ADAM28 is overexpressed in human breast carcinomas: Implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3
ADAM28 is overexpressed in human breast carcinomas: Implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3
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DOI：
10.1158/0008-5472.can-06-0377
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Okada, Yasunori
中科院分区：
文献类型：
--
作者：
Mitsui, Yoko;Mochizuki, Satsuki;Okada, Yasunori
去整合素和金属蛋白酶（adintegrin and metalloproteinases，亚当斯）参与多种生物学过程，包括细胞粘附、细胞融合、膜蛋白脱落和蛋白水解。在本研究中，我们的逆转录-PCR分析表明，在12个不同的ADAM物种与一个假定的金属蛋白酶基序，原型膜锚定型ADAM 28 m和分泌型ADAM 28 s选择性地表达在人类乳腺癌组织。通过实时定量PCR，它们的表达水平显着高于在非肿瘤性乳腺组织中的癌。原位杂交、免疫组化和免疫印迹分析表明，ADAM 28主要在癌组织中的癌细胞中以活性形式表达。mRNA的表达水平与癌细胞的增殖活性呈显著正相关。用胰岛素样生长因子-I（IGF-I）处理表达ADAM 28的乳腺癌细胞（MDA-MB 231）可增加细胞增殖、IGF结合蛋白（IGFBP）-3切割以及IGF-I细胞信号传导;这些过程均被ADAM抑制剂或抗ADAM 28抗体处理显著抑制。用小干扰RNA下调MDA-MB 231细胞中的ADAM 28表达显著降低了小鼠中的细胞增殖、IGFBP-3裂解和异种移植物的生长。此外，乳腺癌组织中IGFBP-3的切割与ADAM 28表达水平相关，并且通过用ADAM抑制剂或抗ADAM 28抗体处理来抑制。这些结果表明，ADAM 28在人乳腺癌细胞中以活化形式过表达，并表明ADAM 28通过增强人乳腺癌中IGFBP-3选择性切割从IGF-I/IGFBP-3复合物释放的IGF-I的生物利用度而参与细胞增殖。
A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.