Department of Surgery, Children's Hospital Boston, Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2011 Jun 10;286(23):20758-68. doi: 10.1074/jbc.M110.216036. Epub 2011 Apr 14.
Increased levels of ADAM12 have been reported in a variety of human cancers. We have previously reported that urinary ADAM12 is predictive of disease status in breast cancer patients and that ADAM12 protein levels in urine increase with progression of disease. On the basis of these findings, the goal of this study was to elucidate the contribution of ADAM12 in breast tumor growth and progression. Overexpression of both the ADAM12-L (transmembrane) and ADAM12-S (secreted) isoforms in human breast tumor cells resulted in a significantly higher rate of tumor take and increased tumor size. Cells expressing the enzymatically inactive form of the secreted isoform, ADAM12-S, had tumor take rates and tumor volumes similar to those of wild-type cells, suggesting that the tumor-promoting activity of ADAM12-S was a function of its proteolytic activity. Of the two isoforms, only the secreted isoform, ADAM12-S, enhanced the ability of tumor cells to migrate and invade in vitro and resulted in a higher incidence of local and distant metastasis in vivo. This stimulatory effect of ADAM12-S on migration and invasion was dependent on its catalytic activity. Expression of both ADAM12 isoforms was found to be significantly elevated in human malignant breast tissue. Taken together, our results suggest that ADAM12 overexpression results in increased tumor take, tumor size, and metastasis in vivo. These findings suggest that ADAM12 may represent a potential therapeutic target in breast cancer.
ADAM12 的水平在各种人类癌症中都有所增加。我们之前曾报道过，尿液中的 ADAM12 可以预测乳腺癌患者的疾病状态，并且尿液中的 ADAM12 蛋白水平随着疾病的进展而增加。基于这些发现，本研究的目的是阐明 ADAM12 在乳腺癌肿瘤生长和进展中的作用。在人乳腺癌细胞中过度表达 ADAM12-L（跨膜）和 ADAM12-S（分泌）同工型，导致肿瘤接种率显著提高，肿瘤体积增大。表达具有酶失活形式的分泌同工型 ADAM12-S 的细胞的肿瘤接种率和肿瘤体积与野生型细胞相似，这表明 ADAM12-S 的促肿瘤活性是其蛋白水解活性的功能。在这两种同工型中，只有分泌型同工型 ADAM12-S 增强了肿瘤细胞在体外迁移和侵袭的能力，并导致体内局部和远处转移的发生率更高。ADAM12-S 对迁移和侵袭的这种刺激作用依赖于其催化活性。在人类恶性乳腺组织中发现两种 ADAM12 同工型的表达均显著升高。综上所述，我们的研究结果表明，ADAM12 的过表达导致体内肿瘤接种率、肿瘤体积和转移的增加。这些发现表明 ADAM12 可能是乳腺癌的潜在治疗靶点。
