We found that downregulation of angulin-1/LSR induced malignancy via upregulation of EGF-dependent CLDN-2 and the TGF-β-dependent cell metabolism in human lung adenocarcinoma, and that both AG1478 and EW-7197 had potent in vitro anti-lung adenocarcinoma therapeutic activity via LSR/CLDN-2 and the cell metabolism. The gene discussed is CLDN2; the disease is lung adenocarcinoma.