aDepartment of Biochemistry and Molecular Biology, Federal University of Parana, Curitiba bChemistry Institute, Department of Biochemistry, Cell and Molecular Therapy Center (NUCEL/NETCEM), School of Medicine, University of São Paulo, São Paulo, Brazil.
Melanoma Res. 2014 Feb;24(1):32-9. doi: 10.1097/CMR.0000000000000039.
The invasive phenotype of many tumors is associated with an imbalance between the matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the membrane-anchored reversion-inducing cysteine-rich protein with Kazal motifs (RECK). RECK inhibits MMP-2, MMP-9, and MT1-MMP, and has been linked to patient survival and better prognosis in several types of tumors. However, despite the wide implication of these MMPs in melanoma establishment and progression, the role of RECK in this type of tumor is still unknown. Here, we analyzed the expression of RECK, TIMP1, TIMP2, TIMP3, MT1MMP, MMP2, and MMP9 in two publicly available melanoma microarray datasets and in a panel of human melanoma cell lines. We found that RECK is downregulated in malignant melanoma, accompanied by upregulation of MT1MMP and TIMP2. In both datasets, we observed that the group of samples displaying higher RECK levels show lower median expression levels of MT1MMP and TIMP2 and higher levels of TIMP3. When tested in a sample-wise manner, these correlations were statistically significant. Inverse correlations between RECK, MT1MMP, and TIMP2 were verified in a panel of human melanoma cell lines and in a further reduced model that includes a pair of matched primary tumor-derived and metastasis-derived cell lines. Taken together, our data indicate a consistent correlation between RECK, MT1MMP, and TIMP2 across different models of clinical samples and cell lines and suggest evidence of the potential use of this subset of genes as a gene signature for diagnosing melanoma.
许多肿瘤的侵袭表型与基质金属蛋白酶 (MMPs) 及其抑制剂、金属蛋白酶组织抑制剂 (TIMPs) 和膜锚定逆转诱导富含半胱氨酸的 Kazal 基序蛋白 (RECK) 之间的失衡有关。RECK 抑制 MMP-2、MMP-9 和 MT1-MMP，并与几种类型肿瘤的患者生存和更好的预后相关。然而，尽管这些 MMPs 在黑色素瘤的建立和进展中广泛存在，但 RECK 在这种肿瘤中的作用仍然未知。在这里，我们分析了两个公开可用的黑色素瘤微阵列数据集和一组人黑色素瘤细胞系中 RECK、TIMP1、TIMP2、TIMP3、MT1-MMP、MMP2 和 MMP9 的表达。我们发现 RECK 在恶性黑色素瘤中下调，伴随着 MT1-MMP 和 TIMP2 的上调。在两个数据集，我们观察到显示更高 RECK 水平的样本组显示更低的 MT1-MMP 和 TIMP2 的中位表达水平和更高的 TIMP3 水平。当以样本为单位进行测试时，这些相关性具有统计学意义。在人黑色素瘤细胞系和进一步包括一对匹配的原发性肿瘤衍生和转移性衍生细胞系的简化模型中验证了 RECK、MT1-MMP 和 TIMP2 之间的负相关。总之，我们的数据表明，在不同的临床样本和细胞系模型中，RECK、MT1-MMP 和 TIMP2 之间存在一致的相关性，并表明这组基因作为诊断黑色素瘤的基因特征具有潜在用途的证据。
