Department of Oral Histology and Developmental Biology, Chosun University, Gwangju 501‑759, Republic of Korea.
Int J Mol Med. 2011 Oct;28(4):527-34. doi: 10.3892/ijmm.2011.726. Epub 2011 Jun 17.
Secretory leukocyte protease inhibitor (SLPI) protects tissue from proteases, and promotes cell proliferation and healing during inflammatory response. SLPI is also overexpressed in gastric, lung and ovarian cancers, which accelerates the metastasis of cancer cells. Matrix metalloproteinases-2, -9 (MMP-2 and MMP-9) are overexpressed in high metastatic cancers, and promote the migration of cancer cells through collagen degradation. SLPI and MMP-2, -9 are critical factors in stimulating the metastatic processes but there are no reports of a direct correlation between these molecules. Therefore, this study examined the role of SLPI related to MMP-2 and MMP-9 using two gastric cancer cell lines, such as characterized non-metastatic SNU484 and highly metastatic SNU638 cells. SLPI, MMP-2 and MMP-9 mRNA and protein expression were higher in SNU638 cells than in SNU484 cells. In addition, the rate of cell migration and invasion was higher in the SNU638 cells than in SNU484 cells. Interestingly, after treatment with SLPI, the rate of migration and invasion was higher in the SNU484 cells than in the positive control (PC) SNU484 cells. The rate of migration was also higher in the SNU638 cells after SLPI treatment than in the SNU638 cells (PC) but the invasion rate was not changed. The expression and secretion of MMP-2 and MMP-9 as well the rate of cell migration and invasion were significantly lower in SLPI-siRNA transfected SNU638 cells (si-SLPI/SNU638) but higher in SLPI-treated SNU484 cells (SNU484 + SLPI). Strong Elk-1 phosphorylation was detected in SNU484 + SLPI and SNU638 cells but was barely detectable in SNU484 and si-SLPI/SNU638 cells. These results show that SLPI promotes the metastasis of SNU638 gastric cancer cells by increasing MMP-2 and MMP-9 expression through Elk-1 signaling, indicating its role as a signaling molecule not a protease inhibitor.
分泌白细胞蛋白酶抑制剂 (SLPI) 可保护组织免受蛋白酶的侵害，并在炎症反应期间促进细胞增殖和愈合。SLPI 在胃癌、肺癌和卵巢癌中过度表达，从而加速癌细胞的转移。基质金属蛋白酶-2、-9（MMP-2 和 MMP-9）在高转移性癌症中过度表达，并通过胶原降解促进癌细胞迁移。SLPI 和 MMP-2、-9 是刺激转移过程的关键因素，但尚无这些分子之间存在直接相关性的报道。因此，本研究使用两种胃癌细胞系，如特征为非转移性 SNU484 和高度转移性 SNU638 细胞，研究了 SLPI 与 MMP-2 和 MMP-9 相关的作用。SNU638 细胞中的 SLPI、MMP-2 和 MMP-9 mRNA 和蛋白表达均高于 SNU484 细胞。此外，SNU638 细胞的细胞迁移和侵袭率高于 SNU484 细胞。有趣的是，用 SLPI 处理后，SNU484 细胞的迁移和侵袭率高于阳性对照（PC）SNU484 细胞。SLPI 处理后 SNU638 细胞的迁移率也高于 SNU638 细胞（PC），但侵袭率没有变化。SLPI-siRNA 转染的 SNU638 细胞（si-SLPI/SNU638）中 MMP-2 和 MMP-9 的表达和分泌以及细胞迁移和侵袭率均显著降低，但 SNU484 细胞（SNU484+SLPI）中 SLPI 处理后的表达和分泌以及细胞迁移和侵袭率均显著升高。在 SNU484+SLPI 和 SNU638 细胞中检测到强烈的 Elk-1 磷酸化，但在 SNU484 和 si-SLPI/SNU638 细胞中几乎检测不到。这些结果表明，SLPI 通过 Elk-1 信号通路增加 MMP-2 和 MMP-9 的表达，促进 SNU638 胃癌细胞的转移，表明其作为信号分子而不是蛋白酶抑制剂的作用。
