Functions of claudin-7 in human lung cancer

Abstract

Lung cancer is the second most common cancer and the most common cause of cancer-related death in both men and women in the United States with a very poor overall 5-year survival rate. Nearly 95% of the lung cancer originates from the epithelial cells of bronchial or bronchioles. Tight junctions are the most apical component of the junctional complex, providing one form of cell-cell adhesion in epithelial cells and playing a critical role in regulating paracellular barrier permeability. Claudins are the major structural and functional components of tight junctions; overexpression or downregulation of certain claudins is frequently observed in epithelial-derived cancers. However, molecular mechanisms by which claudins affect tumorigenesis remain largely unknown. We hypothesize that claudin-7 may act as a tumor suppressor in human lung cancers. In this study, we found that claudin-7 was normally expressed in bronchial epithelial cells of human lungs but was either downregulated or disrupted in its distribution pattern in lung cancer. We also found that claudin-7 is a unique protein in that it is not only localized at the apical tight junctions, but also has a strong expression at the basolateral membrane both in vivo and in vitro. To investigate functions of claudin-7 in lung cancer cells, we transfected claudin-7 cDNA into NCI-H1299, a human lung carcinoma cell line that has no detectable claudin-7 expression. We found that claudin-7 expressing cells showed reduced migration and invasion ability under hepatocyte growth factor treatment when compared to the control cells. These effects were mediated through the ERK/MAPK signaling pathway. We also suppressed claudin-7 expression by lentivirus shRNA technology in a human lung adenocarcinoma cell line HCC827 that has high claudin-7 expression. Our study showed that claudin-7 knockdown cells displayed higher cell proliferation rate, accelerated cell cycle progression, and disrupted cell attachment through integrin beta1. The cell adhesion defect can be rescued by transfecting integrin beta1 into claudin-7 knockdown cells. Transfecting claudin-7 back to knockdown cells slowed cell proliferation, upregulated the integrin beta1 expression level, and rescued the cell attachment defect. Overall, our current study highlights a novel function of claudin-7 in regulating cell migration, cell invasion, cell proliferation and maintaining cell adhesion in human lung cancer cells.