Medical Oncology Research Program, Research Institute Foundation and Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
J Biol Chem. 2010 Jan 22;285(4):2463-73. doi: 10.1074/jbc.M109.055129. Epub 2009 Nov 13.
Metastasis is a sequential process that allows cells to move from the primary tumor and grow elsewhere. Because of their ability to cleave a variety of extracellular signaling and adhesion molecules, metalloproteases have been long considered key components of the metastatic program. However, the function of certain metalloproteases, such as ADAMTS1, is not clear and seems to depend on the cellular environment and/or the stage of tumor progression. To characterize the function of ADAMTS1, we performed two alternative proteomic approaches, difference gel electrophoresis and stable isotope labeling by amino acids in cell culture, to identify novel substrates of the metalloprotease. Both techniques showed that overexpression of ADAMTS1 leads to the release of semaphorin 3C from the extracellular matrix. Although semaphorins are well known regulators of axon guidance, accumulating evidence shows that they may also participate in tumor progression. Here, we show that the cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program.
转移是一个连续的过程，使细胞能够从原发性肿瘤移动并在其他地方生长。由于它们能够切割多种细胞外信号和黏附分子，金属蛋白酶一直被认为是转移程序的关键组成部分。然而，某些金属蛋白酶（如 ADAMTS1）的功能尚不清楚，似乎取决于细胞环境和/或肿瘤进展的阶段。为了表征 ADAMTS1 的功能，我们采用了两种替代的蛋白质组学方法，即差异凝胶电泳和稳定同位素标记的细胞培养中的氨基酸，以鉴定金属蛋白酶的新底物。这两种技术都表明，ADAMTS1 的过表达导致信号素 3C 从细胞外基质中释放。尽管信号素是轴突导向的已知调节剂，但越来越多的证据表明它们也可能参与肿瘤进展。在这里，我们表明 ADAMTS1 诱导的信号素 3C 的切割促进了乳腺癌细胞的迁移，这表明这些分子在肿瘤中的共表达可能有助于转移程序。
