MMP-2 mediates ethanol-induced invasion of mammary epithelial cells over-expressing ErbB2
MMP-2 mediates ethanol-induced invasion of mammary epithelial cells over-expressing ErbB2
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DOI：
10.1002/ijc.21769
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发表时间：
2006-07-01
影响因子：
6.4
通讯作者：
Luo, Jia
中科院分区：
文献类型：
--
作者：
Ke, Zunji;Lin, Hong;Luo, Jia
乙醇是一种肿瘤促进剂，可能促进乳腺癌的转移。我们之前已经证明ErbB2的过表达促进了乙醇介导的乳腺上皮细胞和乳腺癌细胞的侵袭。然而，潜在的细胞/分子机制仍然未知。通过明胶酶谱分析，我们发现ErbB2的过表达增加了人乳腺上皮细胞（HB2）中基质金属蛋白酶-2 （MMP-2）和MMP-9的产生。短暂或稳定转染ErbB2 cDNA至HB2细胞可上调MMP-2/-9基因启动子的转录本和活性；MMP-2/-9表达上调由p38丝裂原活化蛋白激酶（p38 MAPK）和磷脂酰肌醇3-激酶（PI3K）介导。虽然生理相关浓度（100-400 mg/dl）的乙醇不影响MMP-2/-9的产生，但它激活了过表达ErbB2的HB2细胞（HB2(ErbB2)）中的MMP-2，但对HB2细胞没有影响；它促进了形式MMP-2 （72 kDa）裂解为活性形式（62 kDa）。激活依赖于c-jun n -末端激酶（JNKs）和活性氧（ROS）。另一方面，乙醇不影响MMP-9的表达和激活。选择性MMP-2抑制剂（SB-3CT和OA-Hy）和抗氧化剂显著抑制乙醇刺激的HB2（ErbB2）细胞侵袭。此外，通过小干扰RNA敲低MMP-2也会部分阻断乙醇促进的HB2（ErbB2）细胞的侵袭。因此，乙醇刺激过表达ErbB2的细胞的侵袭至少部分是通过MMP-2激活介导的。(c) 2006 Wiley-Liss, Inc。
Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. We have previously demonstrated that over-expression of ErbB2 promoted ethanol-mediated invasion of mammary epithelial cells and breast cancer cells. However, the underlying cellular/molecular mechanisms remain unknown. By gelatin zymography, we showed that over-expression of ErbB2 increased the production of matrix metalloproteinase-2 (MMP-2) and MMP-9 in human mammary epithelial cells (HB2). Transient or stable transfection of ErbB2 cDNA to HB2 cells upregulated the transcripts and the activity of the MMP-2/-9 gene promoter; the upregulation of MMP-2/-9 expression was mediated by p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (PI3K). Although ethanol, at physiologically relevant concentrations (100-400 mg/dl), did not affect the production of MMP-2/-9, it activated MMP-2 in HB2 cells over-expressing ErbB2 (HB2(ErbB2)), but not HB2 cells; it enhanced the cleavage of proform MMP-2 (72 kDa) to an active form (62 kDa). The activation was dependent on c-jun N-terminal kinases (JNKs) and reactive oxygen species (ROS). On the other hand, ethanol affected neither the expression nor the activation of MMP-9. Selective inhibitors of MMP-2 (SB-3CT and OA-Hy) and antioxidants significantly inhibited ethanol-stimulated invasion of HB2(ErbB2) cells. Furthermore, knocking down MMP-2 by small interference RNA also induced a partial blockage on ethanol-promoted invasion of HB2(ErbB2) cells. Thus, ethanol-stimulated invasion of cells over-expressing ErbB2 was mediated, at least partially, by MMP-2 activation. (c) 2006 Wiley-Liss, Inc.