High-Mobility Group Box 1-Mediated Matrix Metalloproteinase-9 Expression in Non-Small Cell Lung Cancer Contributes to Tumor Cell Invasiveness

High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions. It is involved in invasion and metastasis in various human malignancies. However, the role of HMGB1 in non small cell lung cancer (NSCLC) is unclear. We hypothesized that HMGB1 expression is a determinant of cellular invasiveness and metastasis in lung cancer. We examined HMGB1 expression in 48 NSCLC specimens by quantitative real-time PCR. High HMGB1 expression was significantly associated with clinically advanced stages (stage III-IV) (P < 0.05) and was correlated to expression of matrix metalloproteinase-9 (MMP-9) (P < 0.05). Patients with high levels of HMGB1 expression had poorer clinical prognosis. The expression level of MMP-9 and metastatic ability in vitro were significantly higher in an HMGB1-overexpressing human NSCLC cell lines (A549 and H23). The treatment with HMGB1 small interfering RNA reduced MMP-9 expression and the cellular metastatic ability in NSCLC cells. We also demonstrated that phosphoinositide 3-kinase/Akt and NF-kappa B-related pathways contributed to the HMGB1-induced MMP-9 expression and cellular metastatic ability.