Shahab Uddin

Claudins in ovarian cancer: emerging biomarkers and therapeutic targets

Tight junctions (TJ) comprise protein complexes that help with the movement of ions and molecules through the paracellular pathway, thus maintaining both epithelial and endothelial integrity. The TJ proteins are diverse and include claudins, occludins, tricellulins, cingulins, and junctional adhesion molecules (JAM). Claudins are transmembrane proteins that serve as critical components of TJs in epithelial and endothelial cells. The human genome comprises 23 claudin genes, with 27 transmembrane domains recognized in mammals. Ovarian cancer (OC) is the most lethal form of all gynecologic malignancies worldwide, characterized by poor prognosis and a recurrence rate of up to 75%. In OC, several claudins are overexpressed relative to normal ovarian tissue. These elevated expression observed among OC subtypes indicates their potential utility as diagnostic biomarkers. Claudins represent potential targets for innovative therapeutic strategies. Though their exact involvement in OC is still not well understood, they are believed to be crucial for cancer invasion and therapy resistance. Recent studies show that claudins are involved in the EMT pathway and ERK, enlightening the effect of claudins in drug resistance. Clostridium perfringens enterotoxin (CPE) demonstrates potential as a therapy targeting claudins, specifically claudin-3 and -4, which serve as receptors for this toxin. Despite these advancements, challenges remain in comprehensively understanding claudin functions and in the development of effective claudin-targeted therapies. This review consolidates existing knowledge regarding claudins in OC, focusing on their expression patterns, biological functions, diagnostic and prognostic significance, and therapeutic implications. A thorough understanding of claudins in OC establishes a basis for enhancing diagnostic, predictive, and therapeutic approaches, which may result in improved therapy outcomes.

Aryl Hydrocarbon Receptor Promotes Cell Growth, Stemness Like Characteristics, and Metastasis in Human Ovarian Cancer via Activation of PI3K/Akt, β-Catenin, and Epithelial to Mesenchymal Transition Pathways

Ovarian cancer (OC) ranks first in cancer-related deaths out of all female reproductive malignancies with high-pitched tumor relapse and chemoresistance. Several reports correlate cancer occurrences with exposure to xenobiotics via induction of a protein receptor named aryl hydrocarbon receptor (AhR). However, the effect of AhR on OC proliferation, expansion, and chemoresistance remains unrevealed. For this purpose, OC cells A2780 and A2780cis cells were treated with AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the effects were determined by Real-Time Cell Analyzer, clonogenic assay, flow cytometry, immunoblotting and wound healing assay. Our results showed that activation of AhR by TCDD in A2780 cells induced the PI3K/AKT pathway followed by induction of anti-apoptotic proteins BCL-2, BCL-xl, and MCL-1. In addition, a significant increase in stemness marker aldehyde dehydrogenase (ALDH1) was observed. This effect was also associated with an accumulation of β-catenin, a Wnt transcription factor. Moreover, we observed induction of epithelial to mesenchymal transition (EMT) upon AhR activation. In conclusion, the results from the current study confirm that AhR mediates OC progression, stemness characteristics, and metastatic potential via activation of PI3K/Akt, Wnt/β-catenin, and EMT. This study provides a better insight into the modulatory role of AhR that might help in developing novel therapeutic strategies for OC treatment.