- Tight junctions are specialized cell-cell adhesion structures that play a fundamental role in maintaining the polarity and integrity of epithelial tissues. They regulate the paracellular permeability of the epithelial barrier and help to separate the apical and basolateral surfaces of epithelial cells.
- During epithelial-to-mesenchymal transition (EMT), the proteins that form tight junctions are downregulated, contributing to the loss of epithelial characteristics and the acquisition of a more migratory and invasive mesenchymal phenotype.
- Tight junctions are primarily composed of proteins such as Claudins, Occludins, and Zonula Occludens (ZO) proteins, which are responsible for forming the tight seal between adjacent cells. These proteins regulate the permeability of the epithelial layer and prevent the free passage of solutes between cells.
- In the context of EMT, the downregulation or redistribution of these tight junction proteins leads to the loosening of cell-cell adhesion, allowing cells to lose their epithelial integrity and gain the ability to migrate and invade surrounding tissues. The loss of tight junctions is often accompanied by the dissociation of E-cadherin, a hallmark of EMT, further weakening the epithelial cell-cell adhesion.
- The loss of tight junctions during EMT is largely driven by EMT-inducing transcription factors such as Snail, Slug, Twist, and ZEB1, which repress the expression of tight junction proteins and induce mesenchymal traits. These transcription factors are activated by signals such as TGF-β, Wnt, Notch, and NF-κB, which promote the transition to a mesenchymal phenotype by altering the expression of junctional proteins and facilitating cytoskeletal changes. Additionally, protein kinases, such as RhoA, ROCK, and Src, are involved in the regulation of tight junction disassembly during EMT by mediating the phosphorylation of tight junction proteins and altering the actin cytoskeleton.
- The loss of tight junctions during EMT plays a critical role in cancer progression, where it allows epithelial tumor cells to dissociate from the primary tumor and invade surrounding tissues. In cancers such as breast cancer, colorectal cancer, and lung cancer, the breakdown of tight junctions is a key step in tumor invasion and metastasis. Tight junction loss is also observed in fibrotic diseases, where the disruption of epithelial barriers contributes to tissue remodeling and scarring. Moreover, in chronic inflammation, infections, and autoimmune diseases, the loss of tight junction integrity facilitates increased epithelial permeability, allowing immune cells and inflammatory mediators to penetrate tissues and exacerbate disease.
- Overall, tight junctions are essential for maintaining epithelial integrity, and their disruption during EMT contributes to cellular detachment, migration, and invasion. As key regulators of the epithelial barrier, the dissociation of tight junctions serves as both a biomarker and a functional mediator of EMT, contributing to the morphological and behavioral changes that allow epithelial cells to acquire mesenchymal characteristics.
