The Pivotal Role of Integrin β1 in Metastasis of Head and Neck Squamous Cell Carcinoma

Purpose: This study aimed to understand the prognostic value of integrin beta 1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC. Experimental Design: Archival HNSCC tissues including 99 nonmetastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin beta 1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence-activated cell sorting was used to separate the integrin beta 1(high/+) cell population from the integrin beta 1(low/-) population in HNSCC cell lines. These two populations and integrin beta 1 shRNA knockdown HNSCC cells were examined for the effect of integrin beta 1on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMP) were examined by zymography. Results: Statistical analysis showed that integrin b1 expression was significantly higher in the metastatic primary tumors than in the nonmetastatic tumors (42.6% vs. 24.8%, P < 0.0001 and P < 0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin beta 1 expression was inversely correlated with overall survival (P 0.035). The integrin beta 1 knockdown or integrin beta 1(low/-) HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (P < 0.001 and P < 0.05, respectively). Significantly reduced Matrigel invasion capability was also found in integrin beta 1 knockdown or integrin beta 1(low/-) HNSCC cells (P < 0.01). Finally, zymography results showed integrin beta 1-affected HNSCC invasion by regulating MMP-2 activation. Conclusion: These findings indicate that integrin beta 1 has a major impact on HNSCC prognosis through its regulation of metastasis. Clin Cancer Res; 18(17); 4589-99. (C) 2012 AACR.