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.

Keywords: claudin 1; epithelial to mesenchymal transition; metastasis; tight junctions; tumor.

Figure 1

A schematic presentation of tight junction complex involving claudins and other major components. Claudins contain four transmembrane domains (TMD-1, TMD-2, TMD-3, and TMD-4) and two extracellular (ECL) loops. The PDZ-binding domain of the –COOH terminal of claudin undergoes post-transcriptional modification and has been implicated in signal transduction.

Figure 2

Schematic model of role and regulation of CLDN-1 in a normal or diseased state. In normal physiological conditions, CLDN-1 expression/ integrity is regulated by transcription factors, growth factors and cytokines, which in turn maintain the normal gate function and barrier function of tight junctions. Dysregulation of CLDN-1 expression can result in the compromise of membrane barrier functions and gate functions, which subsequently can lead to the upregulation of the expression of pro-inflammatory markers such as IFN-γ and TNF-α. In cancer, the loss of CLDN-1 facilitates the malignant transformation of cancer cells and epithelial-mesenchymal transition (EMT).

Figure 3

CLDN-1 expression in different subtypes of breast cancer as characterized by the presence or absence of estrogen receptor (ER). Luminal A, and Luminal B subtypes of human invasive breast cancer (ER-positive) exhibit low levels of CLDN-1, which suggests the suppressor role of CLDN-1 in these tumors. However, aggressive forms (ER-negative) exhibit overall high levels of CLDN-1 expression, which signifies CLDN-1 role as a tumor promoter.

Figure 4

Survival analysis of CLDN-1 in various cancers. The red line denotes higher expression, and the blue line indicates lower expression. (A) Breast invasive carcinoma (BRCA); (B) rectum adenocarcinoma (READ); (C) cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC); (D) thyroid carcinoma (THCA); (E) adrenocortical carcinoma (ACC); (F) pancreatic adenocarcinoma (PAAD).

Figure 5

Boxplot showing the distribution of CLDN-1 expression in tumors and normal tissues for different types of cancers. Significant differences are shown with an asterisk (*). Boxplots were generated using GEPIA1 webserver and p-value < 0.01 was considered as significant.

Figure 6

CLDN-1 interaction network using the Gene MANIA prediction server.