IFN-γ-mediated IRF1/miR-29b feedback loop suppresses colorectal cancer cell growth and metastasis by repressing IGF1
IFN-γ-mediated IRF1/miR-29b feedback loop suppresses colorectal cancer cell growth and metastasis by repressing IGF1
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DOI：
10.1016/j.canlet.2015.01.003
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发表时间：
2015-04-01
期刊：
影响因子：
9.7
通讯作者：
Li, Xuenong
中科院分区：
文献类型：
--
作者：
Yuan, Li;Zhou, Chang;Li, Xuenong
为探讨microRNA-29 b（miR-29 b）在结直肠癌（CRC）中的临床病理学意义和潜在机制，采用体内和体外试验研究miR-29 b的作用。进行荧光素酶报告基因测定以确定miR-29 b与胰岛素样生长因子1（IGF 1）3'非翻译区（3' UTR）之间的关联。采用染色质免疫沉淀（ChIP）试验评估干扰素调节因子1（IRF 1）与miR-29 b的直接结合。我们发现，干扰素（IFN）-γ可以通过募集IRF 1到miR-29 b启动子的结合位点来诱导miR-29 b。低水平的miR-29 b与侵袭性表型显著相关。miR-29 b抑制CRC细胞生长和侵袭。IGF 1是PI 3 K/Akt信号通路的激活剂，被证实是miR-29 b的新靶点。此外，miR-29 b增加IRF 1表达，并且miR-29 b的抑制抑制IFN-γ诱导的细胞凋亡。我们阐明了潜在的信号通路，IFN-γ/IRF 1/miR-29 b/IGF 1，及其对CRC肿瘤发生的影响。IRF 1和miR-29 b之间的正反馈环可能有助于CRC细胞对IFN-γ的敏感性。靶向miR-29 b可能提供阻断CRC生长和转移的策略。(C)2015爱思唯尔爱尔兰有限公司版权所有。
To investigate the clinicopathological significance and underlying mechanism of microRNA-29b (miR-29b) in colorectal cancer (CRC), the role of miR-29b was investigated using in vivo and in vitro assays. Luciferase reporter assays were conducted to determine the association between miR-29b and the insulin-like growth factor 1 (IGF1) 3' untranslated region (3'UTR). Chromatin immunoprecipitation (ChIP) assays were employed to assess the direct binding of interferon regulatory factor 1 (IRF1) to miR-29b. We found that interferon (IFN)-gamma could induce miR-29b by recruiting IRF1 to binding sites in the miR-29b promoter. A low level of miR-29b was significantly associated with an aggressive phenotype. MiR-29b inhibited CRC cell growth and invasion. IGF1, an activator of PI3K/Akt signaling, was confirmed as a novel target of miR-29b. Moreover, miR-29b increased IRF1 expression, and the inhibition of miR-29b suppressed IFN-gamma-induced apoptosis. We elucidated the potential signaling pathway, IFN-gamma/IRF1/miR-29b/IGF1, and its implication for CRC tumorigenesis. A positive feedback loop between IRF1 and miR-29b may contribute to the sensitivity of CRC cells to IFN-gamma. Targeting miR-29b may provide a strategy for blocking CRC growth and metastasis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.