FOXP3 suppresses breast cancer metastasis through downregulation of CD44
FOXP3 suppresses breast cancer metastasis through downregulation of CD44
复制标题
FOXP3通过下调CD44抑制乳腺癌转移
DOI：
10.1002/ijc.29482
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发表时间：
2015-09-01
影响因子：
6.4
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Zhang, Cun;Xu, Yujin;Zhang, Wei
叉头盒蛋白3 （FOXP3）作为一种x连锁肿瘤抑制基因在乳腺癌中发挥重要作用。然而，FOXP3在乳腺癌转移中的生物学功能和意义尚不清楚。在临床上，我们发现FOXP3核表达与乳腺癌转移呈负相关。此外，我们在体内和体外均证明FOXP3显著抑制乳腺癌细胞的粘附、侵袭和转移。此外，通过转录组序列分析（RNA-seq）发现FOXP3抑制粘附分子CD44。荧光素酶报告试验、染色质免疫沉淀和电泳迁移转移试验确定CD44是FOXP3的直接靶标。在乳腺癌细胞中，CD44的表达被FOXP3下调。重要的是，抗CD44抗体在体外逆转了FOXP3 sirna对乳腺癌细胞的诱导作用，乳腺癌细胞核中FOXP3的表达水平与临床乳腺癌组织中CD44的表达水平呈负相关。综上所述，本研究的结果表明FOXP3是乳腺癌转移的抑制因子。FOXP3直接与CD44的启动子结合，抑制其蛋白表达，从而抑制人乳腺癌细胞的粘附和侵袭。这一发现突出了FOXP3-CD44信号抑制乳腺癌转移的治疗潜力。有什么新鲜事吗?FOXP3是一种x连锁肿瘤抑制基因，通过作为SKP2和HER2等乳腺癌致癌基因的转录抑制因子影响乳腺癌的发生。本研究探讨了FOXP3在乳腺癌转移中的作用。体内和体外实验表明FOXP3抑制乳腺癌细胞粘附、侵袭和转移，而分子机制研究表明FOXP3通过下调CD44表达直接抑制乳腺癌转移。
Forkhead box protein 3 (FOXP3) plays an important role in breast cancer as an X-linked tumor suppressor gene. However, the biological functions and significance of FOXP3 in breast cancer metastasis remain unclear. Here, we find that, clinically, nuclear FOXP3 expression is inversely correlated with breast cancer metastasis. Moreover, we demonstrate that FOXP3 significantly inhibits adhesion, invasion and metastasis of breast cancer cells in vivo and in vitro. In addition, the adhesion molecule CD44 is found to be suppressed by FOXP3 through transcriptome sequence analysis (RNA-seq). A luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay identify CD44 as a direct target of FOXP3. The expression of CD44 is downregulated by FOXP3 in breast cancer cells. Importantly, anti-CD44 antibody reverses the FOXP3 siRNA-induced effects on the breast cancer cells in vitro and FOXP3 expression level in the nucleus of breast cancer cells is inversely correlated with CD44 expression level in clinic breast cancer tissues. Taken together, the results from the present study suggest that FOXP3 is a suppressor of breast cancer metastasis. FOXP3 directly binds to the promoter of CD44 and inhibits its protein expression, thereby suppressing adhesion and invasion of human breast cancer cells. This finding highlights the therapeutic potential of FOXP3-CD44 signaling to inhibit breast cancer metastasis.What's New? FOXP3 is an X-linked tumor suppressor gene that influences mammary carcinogenesis by acting as a transcriptional repressor of breast cancer oncogenes such as SKP2 and HER2. The present study examined the role of FOXP3 in breast cancer metastasis. In vivo and in vitro experiments demonstrated that FOXP3 inhibited breast cancer cell adhesion, invasion and metastasis, while study on the molecular mechanism revealed that FOXP3 inhibited breast cancer metastasis by down-regulating CD44 expression directly.