Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis
Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis
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DOI：
10.1158/1078-0432.ccr-0864-02
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发表时间：
2004-01-15
影响因子：
11.5
通讯作者：
Harabuchi, Y
中科院分区：
文献类型：
--
作者：
Katayama, A;Bandoh, N;Harabuchi, Y
目的：基质金属蛋白酶-2和基质金属蛋白酶-9在恶性肿瘤的转移中起重要作用。膜型1-基质金属蛋白酶(MT1-MMPs)和金属蛋白酶组织抑制因子2(TIMP-2)是激活原-MMP2的重要因子。关于头颈部鳞状细胞癌(SCC)中基质金属蛋白酶家族的表达与临床特征的关系已有报道，但结果并不一致，其表达的预后价值尚不清楚。实验设计：研究对象为53例日本早期口腔鳞状细胞癌患者(T1.2N0M0)。采用免疫组织化学方法检测肿瘤活检标本中基质金属蛋白酶-2、基质金属蛋白酶-9、基质金属蛋白酶-1-基质金属蛋白酶和基质金属蛋白酶-2的表达。结果：MMP2的表达与MMP9(r=0.291；P=0.036)、MT1-MMP1(r=0.286；P=0.039)、TIMP2(r=0.257；P=0.050)呈正相关。有区域淋巴结转移和/或远处转移者MMP9和TIMP2的表达显著高于无转移者(分别为P=0.036和P=0.043)。Kaplan-Meier分析和COX比例风险模型的单因素分析显示，MMP9的表达(P=0.0143和P=0.0418)和TIMP-2的显著表达(分别为P<；0.0001和P=0.0004)与预后相关。多因素分析证实，TIMP-2的显著表达是唯一的独立危险比(风险比，7.543；可信区间，1.693~33.610；P=0.0080)。结论：MMP9和TIMP-2的表达对肿瘤转移和原因特异性生存有一定的预测价值。TIMP-2的高表达是早期口腔鳞癌预后较差的最独立因素。
Purpose: Matrix metalloproteinase (MMP)-2 and MMP-9 are considered to play an important role in the metastasis of malignant tumors. Membrane type 1-MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2) are essential factors for the activation of pro-MMP-2. There are some reports about expressions of MMP family in relationship to clinical features of head and neck squamous cell carcinoma (SCC), but the results were not uniform and the prognostic value of their expressions remains unclear.Experimental Design: The study group consisted of 53 Japanese patients with oral SCC of early stage (T1.2N0M0). Expressions of MMP-2, MMP-9, MT1-MMP, and TIMP-2 were examined using immunohistological methods on the sections of tumor biopsy samples. The intensity of MMP expression was categorized into four grades (score 0-3) by semiquantitative analysis using a computer with NIH image, and correlation between this grade and clinical aspects such as tumor recurrence, metastasis, and prognosis were examined.Results: The expression score of MMP-2 correlated with that of MMP-9 (r = 0.291; P = 0.036), MT1-MMP (r = 0.286; P = 0.039), and TIMP-2 (r = 0.257; P = 0.050). Patients who developed regional lymph node and/or distant metastasis showed significantly higher scores in the expressions of MMP-9 and TIMP-2 than patients without any tumor metastases (P = 0.036 and P = 0.043, respectively). Kaplan-Meier analyses as well as univariate analyses using the Cox proportional hazards model showed that expression of MMP-9 (P = 0.0143 and P = 0.0418, respectively) and marked expression of TIMP-2 (P < 0.0001 and P = 0.0004, respectively) correlated with worse-cause-specific survival. Multivariate analysis confirmed that marked expression of TIMP-2 was the only independent factor for cause-specific death (hazard ratio, 7.543; confidence interval, 1.693-33.610; P = 0.0080).Conclusions: Expressions of MMP-9 and TIMP-2 have predictive value for tumor metastases and cause-specific survival. High expression of TIMP-2 is the most independent factor for worse prognosis in early-stage oral SCC.