The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression.
The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression.
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DOI：
10.1158/1535-7163.mct-13-1001
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发表时间：
2014-12
影响因子：
5.7
通讯作者：
Powis G
中科院分区：
文献类型：
--
作者：
Kim JM;Jeung HC;Rha SY;Yu EJ;Kim TS;Shin YK;Zhang X;Park KH;Park SW;Chung HC;Powis G
进展期胃癌（Advanced gastric cancer，GC）是胃肠道恶性肿瘤中最具侵袭性的肿瘤之一，ADAM-9（A Disintegrin and Metalloproteinase）是一种具有致癌特性的细胞膜糖蛋白，在多种肿瘤中过表达。本研究旨在探讨ADAM 9在胃癌发生、增殖和侵袭中的生物学机制。首先，我们检测了ADAM在胃癌细胞中的表达、加工和蛋白酶活性。蛋白酶活性与ADAM 9蛋白表达中度相关，但更好地与加工的较小分子量（84 kDa）形式的ADAM 9相关。敲除ADAM 9或特异性靶向单克隆抗体（RAV-18）可抑制高表达ADAM 9的细胞中的癌细胞增殖和侵袭，而在低表达细胞中则不抑制。RAV-18在GC异种移植模型中显示出体内抗肿瘤活性。低氧（1%氧）诱导低表达GC细胞中的ADAM 9表达和功能活性，其被siRNA敲低或RAV-18抗体抑制至常氧细胞中的水平。总体而言，我们的研究表明，ADAM 9在GC增殖和侵袭中起重要作用，并且虽然在一些GC细胞中以高水平表达，对催化位点定向抗体的功能抑制和抗肿瘤活性有反应，但其他GC细胞具有低水平表达，并且仅当暴露于缺氧时，ADAM 9水平增加，细胞对ADAM 9抗体抑制有反应。因此，我们的研究结果表明，ADAM 9可能是晚期胃癌的有效治疗靶点。
Advanced gastric cancer (GC) is one of the most aggressive gastrointestinal malignancies, ADAM (A Disintegrin and Metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biological mechanism of ADAM9 in the progression, proliferation and invasion of GC. First, we detected ADAM’s expression, processing and protease activity in GC cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9 expressing cells, not in low expressing cells. RAV-18 showed in vivo antitumor activity in a GC xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low expressing GC cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in GC proliferation and invasion, and that while expressed in some GC cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site directed antibody, other GC cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced GC.