Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-α in breast cancer.
Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-α in breast cancer.
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DOI：
10.1158/0008-5472.can-12-2162
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发表时间：
2013-05-01
期刊：
影响因子：
11.2
通讯作者：
Alahari SK
中科院分区：
文献类型：
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作者：
Jin L;Wessely O;Marcusson EG;Ivan C;Calin GA;Alahari SK
MicroRNA (miR) 是一类关键的小型（21-25 个核苷酸）非编码内源 RNA，涉及基因表达调控。我们鉴定出 miR-23b 和 miR-27b 是在人类乳腺癌中高度上调的 miRNA。我们发现 miR-23b 和 miR-27b 的工程敲除显着抑制了乳腺癌的生长。 miR-23b 和 miR-27b 的敲低可增强 Nischarin (NISCH) 的表达。值得注意的是，这些 miRNA 和 Nischarin 在人类乳腺癌中呈反向表达，强调了它们的生物学相关性。我们证明了这些 miRNA 表达的临床相关性，并表明 miR-23b 和 miR-27b 的高表达与乳腺癌的不良预后相关。此外，在人类乳腺肿瘤的小鼠异种移植模型中，腹腔内递送的抗 miR-27b 可恢复 Nischarin 表达并减少肿瘤负荷。我们还首次报道 HER2/neu (ERBB2)、EGF 和 TNFA 通过 AKT/NF-κB 信号级联促进 miR-23b/27b 表达。 Nischarin 被发现通过抑制 NF-κB 磷酸化通过反馈环机制调节 miR-27b/23b 表达。由于抑制 miR-27b 的抗 miR-27b 化合物会抑制肿瘤生长，因此抗 miR-27b 似乎是开发新抗肿瘤疗法的良好候选者。
MicroRNAs (miRs) are a critical class of small (21–25 nucleotides) non-coding endogenous RNAs implicated in gene expression regulation. We identified miR-23b and miR-27b as miRNAs that are highly upregulated in human breast cancer. We found that engineered knockdown of miR-23b and miR-27b substantially repressed breast cancer growth. Nischarin (NISCH) expression was augmented by knockdown of miR-23b as well as miR-27b. Notably, these miRNAs and Nischarin were inversely expressed in human breast cancers, underscoring their biologic relevance. We demonstrated the clinical relevance of the expression of these miRNAs and showed that high expression of miR-23b and miR-27b correlates with poor outcome in breast cancer. Moreover, intraperitoneally delivered anti-miR-27b restored Nischarin expression and decreased tumor burden in a mouse xenograft model of human mammary tumor. Also we report for the first time that HER2/neu (ERBB2), EGF, and TNFA promote miR-23b/27b expression through the AKT/NF-κB signaling cascade. Nischarin was found to regulate miR-27b/23b expression through a feedback loop mechanism by suppressing NF-κB phosphorylation. Since anti-miR-27b compounds that suppress miR-27b inhibit tumor growth, the anti-miR-27b appears to be a good candidate for the development of new anti-tumor therapies.