A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth.
A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth.
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DOI：
10.18632/oncotarget.7577
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
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作者：
Patel Y;Shah N;Lee JS;Markoutsa E;Jie C;Liu S;Botbyl R;Reisman D;Xu P;Chen H
人表皮生长因子受体2（HER 2或ErBb 2）是一种受体酪氨酸激酶，在20-30%的乳腺癌中过表达，与不良预后和结果相关。几种microRNA（miRNAs）的失调在乳腺癌的进展和转移中起着关键作用。在这项研究中，我们筛选并鉴定了HER 2阳性乳腺癌细胞中失调的miRNAs。我们的分子生物学研究表明miR-489通过HER 2下游信号转导，特别是通过MAPK途径特异性下调。miR-489在HER 2阳性乳腺癌细胞中的恢复或过表达在体外显著抑制细胞生长，并降低异种移植小鼠的致瘤性和肿瘤生长。从机制上讲，我们发现miR-489的过表达导致HER 2和SHP 2水平降低，从而减弱HER 2下游信号传导。此外，我们首次证明HER 2是miR-489的直接靶点，因此HER 2-SHP 2-MAPK和miR-489信号通路形成相互抑制的环。采用实时荧光定量PCR和荧光原位杂交技术（FISH）检测发现，miR-489在肿瘤组织中的表达水平明显低于癌旁正常组织。乳腺癌中miR-489的下调与侵袭性肿瘤表型相关。总的来说，我们的研究结果定义了一个涉及miR-489和HER 2-SHP 2-MAPK信号轴的双负反馈环，可以调节乳腺癌细胞增殖和肿瘤进展，并可能对HER 2阳性乳腺癌具有治疗意义。
Human epidermal growth factor receptor 2 (HER2 or ErBb2) is a receptor tyrosine kinase overexpressed in 20-30% of breast cancers and associated with poor prognosis and outcome. Dysregulation of several microRNAs (miRNAs) plays a key role in breast cancer progression and metastasis. In this study, we screened and identified miRNAs dysregualted in HER2-positive breast cancer cells. Our molecular study demonstrated that miR-489 was specifically downregulated by the HER2-downstream signaling, especially through the MAPK pathway. Restoration or overexpression of miR-489 in HER2-positive breast cancer cells significantly inhibited cell growth in vitro and decreased the tumorigenecity and tumor growth in xenograft mice. Mechanistically, we found that overexpression of miR-489 led to the decreased levels of HER2 and SHP2 and thus attenuated HER2-downstream signaling. Furthermore, we for the first time demonstrated that HER2 is a direct target of miR-489 and therefore HER2-SHP2-MAPK and miR-489 signaling pathways form a mutually inhibitory loop. Using quantitative real-time PCR analysis and Fluorescent in situ hybridization technique (FISH), we found that miR-489 was expressed at significantly lower level in tumor tissues compared to the adjacent normal tissues. Downregulation of miR-489 in breast cancers was associated with aggressive tumor phenotypes. Overall, our results define a double-negative feedback loop involving miR-489 and the HER2-SHP2-MAPK signaling axis that can regulate breast cancer cell proliferation and tumor progression and might have therapeutic relevance for HER2-positive breast cancer.