Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis
Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis
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DOI：
10.1093/carcin/20.5.749
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发表时间：
1999-05-01
期刊：
影响因子：
4.7
通讯作者：
Guillem, JG
中科院分区：
文献类型：
--
作者：
Zeng, ZS;Cohen, AM;Guillem, JG
基底膜（BM）的破坏被认为是肿瘤侵袭和转移的重要步骤，我们先前已经证明基质金属蛋白酶-9（MMP-9），即92 kDa胶原酶表达与人结直肠癌（CRC）的转移相关，本研究探讨了72和92 kDa IV型胶原酶之间的关系，本研究旨在探讨MMP-2和MMP-9在结直肠癌发生过程中的活性变化及IV型胶原表达的规律。免疫组化染色显示，正常粘膜、腺瘤和2例原位癌的BM中IV型胶原呈连续表达，有转移和无转移的大肠癌中IV型胶原的表达分别为100例（19/ 19）和23%（3/13）。通过双重免疫染色，发现MMP-9蛋白表达定位于有限的IV型胶原染色区域内。类似地，IV型胶原蛋白染色在没有MMP-9表达的区域中最大。明胶酶谱法在所有检查的CRC和正常粘膜提取物中检测到92和72 kDa的酶原形式。proMMP-2和proMMP-9酶形式的平均肿瘤/正常倍数增加在腺瘤中分别为1.6 +/- 0.1（平均值+/- SE）和2.4 +/- 0.5，在CRC中分别为2.1 +/- 0.2和4.1 +/- 0.7。62和82 kDa条带分别出现在63（12/19）和74%（14/19）有转移的CRC中，而只有20（3/15）和33%（5/15）无转移的CRC中。这些差异具有显著性（分别为P = 0.045和P = 0.030）。我们的研究结果表明，BM IV型胶原沿着MMP-2和MMP-9表达的升高，尤其是活化形式，在结直肠肿瘤发生过程中发生。我们的数据表明，控制IV型胶原酶的活化可能有利于预防人类结直肠肿瘤的进展。
Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases, We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC), This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis, Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ, Limited or absent type IV collagen staining pattern was seen in 100 (19/ 19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined, The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6 +/- 0.1 (mean +/- SE) and 2.4 +/- 0.5 in adenomas, and 2.1 +/- 0.2 and 4.1 +/- 0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis, Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.