miR-155 downregulates ErbB2 and suppresses ErbB2-induced malignant transformation of breast epithelial cells
miR-155 downregulates ErbB2 and suppresses ErbB2-induced malignant transformation of breast epithelial cells
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miR-155下调ErbB2并抑制ErbB2诱导的乳腺上皮细胞恶性转化
DOI：
10.1038/onc.2016.132
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发表时间：
2016-11-17
期刊：
影响因子：
8
通讯作者：
Liu, M-F
中科院分区：
文献类型：
--
作者：
He, X-H;Zhu, W.;Liu, M-F
ErbB2是一个重要的乳腺癌基因，其过表达在乳腺肿瘤的发生和恶性进展中起决定性作用。然而，乳腺癌细胞中ErbB2失调的分子机制仍然不完全清楚。在这项研究中，我们发现ErbB2阳性乳腺肿瘤中，ErbB2表达与miR-155水平呈负相关，miR-155是一种有充分证据的致癌miRNA。我们进一步确定miR-155在乳腺癌细胞中有效抑制ErbB2。在机制上，miR-155通过两种不同的机制下调ErbB2。首先，miR-155通过靶向ErbB2的转录激活因子HDAC2抑制ErbB2的转录。其次，miR-155通过编码区的调控元件直接靶向ErbB2。有趣的是，miR-155被曲妥珠单抗上调，进而导致曲妥珠单抗治疗的ErbB2阳性乳腺癌细胞中ErbB2表达降低。功能研究表明，miR-155抑制erbb2诱导的人乳腺上皮细胞的恶性转化。因此，我们的研究结果揭示了miR-155- erbb2在调节乳腺上皮细胞恶性转化中的有趣背景，从而表明miR-155在erbb2阳性乳腺癌中的一种新的作用模式。
ErbB2 is a vital breast cancer gene and its overexpression has a decisive role in breast tumor initiation and malignant progression. However, the molecular mechanisms that underlie ErbB2 dysregulation in breast cancer cells remain incompletely understood. In this study, we found that ErbB2 expression is inversely correlated with the level of miR-155, a well-documented oncogenic miRNA, in ErbB2-positive breast tumors. We further determined that miR-155 potently suppresses ErbB2 in breast cancer cells. Mechanistically, miR-155 acts to downregulate ErbB2 via two distinct mechanisms. First, miR-155 represses ErbB2 transcription by targeting HDAC2, a transcriptional activator of ErbB2. Second, miR-155 directly targets ErbB2 via a regulatory element in its coding region. Intriguingly, miR-155 is upregulated by trastuzumab and in turn leads to a reduction of ErbB2 expression in trastuzumab-treated ErbB2-positive breast cancer cells. Functional studies showed that miR-155 inhibits ErbB2-induced malignant transformation of human breast epithelial cells. Thus, our findings reveal an intriguing miR-155-ErbB2 context in regulating the malignant transformation of breast epithelial cells, and thereby indicate a novel mode of action for miR-155 in ErbB2-positive breast cancer.