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Studies on the roles of the membrane-associated matrix metalloproteinase regulator BECK in angiogenesis

膜相关基质金属蛋白酶调节因子BECK在血管生成中的作用研究

基本信息

批准号：
13307008
负责人：
NODA Makoto
金额：
$ 18.14万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We have discovered that forced expression of RECK in the HT1080 fibrosarcoma cells affects the processing of pro-MMP-2 in the culture supernatant and that mice lacking RECK expression die around embryonic day 10.5 with hemorrhage. We investigated the mechanisms of these phenomena and found that RECK inhibits both MT1-MMP and MMP-2 in vitro and that in mice lacking RECK expression, pro-MMP-2 processing is accelerated and collagen fibrils are dramatically reduced. Thus, the blood vessel disruption and mesenchymal disarray found in these mice may be due to the increased MMP-2 activation and this notion was further supported by the finding that MMP-2/RECK double mutant mice showed milder tissue damage and longer survival (0.5 day) (Oh et al. Cell 2001). In another line of studies which uses clinical samples, we found that RECK expression in several types of cancer (such as hepatocellular-carcinoma, pancreatic ductal carcinoma, non-samll cell Lung carcinoma), RECK expression in tumor tissues positively correlates with better prognosis (longer survival) and negatively correlates with activation of pro-MMP-2, invasiveness, and blood vessel density in tumors (Furumoto et al. Hepatology 2001; Masui et al. Clin. Cancer Res. 2003; Takanaka et al. Eur. J. Cancer 2004). We have also generated MMP-2/MT1-MMP double null mice, which are probably similar in effect to RECK-overexpressing mice, and found that they show peri-natal death with defects in blood vessel enlargement and muscle development (Oh et al. Oncogene 2004). The finding unexpectedly demonstrate that two MMPs with distinct molecular nature and subcellular localization are functionally redundant in vivo and that MMPs are indeed essential for extracellular matrix remodeling during mammalian embryonic development.

我们发现，HT1080 纤维肉瘤细胞中 RECK 的强制表达会影响培养物上清液中 pro-MMP-2 的加工，并且缺乏 RECK 表达的小鼠在胚胎第 10.5 天左右因出血而死亡。我们研究了这些现象的机制，发现 RECK 在体外抑制 MT1-MMP 和 MMP-2，并且在缺乏 RECK 表达的小鼠中，pro-MMP-2 加工加速，胶原纤维显着减少。因此，在这些小鼠中发现的血管破坏和间质紊乱可能是由于 MMP-2 激活增加所致，并且 MMP-2/RECK 双突变小鼠表现出更轻微的组织损伤和更长的存活期（0.5 天）这一发现进一步支持了这一观点（Oh 等人，Cell 2001）。在另一项使用临床样本的研究中，我们发现RECK在几种类型的癌症（如肝细胞癌、胰腺导管癌、非小细胞肺癌）中表达，肿瘤组织中的RECK表达与更好的预后（更长的生存期）呈正相关，与肿瘤中pro-MMP-2的激活、侵袭性和血管密度呈负相关（Furumoto 等人，Hepatology 2001；Masui 等人，Clin. Cancer Res. 2003；Takanaka 等人，Eur. J. Cancer 2004）。我们还培育了 MMP-2/MT1-MMP 双无效小鼠，其效果可能与 RECK 过表达小鼠类似，并发现它们表现出围产期死亡，并伴有血管扩张和肌肉发育缺陷（Oh et al. Oncogene 2004）。这一发现出人意料地证明，两种具有不同分子性质和亚细胞定位的MMP在体内功能上是冗余的，并且MMP确实对于哺乳动物胚胎发育过程中的细胞外基质重塑至关重要。