Brown P D, Bloxidge R E, Stuart N S, Gatter K C, Carmichael J
British Bio-technology Limited, Oxford, England.
J Natl Cancer Inst. 1993 Apr 7;85(7):574-8. doi: 10.1093/jnci/85.7.574.
Matrix metalloproteinases, in particular the 92-kd and 72-kd gelatinases, have been implicated in the progression of breast, colorectal, and gastric carcinomas, but involvement of the gelatinases in progression of non-small-cell lung carcinoma has not been documented. Immunohistochemical studies have measured the overall expression of these enzymes in tumor tissue but have failed to determine the proportion of active enzyme to latent proenzyme. Because the conversion of the latent proenzyme to active enzyme results in removal of a 10-kd amino-terminal domain, the expression of each proteinase can be determined by zymography, which separates substances according to molecular weight.
The purpose of this study was to examine the expression and activation of 92-kd and 72-kd proenzymes in non-small-cell lung carcinoma.
Gelatin zymography was used to study the expression of 92-kd and 72-kd gelatinases in 22 samples of non-small-cell lung carcinoma and adjacent uninvolved tissue. Medium conditioned by human RPMI-7951 melanoma cells was used as a marker for the 72-kd proenzyme, and medium conditioned by concanavalin A-treated human HT-1080 fibrosarcoma cells was used as a marker for both the 92-kd proenzyme and the 62-kd activated form of the 72-kd proenzyme.
Both 92-kd and 72-kd proenzymes were expressed to varying degrees in the samples studied. The 82-kd activated form of the 92-kd proenzyme was detected in eight tumor samples but in none of the matched uninvolved tissues. Expression of the 62-kd activated form of the 72-kd proenzyme ranged from a strong band in the tumor tissue, with little or none detectable in the adjacent uninvolved tissue, to the presence of only trace amounts of enzyme in both tumor and uninvolved tissue. There was, however, a highly significant statistical association between the level of expression of the 62-kd activated enzyme in the tumor tissue and evidence of tumor spread (P = .001).
These results demonstrate elevated expression of the activated forms of both the 92-kd and 72-kd proenzymes in non-small-cell lung carcinoma tissue relative to adjacent uninvolved tissue.
These results indicate that non-small-cell lung carcinoma should be considered as a possible target for metalloproteinase inhibitory therapy.
基质金属蛋白酶，尤其是92-kd和72-kd明胶酶，已被认为与乳腺癌、结直肠癌和胃癌的进展有关，但尚未有文献记载明胶酶与非小细胞肺癌进展的关系。免疫组织化学研究测量了这些酶在肿瘤组织中的总体表达，但未能确定活性酶与潜在酶原的比例。由于潜在酶原转化为活性酶会导致去除一个10-kd的氨基末端结构域，因此每种蛋白酶的表达可通过酶谱法来确定，该方法根据分子量分离物质。
本研究的目的是检测非小细胞肺癌中92-kd和72-kd酶原的表达和激活情况。
采用明胶酶谱法研究22例非小细胞肺癌样本及相邻未受累组织中92-kd和72-kd明胶酶的表达。用人RPMI-7951黑色素瘤细胞培养的培养基作为72-kd酶原的标志物，用伴刀豆球蛋白A处理的人HT-1080纤维肉瘤细胞培养的培养基作为92-kd酶原和72-kd酶原的62-kd激活形式的标志物。
在所研究的样本中，92-kd和72-kd酶原均有不同程度的表达。在8个肿瘤样本中检测到92-kd酶原的82-kd激活形式，但在匹配的未受累组织中均未检测到。72-kd酶原的62-kd激活形式的表达范围从肿瘤组织中的强条带（相邻未受累组织中几乎检测不到或未检测到）到肿瘤组织和未受累组织中仅存在微量酶。然而，肿瘤组织中62-kd激活酶的表达水平与肿瘤扩散证据之间存在高度显著的统计学关联（P = .001）。
这些结果表明，相对于相邻未受累组织，非小细胞肺癌组织中92-kd和72-kd酶原激活形式的表达升高。
这些结果表明，非小细胞肺癌应被视为金属蛋白酶抑制治疗的可能靶点。
