Placental Growth Factor Promotes Metastases of Non-Small Cell Lung Cancer Through MMP9
Placental Growth Factor Promotes Metastases of Non-Small Cell Lung Cancer Through MMP9
复制标题
胎盘生长因子通过MMP9促进非小细胞肺癌转移
DOI：
10.1159/000430244
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发表时间：
2015-09-01
影响因子：
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通讯作者：
Han, Baohui
中科院分区：
文献类型：
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作者：
Zhang, Wei;Zhang, Ting;Han, Baohui
背景/目的：非小细胞肺癌（NSCLC）的新生血管形成和侵袭协调癌转移。然而，人们对其潜在的分子机制知之甚少。最近，胎盘生长因子（PLGF）在癌细胞侵袭中的重要作用已经在几种类型的癌症中得到承认，而PLGF在非小细胞肺癌转移中的可能参与尚未研究。方法：分析非小细胞肺癌标本中PLGF和基质金属蛋白酶9 （MMP9）的水平。我们修改了非小细胞肺癌细胞系A549中PLGF或MMP9的水平，并检测了对MMP9和PLGF水平的影响。用transwell细胞迁移法测定细胞侵袭性。应用途径抑制剂来确定PLGF控制MMP9的分子机制。结果：我们发现PLGF和MMP9水平在NSCLC标本中均显著升高，且呈强相关。在NSCLC细胞中，PLGF的过表达增加了MMP9的水平和细胞侵袭性，而在NSCLC细胞中抑制PLGF则降低了MMP9的水平和细胞侵袭性。然而，在非小细胞肺癌细胞中，MMP9水平的改变并没有改变PLGF的水平。这些数据表明，在非小细胞肺癌细胞中，PLGF可能调节MMP9，反之则不然。此外，在PLGF过表达的非小细胞肺癌细胞中，抑制MMP9可消除PLGF对细胞侵袭的作用，表明PLGF通过MMP9增加细胞侵袭。此外，抑制MAPK-p38，而不抑制MAPK-p42/p44或PI3k或JNK信号，基本上消除了PLGF对MMP9的作用，这表明PLGF可能通过MAPK-p38信号通路激活MMP9。结论：plgf刺激的肿瘤侵袭可能通过其对非小细胞肺癌细胞MMP9激活的影响介导。
Background/Aims: Neovascularization and invasion coordinate cancer metastases in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are poorly understood. Recently, a substantial role of placental growth factor (PLGF) in cancer cell invasion has been acknowledged in several types of cancer, whereas a possible involvement of PLGF in the metastases of NSCLC has not been studied. Methods: Here, we analyzed the levels of PLGF and matrix metalloproteinase 9 (MMP9) in NSCLC specimens. We modified either PLGF or MMP9 levels in a NSCLC cell line A549, and examined the effects on the levels of MMP9 and PLGF. The cell invasiveness was quantified in a transwell cell migration assay. Pathway inhibitors were applied to determine the molecular mechanisms underlying the control of MMP9 by PLGF. Results: We found that PLGF and MMP9 levels both significantly increased in the NSCLC specimens and were strongly correlated. Overexpression of PLGF in NSCLC cells increased the levels of MMP9 and cell invasiveness, while inhibition of PLGF in NSCLC cells decreased the levels of MMP9 and cell invasiveness. However, modification of MMP9 levels in NSCLC cells did not alter the levels of PLGF. These data suggest that PLGF may regulate MMP9 in NSCLC cells, but not vice versa. Moreover, inhibition of MMP9 in PLGF-overexpressing NSCLC cells abolished the effects of PLGF on cell invasiveness, suggesting that PLGF increases cell invasion via MMP9. Furthermore, suppression of MAPK-p38, but not suppression of either MAPK-p42/p44, or PI3k, or JNK signaling, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may activate MMP9 via MAPK-p38 signaling pathway. Conclusion: PLGF-stimulated cancer invasion may be mediated through its effects on MMP9 activation in NSCLC cells.