Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People's Republic of China.
Carcinogenesis. 2014 Feb;35(2):469-78. doi: 10.1093/carcin/bgt330. Epub 2013 Oct 1.
Breast cancer is the leading cause of cancer death among females, with tumor metastasis being primarily responsible for breast cancer-associated mortality. Current literatures have shown that microRNAs (miRNAs) are implicated in tumor metastasis. In this study, we found that the expression of miR-720 was significantly downregulated in primary breast cancer, with greater downregulation in metastatic tumors. Statistical analysis of 105 cases of primary human breast cancer demonstrated that decreased expression of miR-720 was correlated with lymph node metastasis. Furthermore, reexpression of miR-720 in breast cancer cells remarkably inhibited cell invasiveness and migration both in vitro and in vivo. Mechanistically, downregulation of TWIST1, a promoter of metastasis that was identified as a direct functional target of miR-720, was attributed to the inhibition of metastasis. Consistent with the reduced TWIST1 levels in breast cancer, reexpression of miR-720 upregulated epithelial markers (E-cadherin and β-catenin) and downregulated mesenchymal markers (N-cadherin, fibronectin, vimentin and matrix metalloproteinase-2). Expression of miR-720 was inversely associated with TWIST1 in human breast cancer tissues. Knockdown of TWIST1 expression by small interfering RNA exhibited similar effects to reintroduction of miR-720, whereas overexpression of TWIST1 (without the 3'-untranslated region) abrogated miR-720-mediated metastasis inhibition. Collectively, our data indicate that miR-720 is frequently decreased in breast cancer and manifests antimetastatic activity by downregulating TWIST1, presenting a novel mechanism of miRNA-mediated regulation of tumor metastasis.
乳腺癌是女性癌症死亡的主要原因，肿瘤转移是导致乳腺癌相关死亡的主要原因。目前的文献表明，microRNAs（miRNAs）与肿瘤转移有关。在这项研究中，我们发现 miR-720 在原发性乳腺癌中的表达明显下调，转移性肿瘤中的下调更为明显。对 105 例原发性人乳腺癌的统计分析表明，miR-720 的表达降低与淋巴结转移有关。此外，miR-720 在乳腺癌细胞中的重新表达显著抑制了体外和体内的细胞侵袭和迁移。从机制上讲，TWIST1 的下调是导致转移抑制的原因，TWIST1 是转移的启动子，被鉴定为 miR-720 的直接功能靶标。与乳腺癌中 TWIST1 水平降低一致，miR-720 的重新表达上调了上皮标记物（E-钙粘蛋白和β-连环蛋白），下调了间充质标记物（N-钙粘蛋白、纤维连接蛋白、波形蛋白和基质金属蛋白酶-2）。miR-720 在人乳腺癌组织中的表达与 TWIST1 呈负相关。TWIST1 表达的小干扰 RNA 敲低表现出与 miR-720 重新引入相似的效果，而 TWIST1 的过表达（没有 3'-非翻译区）则消除了 miR-720 介导的转移抑制。总的来说，我们的数据表明，miR-720 在乳腺癌中经常下调，并通过下调 TWIST1 表现出抗转移活性，为 miRNA 介导的肿瘤转移调控提供了一种新的机制。
