MicroRNA-145 Suppresses Cell Invasion and Metastasis by Directly Targeting Mucin 1
MicroRNA-145 Suppresses Cell Invasion and Metastasis by Directly Targeting Mucin 1
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DOI：
10.1158/0008-5472.can-09-2021
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Mo, Yin-Yuan
中科院分区：
文献类型：
--
作者：
Sachdeva, Mohit;Mo, Yin-Yuan
MicroRNA 是重要的基因调节因子，可以在肿瘤发生中发挥深远的作用。我们之前的研究表明，miR-145 是一种肿瘤抑制因子，能够在体外和体内抑制肿瘤细胞的生长。在这项研究中，我们证明 miR-145 以细胞特异性方式发挥其功能。尽管miR-145抑制MCF-7和HCT-116细胞的细胞生长，但它对转移性乳腺癌细胞系的细胞生长没有显着影响。然而，miR-145 显着抑制这些细胞的细胞侵袭；相反，针对 miR-145 的反义寡核苷酸会增加细胞侵袭。 miR-145 还能够在实验性转移动物模型中抑制肺转移。这种 miR-145 介导的细胞侵袭抑制部分是由于转移基因粘蛋白 1 (MUC1) 的沉默所致。使用携带 MUC1 3'-非翻译区的荧光素酶报告基因，结合蛋白质印迹和免疫荧光染色，我们将 MUC1 确定为 miR-145 的直接靶标。此外，MUC1 的异位表达会增强细胞侵袭，而这种作用可以被 miR-145 阻断。有趣的是，miR-145 对 MUC1 的抑制会导致 β-连环蛋白以及致癌钙粘蛋白 11 的减少。最后，RNAi 对 MUC1 的抑制模拟了 miR-145 在抑制侵袭方面的作用，这与 β-连环蛋白和钙粘蛋白 11 的下调有关。总而言之，这些结果表明，作为一种肿瘤抑制剂，miR-145 不仅抑制肿瘤生长，而且还抑制肿瘤生长。 细胞侵袭和转移。癌症研究； 70(1)； 378-87。 (C) 2010 AACR。
MicroRNAs are important gene regulators that could play a profound role in tumorigenesis. Our previous studies indicate that miR-145 is a tumor suppressor capable of inhibiting tumor cell growth both in vitro and in vivo. In this study, we show that miR-145 exerts its function in a cell-specific manner. Although miR-145 inhibits cell growth in MCF-7 and HCT-116 cells, it has no significant effect on cell growth in metastatic breast cancer cell lines. However, miR-145 significantly suppresses cell invasion in these cells; in contrast, the antisense oligo against miR-145 increases cell invasion. miR-145 is also able to suppress lung metastasis in an experimental metastasis animal model. This miR-145-mediated suppression of cell invasion is in part due to the silencing of the metastasis gene mucin 1 (MUC1). Using luciferase reporters carrying the 3'-untranslated region of MUC1 combined with Western blot and immunofluorescence staining, we identify MUC1 as a direct target of miR-145. Moreover, ectopic expression of MUC1 enhances cell invasion, which can be blocked by miR-145. Of interest, suppression of MUC1 by miR-145 causes a reduction of beta-catenin as well as the oncogenic cadherin 11. Finally, suppression of MUC1 by RNAi mimics the miR-145 action in suppression of invasion, which is associated with downregulation of beta-catenin and cadherin 11. Taken together, these results suggest that as a tumor suppressor, miR-145 inhibits not only tumor growth but also cell invasion and metastasis. Cancer Res; 70(1); 378-87. (C) 2010 AACR.