The Pivotal Role of Integrin beta 1 in Metastasis of Head and Neck Squamous Cell Carcinoma
Menée sur 99 tumeurs primitives non métastatiques et 101 tumeurs primitives métastatiques de carcinome épidermoïde de la tête et du cou, cette étude met en évidence le rôle joué par l'intégrine bêta1 dans le processus métastatique
Purpose:To understand the prognostic value of integrin beta1 expression in squamous cell carcinoma of the head and neck (HNSCC) and the mechanism underlying its association with metastatic HNSCC. Experimental Design:Archival HNSCC tissues including 99 non-metastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin beta1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence activated cell sorting was used to separate the integrin beta1high+ cell population from the integrin beata1low- population in HNSCC cell lines. These two populations and integrin beta1 shRNA knock-down HNSCC cells were examined for the effect of integrin beta1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMPs) were examined by zymography. Results:Statistical analysis showed that integrin beta1 expression was significantly higher in the metastatic primary tumors than in the non-metastatic tumors (42.6% vs 24.8%, p less than 0.0001 and p less than 0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin beta1 expression was inversely correlated with overall survival (p=0.035). The integrin beta1 knock-down or integrin beta1low/- HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (p less than 0.001 and p less than 0.05, respectively). Significantly reduced matrigel invasion capability was also found in integrin beta1 knock-down or integrin beta1low/- HNSCC cells (p less than; 0.01). Finally, zymography results showed integrin beta1 affected HNSCC invasion by regulating MMP-2 activation. Conclusions:These findings indicate that integrin beta1 has a major impact on HNSCC prognosis through its regulation of metastasis.