Zhang Wei, Zhang Ting, Lou Yuqing, Yan Bo, Cui Shaohua, Jiang Liyan, Han Baohui
Cell Physiol Biochem. 2015;37(3):1210-8. doi: 10.1159/000430244. Epub 2015 Sep 30.
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.
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.
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.
PLGF-stimulated cancer invasion may be mediated through its effects on MMP9 activation in NSCLC cells.
背景/目的：新生血管形成和侵袭共同作用于非小细胞肺癌（NSCLC）的转移。然而，其潜在的分子机制仍知之甚少。最近，胎盘生长因子（PLGF）在几种癌症类型的癌细胞侵袭中所起的重要作用已得到认可，而PLGF在NSCLC转移中的可能作用尚未得到研究。
在此，我们分析了NSCLC标本中PLGF和基质金属蛋白酶9（MMP9）的水平。我们在NSCLC细胞系A549中改变PLGF或MMP9的水平，并检测其对MMP9和PLGF水平的影响。通过Transwell细胞迁移试验对细胞侵袭性进行定量分析。应用通路抑制剂来确定PLGF调控MMP9的分子机制。
我们发现NSCLC标本中PLGF和MMP9水平均显著升高且呈强相关性。NSCLC细胞中PLGF的过表达增加了MMP9水平和细胞侵袭性，而NSCLC细胞中PLGF的抑制则降低了MMP9水平和细胞侵袭性。然而，NSCLC细胞中MMP9水平的改变并未改变PLGF的水平。这些数据表明PLGF可能在NSCLC细胞中调控MMP9，但反之则不然。此外，在PLGF过表达的NSCLC细胞中抑制MMP9消除了PLGF对细胞侵袭性的影响，表明PLGF通过MMP9增加细胞侵袭。此外，抑制丝裂原活化蛋白激酶（MAPK）-p38，而非抑制MAPK-p42/p44、磷脂酰肌醇-3激酶（PI3k）或c-Jun氨基末端激酶（JNK）信号通路，可显著消除PLGF对MMP9的影响，表明PLGF可能通过MAPK-p38信号通路激活MMP9。
PLGF刺激的癌症侵袭可能通过其对NSCLC细胞中MMP9激活的作用来介导。
