Human Cancer Biology ThePivotalRoleof Integrinb1 inMetastasisofHeadandNeck Squamous Cell Carcinoma

Purpose: This study aimed to understand the prognostic value of integrin b1 expression in head andneck squamous cell carcinoma (HNSCC) and themechanismunderlying its associationwithmetastatic HNSCC. Experimental Design: Archival HNSCC tissues including 99 nonmetastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin b1 expression with metastasis and disease prognosis by appropriate statisticalmethods. Fluorescence-activated cell sortingwas used to separate the integrin b1high/þ cell population from the integrin b1 population in HNSCC cell lines. These two populations and integrin b1 shRNA knockdownHNSCC cells were examined for the effect of integrin b1 on 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 b1 expressionwas inversely correlatedwith overall survival (P1⁄4 0.035). The integrin b1 knockdownor integrin b1 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 b1 knockdown or integrin b1 HNSCC cells (P < 0.01). Finally, zymography results showed integrin b1affected HNSCC invasion by regulating MMP-2 activation. Conclusion: These findings indicate that integrinb1has amajor impact onHNSCCprognosis through its regulation of metastasis. Clin Cancer Res; 18(17); 1–11. 2012 AACR.