Claudins are a family of tight junction (TJ) membrane proteins involved in a broad spectrum of human diseases including cancer. Claudin-7 is a unique TJ membrane protein in that it has a strong basolateral membrane distribution in epithelial cells and in tissues. Therefore, this study aims to investigate the functional significance of this non-TJ localization of claudin-7 in human lung cancer cells. Claudin-7 expression was suppressed or deleted by lentivirus shRNA or by targeted-gene deletion. Cell cycle analysis and antibody blocking methods were employed to assay cell proliferation and cell attachment, respectively. Electron microscopy and transepthelial electrical resistance measurement were performed to examine the TJ ultrastructure and barrier function. Co-immunolocalization and co-immunoprecipitation was used to study claudin-7 interaction with integrin β1. Tumor growth in vivo were analyzed using athymic nude mice. Claudin-7 co-localizes and forms a stable complex with integrin β1. Both suppressing claudin-7 expression by lentivirus shRNA in human lung cancer cells (KD cells) and deletion of claudin-7 in mouse lungs lead to the reduction in integrin β1 and phospho-FAK levels. Suppressing claudin-7 expression increases cell growth and cell cycle progression. More significantly, claudin-7 KD cells have severe defects in cell-matrix interactions and adhere poorly to culture plates with a remarkably reduced integrin β1 expression. When cultured on uncoated glass coverslips, claudin-7 KD cells grow on top of each other and form spheroids while the control cells adhere well and grow as a monolayer. Reintroducing claudin-7 reduces cell proliferation, upregulates integrin β1 expression and increases cell-matrix adhesion. Integrin β1 transfection partially rescues the cell attachment defect. When inoculated into nude mice, claudin-7 KD cells produced significantly larger tumors than control cells. In this study, we identified a previously unrecognized function of claudin-7 in regulating cell proliferation and maintaining epithelial cell attachment through engaging integrin β1.

Lung cancer is among the most common malignant tumors worldwide, and is characterized by a low survival rate compared with other cancers. Toll-like receptors (TLRs) are highly conserved in evolution and widely expressed on immune cells, where they serve an important role in the innate immune system by evoking inflammatory responses. Evasion of immune destruction is an important hallmark in the development of cancer. There is an established association between chronic inflammation and cancer, with TLRs serving important roles in the immune response against tumor cells. Recently, TLRs have been identified on tumor cells, where their activation may orchestrate the downstream signaling pathways that serve crucial functions in tumorigenesis and tumor progression. The present review summarizes the roles of TLRs as sensors on lung cancer cells that regulate lung cancer progression with regard to cell growth and invasion, angiogenesis and cancer stem cell behavior. This aimed to provide theoretical support for the development of therapies that target TLR signaling pathways for the treatment of lung cancer.