as signaling proteins, participating in the pathogenesis of IBD and consequent tumorigenesis [11]
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