Claudin-1, A Double-Edged Sword in Cancer

Abstract

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.

Increase in Toxicity of Anticancer Drugs by PMTPV, a Claudin-1-Binding Peptide, Mediated via Down-Regulation of Claudin-1 in Human Lung Adenocarcinoma A549 Cells

“…CLDN1 is necessary to regulate physiological barrier function in various tissues, but its pathophysiological role in cancer is controversial [ 23 ]. CLDN1 up-regulates invasive activity in the colorectal cancer cells [ 24 ].…”

Special Issue on “The Tight Junction and Its Proteins: More than Just a Barrier”

“…Nevertheless, claudins are emerging targets for therapeutic approaches and the elucidation of cancer malignancy, as they have been shown to be causally linked to mesenchymal transition [ 45 ]. Especially, on the example of claudin-1, it becomes clear that it can be involved in different ways in cancer development and that the generation of therapeutics relies on further investigations that explore the involvement of the respective claudins in the different types of cancer [ 46 ].…”

Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer

“…CLDNs frequently show aberrant expression and/or subcellular localization in a wide variety of cancers, resulting in either promotion or repression of tumor progression [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ], hypothetically due to dysregulated CLDN signaling. We previously reported that high CLDN6 expression in endometrial cancer is an independent prognostic factor that is significantly associated with several clinicopathological variables [ 23 ].…”