Fibronectin promotes nasopharyngeal cancer cell motility and proliferation

Abstract

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated carcinoma. Fibronectin is regarded as a prognosticator in NPC and its involvement in cell motility has been reported in EBV infection and viral latent membrane protein 1 (LMP1) overexpression NPC cell lines. However, its malignant potential in NPC cell lines without harbouring the EBV genome has not been investigated. We investigatd and compared among four NPC cell lines, and the results revealed a positive association between fibronectin levels and NPC cell motility as well as proliferation. Studies of antibody neutralization, exogenous addition, overexpression, and RNA interference confirmed a migration role of fibronectin in NPC cells involving integrin α5, Src, Rac1, and Cdc42, implying a mesenchymal-like cell movement. Furthermore, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) were identified as alternative activators of fibronectin expression and NPC cell migration. Besides cell migration, studies of RNA interference also showed a stimulatory effect of fibronectin in NPC cell proliferation. Mechanistic studies further revealed a subsequent reduction of HIF-1α, TGF-β1, cyclin D1, β-catenin, vimentin, and Slug together with decreased Src and Akt phosphorylation after fibronectin knockdown. Parallel studies in a xenograft tumor mice model further showed that tumor growth correlated well with elevation of circulating fibronectin and activation of the identified intracellular signaling molecules. The results of our study highlight a role of fibronectin in NPC cell motility and proliferation in concerted action with HIF-1α and TGF-β1 possibly through linking molecules Src and Akt. Fibronectin overexpression and autoantibody are known to have potential prognostic value in patients with NPC. Our findings shed light on the biochemical and molecular mechanisms underlying the pathogenic role of fibronectin in this disease.

Keywords: Epithelial-to-mesenchymal transition; Extracellular matrix protein; Fibronectin; Motility; Nasopharyngeal cancer.