Integrin αvβ6 Promotes Lung Cancer Proliferation and Metastasis through Upregulation of IL-8-Mediated MAPK/ERK Signaling

Lung cancer is notorious for high morbidity and mortality around the world. Interleukin (IL)-8, a proinflammatory chemokine with tumorigenic and proangiogenic effects, promotes lung cancer cells growth and migration and contributes to cell aggressive phenotypes. Integrin alpha v beta 6 is a receptor of transmembrane heterodimeric cell surface adhesion, and its overexpression correlates with poor survival from non-small cell lung cancer. However, the cross talk between alpha v beta 6 and IL-8 in lung cancer has not been characterized so far. Herein, human lung cancer samples were analyzed, and it revealed that the immunohistochemical and mRNA expression of integrin alpha v beta 6 was significantly correlated with the expression of IL-8. Furthermore, in vitro, integrin alpha v beta 6 increased cell proliferation, migration, and invasion by impairing the expressions of MMP-2 and MMP-9 and inhibited cell apoptosis in human lung cancer cells A549 and H460. In addition, integrin alpha v beta 6 upregulated IL-8 expression through activating MAPK/ERK signaling. The in vivo experiment showed that integrin alpha v beta 6 promoted tumor growth in xenograft model mice by accelerating tumor volume and reducing apoptosis. Meanwhile, lung metastasis model experiment suggested that integrin alpha v beta 6 stimulated tumor metastasis with the increase of lung/total weight and tumor nodules. Simultaneously, integrin alpha v beta 6 upregulated IL-8 expression detected by both Western blots and immunohistochemistry, along with the activation of MAPK/ERK signaling. Overall, these data suggested that, in vitro and in vivo, integrin alpha v beta 6 promoted lung cancer proliferation and metastasis, at least in part, through upregulation of IL-8-mediated MAPK/ERK signaling. Thus, the inhibition of integrin alpha v beta 6 and IL-8 may be the key for the treatment of lung cancer.