Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Suite C3086, Atlanta, GA 30322, USA.
Clin Cancer Res. 2012 Sep 1;18(17):4589-99. doi: 10.1158/1078-0432.CCR-11-3127. Epub 2012 Jul 24.
This study aimed to understand the prognostic value of integrin β1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC.
Archival HNSCC tissues including 99 nonmetastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin β1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence-activated cell sorting was used to separate the integrin β1(high/+) cell population from the integrin β1(low/-) population in HNSCC cell lines. These two populations and integrin β1 shRNA knockdown HNSCC cells were examined for the effect of integrin β1 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.
Statistical analysis showed that integrin β1 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 β1 expression was inversely correlated with overall survival (P = 0.035). The integrin β1 knockdown or integrin β1(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 β1 knockdown or integrin β1(low/-) HNSCC cells (P < 0.01). Finally, zymography results showed integrin β1-affected HNSCC invasion by regulating MMP-2 activation.
These findings indicate that integrin β1 has a major impact on HNSCC prognosis through its regulation of metastasis.
本研究旨在探讨整合素β1 在头颈部鳞状细胞癌（HNSCC）中的预后价值及其与转移性 HNSCC 相关的机制。
通过适当的统计方法，检测 99 例非转移性原发性肿瘤和 101 例转移性原发性肿瘤组织中整合素β1 的表达与转移和疾病预后的关系。利用荧光激活细胞分选技术，从 HNSCC 细胞系中分离出整合素β1（高/+)细胞群和整合素β1（低/-)细胞群。检测这两个群体以及整合素β1 shRNA 敲低的 HNSCC 细胞，观察整合素β1 对体外侵袭以及异种移植小鼠模型中淋巴结和肺转移的影响。通过酶谱法检测基质金属蛋白酶（MMP）的表达和激活。
统计分析显示，转移性原发性肿瘤中的整合素β1 表达明显高于非转移性肿瘤（42.6%对 24.8%，单因素和多因素分析分别为 P<0.0001 和 P<0.0001）。在有淋巴结转移的患者中，整合素β1 的表达与总生存率呈负相关（P=0.035）。整合素β1 敲低或整合素β1（低/-) HNSCC 细胞在体内的淋巴结和肺转移明显减少（P<0.001 和 P<0.05）。还发现整合素β1 敲低或整合素β1（低/-) HNSCC 细胞的 Matrigel 侵袭能力显著降低（P<0.01）。最后，酶谱结果表明整合素β1 通过调节 MMP-2 激活影响 HNSCC 的侵袭。
这些发现表明，整合素β1 通过调节转移对 HNSCC 的预后有重大影响。
