Claudin family of proteins and cancer: an overview

Abstract

Tight junctions are the apical cell-cell adhesion that regulate paracellular permeability and are critical for epithelial cell polarity. Molecular architecture of tight junction has been studied extensively, which has confirmed that claudin family of proteins is integral component of tight junction. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential; however, the role of claudin family of proteins play in a series of pathophysiological events, including human carcinoma development, is only now beginning to be understood. Several claudin mouse knockout models have been generated and the diversity of phenotypes observed clearly demonstrates their important roles in the maintenance of tissue integrity in various organs and suggest that claudins also participate in cellular contexts other than tight junctions. The mechanisms of claudin regulation and their exact roles in normal physiology and disease are being elucidated, but much work remains to be done. In this review, we have discussed the conceptual framework concerning claudins and their potential implication in cancer. We predict that next several years will likely witness a boom in our understanding of the potential role of claudins in the regulation of tumorigenesis, which may, in turn, provide new approaches for the targeted therapy.

Figure 1

Schematic presentation of tight junction location between the epithelial cells and paracellular transport. Lower part represents tight junction strands and interaction of their major components.

Figure 2

Schematic representation of structure of claudins. Claudins are transmembrane proteins with domains 1 to 4 (TMD-1, TMD-2, TMD-3, and TMD-4) and extracellular loops represent promising target for therapy. The –COOH terminal of claudins contains PDZ-binding domain which undergoes posttranscriptional modification that is important for signal transduction.

Figure 3

Schematic representation of multiple mechanisms implicated in the regulation of the expression and function of claudins. Broken lines indicate indirect pathways and solid lines represent direct pathways. Abbreviations: HDAC-Histone deacetylase; MAPKs- mitogen-activated protein kinases; RUNX3—Runt-related transcription factor 3; FOXO1—Forkhead box O-1; PAR3/PAR6-Partitioning defective; PI3K- Phosphoinositide 3-kinases; NF-κB - nuclear factor kappa-light-chain-enhancer of activated B cells.