Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk

Abstract

The ability of epithelial cells to organize through cell–cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.

An engineering probiotic producing defensin-5 ameliorating dextran sodium sulfate-induced mice colitis via Inhibiting NF-kB pathway

“…Alterations occurring to the barrier function are known to contribute to IBD. TJ molecules are crucial for maintaining the integrity of the intestinal epithelial barrier and permeability [6]. Our data showed the protective effect of the NZ9000SHD-5 strain on intestinal barrier function occurs through inhibiting the DSS-induced reduction in TJ protein expression and its subsequent increase in intestinal permeability.…”

“…Occludins and claudins are the core TJ proteins that control the structure and permeability of intestinal epithelium. Zonula occludens (ZO-1, ZO-2, ZO-3) are framework forming proteins connecting the actin cytoskeleton with above two transmembrane proteins [6]. As a result of either inflammation, gene mutations or an aberrant signaling transduction, TJ barrier defects disturbs the epithelial permeability and homeostasis, consequently results in the development of disease such as IBD and other intestinal barrier related abnormalities.…”

Claudins: New Players in Human Fertility and Reproductive System Cancers

“…In most living organisms, a basic function of epithelial and endothelial cells is to protect organs from their surroundings and maintain homeostasis [1]. The protective barrier of cells is provided by tight junctions (TJs), adherence junctions (AJs), and desmosomes [1].…”

Tyrosine-based Signals Regulate the assembly of Daple•PARD3 Complex at Cell-cell Junctions during Polarized Planar Cell Migration

“…In addition to an apical-basal polarity, cells are also polarized along the plane of the epithelium, referred to as planar cell polarity (PCP) [3]. Dysregulation of these cell adhesion complexes and cell polarity can lead to maladies such as inflammatory bowel diseases, hydrocephalus, abnormal skin barrier function and tumor initiation and progression [4]. In fact, disruption of cellular junctions is one of the first events during epithelial-to-mesenchymal transition (EMT), a phenomenon that is encountered during cancer initiation and progression [4,5].…”

“…Dysregulation of these cell adhesion complexes and cell polarity can lead to maladies such as inflammatory bowel diseases, hydrocephalus, abnormal skin barrier function and tumor initiation and progression [4]. In fact, disruption of cellular junctions is one of the first events during epithelial-to-mesenchymal transition (EMT), a phenomenon that is encountered during cancer initiation and progression [4,5]. Thus, cell-cell junctions are widely believed to serve as tumor suppressors [6,7].…”