Emerging Roles of Claudins in Human Cancer

Abstract

Claudins are major integral membrane proteins of tight junctions. Altered expression of several claudin proteins, in particular claudin-1, -3, -4 and -7, has been linked to the development of various cancers. Although their dysregulation in cancer suggests that claudins play a role in tumorigenesis, the exact underlying mechanism remains unclear. The involvement of claudins in tumor progression was suggested by their important role in the migration, invasion and metastasis of cancer cells in a tissue-dependent manner. Recent studies have shown that they play a role in epithelial to mesenchymal transition (EMT), the formation of cancer stem cells or tumor-initiating cells (CSCs/TICs), and chemoresistance, suggesting that claudins are promising targets for the treatment of chemoresistant and recurrent tumors. A recently identified claudin-low breast cancer subtype that is characterized by the enrichment of EMT and stem cell-like features is significantly associated with disease recurrence, underscoring the importance of claudins as predictors of tumor recurrence. The critical role of epigenetic mechanisms in the regulation of claudin expression indicates the possible application of epigenetic therapy to target claudins. A better understanding of the emerging role of claudins in CSC/TICs and chemoresistance may help to develop therapies against recurrent cancers.

Differential Expression of Tight Junctions and Cell Polarity Genes in Human Colon Cancer

“…Understanding the molecular mechanism of claudins and tight junction disruption and its clinical significance in epithelial to mesenchymal transition may provide novel insight into colorectal carcinogenesis. 24 …”

Claudins, Inflammation and Epithelial-Mesenchymal Transition in Gastric Tissue

“…Claudin modification has been clearly established in several cancers including gastric cancer [117][118][119] and the loss of cell polarity, a function clearly regulated by tight junction proteins [120], is considered a hallmark of EMT. Interleukin 8 participation in oncogenesis has been clearly established [121], therefore in the frame of all these considerations it is clear that the sole prophylaxis of H. pylori infection with antibiotic therapy might not be sufficient to avoid gastric carcinogenesis [122] especially when pre-malignant lesions are already present.…”

Claudin-1 expression in cervical cancer

“…Claudins are crucial for cell migration, invasion and metastasis; this was demonstrated in a xenograft colorectal cancer mouse model, where tumor growth and metastasis were linked to E-Cadherin expression and β-catenin/T-cell factor (TCF) signaling cascade (5). In basal-like high-grade ductal breast cancer, colorectal cancer, gastric cancer, melanoma and cervical cancer, the protein expression of claudin-1 was enhanced, whereas in hepatocellular carcinoma, esophageal cancer and prostate cancer, claudin-1 expression was reduced (5). Initial attempts have been made to introduce pre-clinical tests for an anti-claudin antibody-based anti-tumor-therapy targeting the second extracellular domain of claudin-3 and -4 which is overexpressed in pancreatic, prostate, breast and ovarian cancer.…”

“…Loss of tight junction complex integrity serves a role in tumorigenesis of solid tumors, and it has been hypothesized that claudin-1 can act tissue-specifically as a tumor suppressor or as an oncoprotein (4). Thus, claudin-1 can be either downregulated or upregulated according to the specific tumor entity (2,5). Claudins are crucial for cell migration, invasion and metastasis; this was demonstrated in a xenograft colorectal cancer mouse model, where tumor growth and metastasis were linked to E-Cadherin expression and β-catenin/T-cell factor (TCF) signaling cascade (5).…”

“…Thus, claudin-1 can be either downregulated or upregulated according to the specific tumor entity (2,5). Claudins are crucial for cell migration, invasion and metastasis; this was demonstrated in a xenograft colorectal cancer mouse model, where tumor growth and metastasis were linked to E-Cadherin expression and β-catenin/T-cell factor (TCF) signaling cascade (5). In basal-like high-grade ductal breast cancer, colorectal cancer, gastric cancer, melanoma and cervical cancer, the protein expression of claudin-1 was enhanced, whereas in hepatocellular carcinoma, esophageal cancer and prostate cancer, claudin-1 expression was reduced (5).…”