Abstract
Claudin-1 (CLDN1) is overexpressed in gastric cancer and correlated with tumor invasion, metastasis and poor outcome. Here, we both down and up regulated CLDN1 expression in gastric cancer cells to elucidate its role in gastric carcinogenesis and tumor progression. We found that deficiency of CLDN1 inhibited cells migration, invasion, and colony formation in vitro and tumorigenicity, metastasis in vivo. Also, CLDN1 promoted cell aggregation and increased anoikis resistance. Down or up regulation of CLDN1 was accompanied with changes of membrane β-catenin expression as well as Akt and Src activities. When β-catenin was up-regulated in CLDN1-KD cells, cell aggregation and anoikis resistance were restored, and Akt and Src signal pathways were re-activated. Taken together, these findings suggest that CLDN1 is oncogenic in gastric cancer and its malignant potential may be attributed in part to regulation of anoikis, by mediating membrane β-catenin-regulated cell-cell adhesion and cell survival.
Highlights
Tight junctions (TJs) are the important functional constitutes in cell-cell adhesion of normal epithelium, they mechanically link cells, form the epithelial barrier against paracellular transport and maintain epithelial cell polarity [1, 2]
CLDN1 was overexpressed in gastric cancer tissues, its expression was correlated with tumor invasiveness and metastasis, and was a prognostic factor of poor outcome [15, 17, 19, 35, 36]
By using CLDN1-KD gastric cancer cell lines as a model, we found that CLDN1-KD cells exhibited decreased cell migration and invasion in vitro
Summary
Tight junctions (TJs) are the important functional constitutes in cell-cell adhesion of normal epithelium, they mechanically link cells, form the epithelial barrier against paracellular transport and maintain epithelial cell polarity [1, 2]. As the most important structural and functional components of TJs, claudins (CLDNs) have been found involved in various pathological conditions, including abnormal inflammation and tumor progression [3]. Dysregulation and remodeling of CLDNs may cause change of cell polarity and cell-cell adhesion structures which is associated with a transform in motility, invasiveness and metastasis in epithelial cancers [7]. The second leading cause of cancer death worldwide, the heterogeneous expression of CLDNs subtypes such as claudin-1, -3, -4, -6, -7, -9 and -18 have been found. Down-regulation of CLDN3 is associated with proliferative potential in early gastric cancers [9]. Downregulation of CLDN18 expression, possibly regulated by PKC/MAPK/AP-1 pathway and DNA methylation, is associated with poor survival in gastric carcinoma [12,13,14]
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