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The Membrane-Anchored Matrix Metalloproteinase Regulator RECK in Combination with MMP-9 as a novel prognostic indicator for digestive cancer.

膜锚定基质金属蛋白酶调节剂 RECK 与 MMP-9 组合作为消化道癌症的新型预后指标。

基本信息

批准号：
16591342
负责人：
HISANAGA Michiyoshi
金额：
$ 2.18万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591342/
关键词：
RECK MMP-9 colorectal cancer VEGF micro vascular density 大腸癌

项目摘要

RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue.The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were devided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically/RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group ; P=0.011). Moreover, RECK-dominant (RECK score≧MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9 dominant patients (P=0.0003). Multivariate analysis revealed that the RECL/MMP-9 balance was an independent prognostic factor (P=0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression.The results led us to conclude that RECK/MMP-9 balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tunor tissues.

RECK 是基质金属蛋白酶 (MMP) 的膜锚定调节因子，在健康组织中广泛表达，而在许多肿瘤来源的细胞系中表达水平较低。对小鼠和培养细胞的研究表明，恢复 RECK 表达可抑制肿瘤侵袭、转移和血管生成。然而，这些发现的临床相关性仍有待充分记录。本研究检测了结直肠癌组织中 RECK 及其靶标之一 MMP-9 的表达情况。采用免疫组化技术测定了 53 例患者结直肠癌样本中 RECK 和 MMP-9 的表达水平。对每种蛋白质的表达水平进行评分，并根据这些评分将患者分为两组。在 33 个病例中，我们进行了明胶酶谱分析来评估 MMP-2 和 MMP-9 的激活程度。还对微血管密度和血管内皮生长因子 (VEGF) 表达进行了组织学评估/在 53 个样本中的 30 个 (56.6%) 样本中检测到 RECK 蛋白。重要的是，表达相对较高 RECK 水平的肿瘤患者（高 RECK 组）的复发风险显着低于表达相对较低 RECK 水平的肿瘤患者（低 RECK 组；P=0.011）。此外，RECK占主导地位（RECK评分≥MMP-9评分）的患者的复发率显着低于MMP-9占主导地位的患者（P=0.0003）。多变量分析显示RECL/MMP-9平衡是独立的预后因素（P=0.0122）。 VEGF的表达和微血管密度与RECK的表达水平呈负相关。结果使我们得出结论：RECK/MMP-9平衡是结直肠癌的一个信息性预后指标。我们的数据还表明 RECK 可能通过限制肿瘤组织中 VEGF 的可用性来抑制肿瘤血管生成。