α1-antitrypsin promotes lung adenocarcinoma metastasis through upregulating fibronectin expression.

α1-antitrypsin (AAT) has been recognized to be associated with lung adenocarcinoma metastasis. However, the mechanisms by which AAT promotes tumor metastasis remain to be investigated. Herein, we first examined AAT expression in a panel of formalin-fixed paraffin-embedded tumor tissues from 88 lung adenocarcinoma patients undergoing curative resection, using immunohistochemical methods. Lung adenocarcinoma patients with high AAT expression showed a significantly shorter overall survival compared to those with low AAT expression by Kaplan-Meier method (P=0.008). High AAT expression was also identified as an independent prognostic factor by Cox regression analysis (adjusted hazard ratio: 2.05; P=0.04). Second, the role of AAT in lung adenocarcinoma cell migration was evaluated in vitro using wound healing and Transwell assays, by transfecting the lentivirus vector with interfering sequence or coding sequence of AAT. The migration property of A549 and SPC-A1 cells was significantly diminished by downregulating AAT expression. Conversely, the migration of both cell lines was significantly increased through upregulating AAT. Furthermore, AAT could increase the expression of fibronectin (FN). FN down-regulation reversed AAT-induced promotion of adenocarcinoma cell migration. Third, a cancer cell/endothelial cell co-culture model was established to investigate the effect of AAT on adenocarcinoma cell adhesion using immunofluorescence examination. The results showed that downregulation of AAT inhibited adhesion between lung adenocarcinoma cells and human umbilical vein endothelial cells whereas upregulation of AAT promoted adhesion, which may attribute to interactions between FN and integrin α5. Finally, AAT also showed the regulation effect on the metastatic behavior of lung adenocarcinoma cells in a mouse model, which may be through regulating FN expression. This study suggested that high AAT expression might be a negative prognostic marker for lung adenocarcinoma. AAT promoted lung adenocarcinoma metastasis, whose functional target may be FN. Our findings provide new insight into the mechanisms of lung adenocarcinoma metastasis.