MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling
MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling
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DOI：
10.1242/jcs.118299
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发表时间：
2013-03-15
影响因子：
4
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
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作者：
Du, William W.;Fang, Ling;Yang, Burton B.
已知microRNA在与癌症发展相关的基因表达中起调节作用。我们分析了乳腺癌患者中microRNA miR-24的水平，发现乳腺癌样本中的miR-24高于良性乳腺组织。我们构建了表达miR-24的构建体，并使用体外和体内技术研究了其功能。我们发现miR-24的异位表达促进了乳腺癌细胞的侵袭和迁移。小鼠体内实验表明，miR-24的表达增强了肿瘤生长、侵入局部组织、转移到肺组织，并降低了小鼠的总体存活率。在表达miR-24的细胞和肿瘤中，EGFR高度磷酸化，而磷酸酶酪氨酸蛋白磷酸酶非受体9型（PTPN 9）和受体型酪氨酸蛋白磷酸酶F（PTPRF）的表达受到抑制。我们证实miR-24可以直接靶向PTPN 9和PTPRF。与此一致，我们发现，在转移性乳腺癌患者中，磷酸化表皮生长因子受体（pEGFR）的水平较高，而PTPN 9和PTPRF的水平较低。PTPN 9和PTPRF的异位表达降低了pEGFR水平、细胞侵袭、迁移和肿瘤转移。此外，我们发现MMP 2、MMP 11、pErk和ADAM 15上调，而TIMP 2下调;所有这些都支持miR-24在肿瘤侵袭和转移中的作用。我们的研究结果表明，miR-24在乳腺癌的侵袭和转移中起着关键作用。miR-24可能成为癌症干预的靶点。
MicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.