Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People's Republic of China.
Int J Cancer. 2010 May 1;126(9):2102-11. doi: 10.1002/ijc.24901.
Snail, a key inducer of epithelial-mesenchymal transition (EMT), plays an important role in cancer metastasis. To better understand the role of Snail in the metastasis of ovarian carcinoma, expression of Snail was knocked down by antisense-Snail in the highly metastatic ovarian cancer cell line HO8910PM. Gene array analysis revealed that blocking Snail expression suppressed the activity of matrix metalloproteinases (MMPs) and upregulated TIMP3, an MMP inhibitor. These findings suggest that Snail interacts with MMP during tumor invasion and metastasis. In addition, we examined the role of Snail in an ovarian cancer orthotopic model by using the antisense-Snail HO8910PM cell line. We found that the size of primary ovarian cancer tumor and the number of metastatic lesions were significantly reduced when Snail was knocked down. Confirming our initial findings, the activity of MMP2 was greatly inhibited in tumors from antisense-Snail cells. Furthermore, immunohistochemical analysis on ovarian cancer progression tissue array demonstrated that the expression of Snail was significantly higher in metastatic lesions, and Snail expression correlated with the stage of ovarian cancer. Interestingly, in early-stage tumors, Snail was localized in both the cytoplasm and nucleus. In late stage and metastatic lesions, the level of Snail was elevated, and Snail was localized to the nucleus. The expression level and nuclear localization of Snail were also inversely correlated with E-cadherin expression. Overall, our study indicates that Snail plays a critical role in tumor growth and metastasis of ovarian carcinoma through regulation of MMP activity.
蜗牛是上皮间质转化（EMT）的关键诱导因子，在癌症转移中发挥重要作用。为了更好地理解 Snail 在卵巢癌转移中的作用，我们使用反义-Snail 敲低了高转移性卵巢癌细胞系 HO8910PM 中的 Snail 表达。基因阵列分析显示，阻断 Snail 表达抑制了基质金属蛋白酶（MMPs）的活性，并上调了 MMP 抑制剂 TIMP3。这些发现表明 Snail 在肿瘤侵袭和转移过程中与 MMP 相互作用。此外，我们通过使用反义-Snail HO8910PM 细胞系在卵巢癌原位模型中研究了 Snail 的作用。我们发现，当敲低 Snail 时，原发性卵巢癌肿瘤的大小和转移病变的数量明显减少。证实了我们的初步发现，MMP2 的活性在反义-Snail 细胞的肿瘤中受到了极大抑制。此外，对卵巢癌进展组织阵列的免疫组织化学分析表明，转移病变中 Snail 的表达明显升高，并且 Snail 的表达与卵巢癌的分期相关。有趣的是，在早期肿瘤中，Snail 定位于细胞质和细胞核中。在晚期和转移病变中，Snail 的水平升高，并且 Snail 定位于细胞核。Snail 的表达水平和核定位也与 E-钙黏蛋白的表达呈负相关。总体而言，我们的研究表明，Snail 通过调节 MMP 活性在卵巢癌的肿瘤生长和转移中发挥关键作用。
