Division of Frontier Medical Science, Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
PLoS One. 2011;6(10):e25438. doi: 10.1371/journal.pone.0025438. Epub 2011 Oct 5.
Periostin, IFN-induced transmembrane protein 1 (IFITM1) and Wingless-type MMTV integration site family, member 5B (Wnt-5b) were previously identified as the invasion promoted genes of head and neck squamous cell carcinoma (HNSCC) by comparing the gene expression profiles between parent and a highly invasive clone. We have previously reported that Periostin and IFITM1 promoted the invasion of HNSCC cells. Here we demonstrated that Wnt-5b overexpression promoted the invasion of HNSCC cells. Moreover, stromelysin-2 (matrix metalloproteinase-10; MMP-10) was identified as a common up-regulated gene among Periostin, IFITM1 and Wnt-5b overexpressing HNSCC cells by using microarray data sets. In this study, we investigated the roles of MMP-10 in the invasion of HNSCC.
We examined the expression of MMP-10 in HNSCC cases by immunohistochemistry. High expression of MMP-10 was frequently observed and was significantly correlated with the invasiveness and metastasis in HNSCC cases. Next, we examined the roles of MMP-10 in the invasion of HNSCC cells in vitro. Ectopic overexpression of MMP-10 promoted the invasion of HNSCC cells, and knockdown of MMP-10 suppressed the invasion of HNSCC cells. Moreover, MMP-10 knockdown suppressed Periostin and Wnt-5b-promoted invasion. Interestingly, MMP-10 overexpression induced the decreased p38 activity and MMP-10 knockdown induced the increased p38 activity. In addition, treatment with a p38 inhibitor SB203580 in HNSCC cells inhibited the invasion.
These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC.
先前通过比较亲本细胞和高度侵袭性克隆之间的基因表达谱，鉴定出骨桥蛋白、IFN 诱导跨膜蛋白 1（IFITM1）和 Wnt 型 MMV 整合位点家族成员 5B（Wnt-5b）为头颈部鳞状细胞癌（HNSCC）的侵袭促进基因。我们之前报道过骨桥蛋白和 IFITM1 促进了 HNSCC 细胞的侵袭。在这里，我们证明了 Wnt-5b 的过表达促进了 HNSCC 细胞的侵袭。此外，通过使用微阵列数据集，我们发现基质金属蛋白酶 10（MMP-10）是骨桥蛋白、IFITM1 和 Wnt-5b 过表达的 HNSCC 细胞中共同上调的基因之一。在这项研究中，我们研究了 MMP-10 在 HNSCC 侵袭中的作用。
我们通过免疫组织化学检查了 HNSCC 病例中 MMP-10 的表达。MMP-10 的高表达经常观察到，并与 HNSCC 病例的侵袭性和转移显著相关。接下来，我们研究了 MMP-10 在体外 HNSCC 细胞侵袭中的作用。MMP-10 的异位过表达促进了 HNSCC 细胞的侵袭，而 MMP-10 的敲低则抑制了 HNSCC 细胞的侵袭。此外，MMP-10 的敲低抑制了骨桥蛋白和 Wnt-5b 促进的侵袭。有趣的是，MMP-10 的过表达诱导了 p38 活性的降低，而 MMP-10 的敲低诱导了 p38 活性的增加。此外，在 HNSCC 细胞中用 p38 抑制剂 SB203580 处理抑制了侵袭。
这些结果表明 MMP-10 在 HNSCC 的侵袭和转移中发挥重要作用，并且 MMP-10 驱动的侵袭部分与 p38 MAPK 抑制有关。我们建议 MMP-10 可以用作预测 HNSCC 转移的标志物。
