血清 MMP-8 和 TIMP-1 可预测结直肠癌的预后。
Serum MMP-8 and TIMP-1 predict prognosis in colorectal cancer.
机构信息
Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.
Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.
出版信息
BMC Cancer. 2018 Jun 22;18(1):679. doi: 10.1186/s12885-018-4589-x.
BACKGROUND
Almost all of the extracellular matrix (ECM) components can be degraded by the endoproteinases matrix metalloproteinases (MMPs). Important regulators of MMPs, and thereby of the extracellular environment, are tissue inhibitors of metalloproteinases (TIMPs), and especially TIMP-1. Early tumor development, as well as distant metastasis, may be results of an MMP/TIMP ratio imbalance altering the ECM. MMPs are elevated in several inflammatory conditions. Our aim is to investigate the prognostic role of MMP-8, - 9, and TIMP-1 in colorectal cancer (CRC) and their relationship to inflammation.
METHODS
We included 337 colorectal cancer patients and 47 controls undergoing surgery at Helsinki University Hospital in Finland, 1998-2011. Serum levels of MMP-8 and plasma levels of C-reactive protein (CRP) were determined with a time-resolved immunofluorometric assay (IFMA), and MMP-9 and TIMP-1 with commercial enzyme-linked immunosorbent assay (ELISA) kits. Association and correlation analyses were performed with the Mann-Whitney U, Kruskal-Wallis, and Spearman rank correlation tests. Survival curves were constructed according to the Kaplan-Meier method and compared with the log-rank test.
RESULTS
Among patients with advanced disease, serum levels of MMP-8 and TIMP-1 were elevated. CRC patients with high MMP-8 (HR (hazard ratio) 1.72, 95% confidence interval (CI) 1.17-2.52, P = 0.005) and those with high TIMP-1 (HR 1.80, 95% CI 1.23-2.64, P = 0.002) had worse prognoses. MMP-9 level failed to serve as a prognostic factor. In multivariable survival analysis, Dukes stage, and low MMP-9/TIMP-1 molar ratio (HR 0.46, 95% CI 0.33-0.98, P = 0.042) were independently predicted prognosis. A weak correlation between CRP and MMP-8 (r = 0.229, P < 0.001), and TIMP-1 (r = 0.280, P < 0.001) was noted. Among patients showing no systemic inflammatory response, MMP-8 (HR 1.66, 95% CI 1.10-2.53, P = 0.017) and TIMP-1 (HR 1.59, 95% CI 1.05-2.42, P = 0.029) were prognostic factors.
CONCLUSIONS
MMP-8 and TIMP-1 in serum, but not MMP-9, identified CRC patients with bad prognosis. Among patients showing no systemic inflammatory response, MMP-8 and TIMP-1 may associate with poor prognosis.
背景
几乎所有细胞外基质（ECM）成分都可以被基质金属蛋白酶（MMPs）内肽酶降解。MMPs 的重要调节因子是金属蛋白酶组织抑制剂（TIMPs），尤其是 TIMP-1。早期肿瘤的发展以及远处转移可能是 MMP/TIMP 比值失衡改变细胞外环境的结果。MMPs 在几种炎症情况下升高。我们的目的是研究 MMP-8、-9 和 TIMP-1 在结直肠癌（CRC）中的预后作用及其与炎症的关系。
方法
我们纳入了芬兰赫尔辛基大学医院 1998-2011 年间进行手术的 337 名结直肠癌患者和 47 名对照者。使用时间分辨免疫荧光分析（IFMA）测定 MMP-8 的血清水平和 C-反应蛋白（CRP）的血浆水平，使用商业酶联免疫吸附测定（ELISA）试剂盒测定 MMP-9 和 TIMP-1。采用 Mann-Whitney U、Kruskal-Wallis 和 Spearman 秩相关检验进行关联和相关性分析。根据 Kaplan-Meier 方法构建生存曲线，并与对数秩检验进行比较。
结果
在晚期疾病患者中，血清 MMP-8 和 TIMP-1 水平升高。MMP-8 水平较高的 CRC 患者（HR（危险比）1.72，95%置信区间（CI）1.17-2.52，P=0.005）和 TIMP-1 水平较高的患者（HR 1.80，95%CI 1.23-2.64，P=0.002）预后较差。MMP-9 水平不能作为预后因素。在多变量生存分析中，Dukes 分期和低 MMP-9/TIMP-1 摩尔比（HR 0.46，95%CI 0.33-0.98，P=0.042）是独立的预后预测因素。CRP 与 MMP-8（r=0.229，P<0.001）和 TIMP-1（r=0.280，P<0.001）呈弱相关。在无全身炎症反应的患者中，MMP-8（HR 1.66，95%CI 1.10-2.53，P=0.017）和 TIMP-1（HR 1.59，95%CI 1.05-2.42，P=0.029）是预后因素。
结论
血清中的 MMP-8 和 TIMP-1，但不是 MMP-9，可识别预后不良的 CRC 患者。在无全身炎症反应的患者中，MMP-8 和 TIMP-1 可能与不良预后相关。
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