Abstract
Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.
Highlights
CLDN6 has been explored from the perspective of pan-cancer analysis, in which CLDN6 was found significantly upregulated in 20 types of cancers while it is downregulated in glioblastoma multiforme (GBM), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML), and brain lower-grade glioma (LGG) [48]
CLDN6 is involved in the regulation of cancer cell proliferation and apoptosis through different pathways (Table 2), which results in pro- or anti-cancer effects of CLDN6 in different cancers
CLDN6 is transcriptionally upregulated by HIF-1α and inhibits breast cancer cells migration and invasion by combining and decreasing β-catenin in the cytoplasm, reducing the transcriptional regulation of SENP1 by β-catenin, which prevents the deSUMOylation of HIF-1α and leads to HIF-1α degradation, suggesting there is a negative feedback loop between HIF-1α and CLDN6 [22]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. TJs are essential for epithelial and endothelial to establish a barrier between different tissue compartments to regulate the passage of molecules and ions between cells, which is the gate function of TJs [2]. Quan C [14]rats, found that CLDN6 was preferentially mamepithelial cells of Copenhagen which were extremely resistant toexpressed mammaryincancer mary epithelial cells of Copenhagen rats, which were extremely resistant to mammary development, compared with susceptible Buffalo. This important finding suggested that cancer development, compared with. We focused on theNext, emerging roles of CLDN6 in cancers.barrier function of CLDN6. We focused on the emerging roles of CLDN6 in cancers
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