Zhang Zhiqian, Zhang Baotong, Li Weidong, Fu Liya, Fu Li, Zhu Zhengmao, Dong Jin-Tang
College of Life Sciences, Nankai University, Tianjin, China.
Genes Cancer. 2011 Aug;2(8):782-91. doi: 10.1177/1947601911429743.
It has become increasingly clear that microRNAs (miRNAs) play important roles in tumorigenesis and metastasis. Recently, miR-203 was reported as a suppressor microRNA often silenced in different malignancies including hepatocellular carcinoma, prostate cancer, oral cancer, and hematopoietic malignancy, but little is known about its potential role in breast carcinogenesis. In this study, we found that in breast cancer, miR-203 was upregulated in primary tumors and some nonmetastatic cell lines but was significantly downregulated in metastatic cell lines including BT549, Hs578T, and MDA-MB-231, as measured by regular and real-time PCR. Downregulation of miR-203 in metastatic breast cancer cells appeared to be caused by hypermethylation of its promoter. Functionally, ectopic expression of miR-203 in BT549 and MDA-MB-231 breast cancer cell lines caused cell cycle arrest and apoptosis and inhibited cell invasion and migration in vitro. Bioinformatic analysis predicted the snail homolog 2 (SNAI2 or SLUG), a transcription factor that promotes cell invasion and tumor metastasis, as a target of miR-203, and the prediction was validated by expression analysis and luciferase reporter assay of the 3' untranslated region of SNAI2 that contains the miR-203 target sequences. These results suggest that in malignant breast cancer cells, miR-203 is epigenetically silenced, and the silencing promotes tumor cell growth and invasion at least in part by upregulating the SNAI2 transcription factor.
越来越清楚的是，微小RNA（miRNA）在肿瘤发生和转移中发挥重要作用。最近，miR - 203被报道为一种抑制性微小RNA，在包括肝细胞癌、前列腺癌、口腔癌和血液系统恶性肿瘤在内的不同恶性肿瘤中常被沉默，但对其在乳腺癌发生中的潜在作用知之甚少。在本研究中，我们发现，在乳腺癌中，通过常规PCR和实时PCR检测，miR - 203在原发性肿瘤和一些非转移性细胞系中上调，但在包括BT549、Hs578T和MDA - MB - 231在内的转移性细胞系中显著下调。转移性乳腺癌细胞中miR - 203的下调似乎是由其启动子的高甲基化引起的。在功能上，miR - 203在BT549和MDA - MB - 231乳腺癌细胞系中的异位表达导致细胞周期停滞和凋亡，并在体外抑制细胞侵袭和迁移。生物信息学分析预测促进细胞侵袭和肿瘤转移的转录因子蜗牛同源物2（SNAI2或SLUG）是miR - 203的一个靶标，通过对包含miR - 203靶序列的SNAI2的3'非翻译区进行表达分析和荧光素酶报告基因检测验证了该预测。这些结果表明，在恶性乳腺癌细胞中，miR - 203通过表观遗传沉默，而这种沉默至少部分通过上调SNAI2转录因子促进肿瘤细胞生长和侵袭。
