Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer.
Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer.
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DOI：
10.18632/oncotarget.24484
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发表时间：
2018-03-06
期刊：
影响因子：
--
通讯作者：
Word RA
中科院分区：
文献类型：
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作者：
Manders DB;Kishore HA;Gazdar AF;Keller PW;Tsunezumi J;Yanagisawa H;Lea J;Word RA
纤维蛋白5（FBLN 5）是一种细胞外基质糖蛋白，其抑制基质金属蛋白酶9（MMP-9）、血管生成和上皮细胞运动。在此，我们研究了FBLN 5在上皮性卵巢癌（EOC）中的调节和功能。FBLN 5 mRNA在卵巢上皮性癌中的表达是良性卵巢的5倍。毫不奇怪，MMP 9 mRNA和酶活性显著增加，并与FBLN 5基因表达呈负相关。52.8和41.3 kDa的FBLN 5降解产物在EOC中显著增加。我们鉴定了两种切割FBLN 5的候选蛋白酶（丝氨酸弹性蛋白酶和MMP-7，但不包括MMP-9）。MMP-7，而不是中性粒细胞弹性蛋白酶，基因表达显着增加EOC。重组FBLN 5显著抑制EOC细胞与层粘连蛋白和胶原I的粘附。最后，使用免疫组织化学，我们发现免疫反应性FBLN 5肿瘤巨噬细胞在整个人类EOC肿瘤。这项工作表明，FBLN 5在EOC中最有可能被肿瘤微环境的巨噬细胞中富集的蛋白酶降解。FBLN 5蛋白水解促进卵巢癌细胞粘附和局部转移。在肿瘤基质中促进具有完整FBLN 5的稳定ECM可以作为预防卵巢癌扩散的新的治疗辅助手段。
Fibulin 5 (FBLN5) is an extracellular matrix glycoprotein that suppresses matrix metalloprotease 9 (MMP-9), angiogenesis and epithelial cell motility. Here, we investigated the regulation and function of FBLN5 in epithelial ovarian cancer (EOC). FBLN5 mRNA was down-regulated 5-fold in EOC relative to benign ovary. Not surprisingly, MMP9 mRNA and enzyme activity were increased significantly, and inversely correlated with FBLN5 gene expression. FBLN5 degradation products of 52.8 and 41.3 kDa were increased substantially in EOC. We identified two candidate proteases (serine elastase and MMP-7, but not MMP-9) that cleave FBLN5. MMP-7, but not neutrophil elastase, gene expression was increased dramatically in EOC. Recombinant FBLN5 significantly inhibited adhesion of EOC cells to both laminin and collagen I. Finally, using immunohistochemistry, we found immunoreactive FBLN5 within tumor macrophages throughout human EOC tumors. This work indicates that FBLN5 is degraded in EOC most likely by proteases enriched in macrophages of the tumor microenvironment. Proteolysis of FBLN5 serves as a mechanism to promote cell adhesion and local metastasis of ovarian cancer cells. Promotion of a stable ECM with intact FBLN5 in the tumor matrix may serve as a novel therapeutic adjunct to prevent spread of ovarian cancer.