The tumor suppressor interferon regulatory factor 8 inhibits β-catenin signaling in breast cancers, but is frequently silenced by promoter methylation.
The tumor suppressor interferon regulatory factor 8 inhibits β-catenin signaling in breast cancers, but is frequently silenced by promoter methylation.
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抑癌干扰素调节因子 8 抑制乳腺癌中的 β-连环蛋白信号传导，但经常被启动子甲基化沉默
DOI：
10.18632/oncotarget.16511
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发表时间：
2017-07-25
期刊：
影响因子：
--
通讯作者：
Ren G
中科院分区：
文献类型：
--
作者：
Luo X;Xiong X;Shao Q;Xiang T;Li L;Yin X;Li X;Tao Q;Ren G
干扰素（IFN）调节因子8（IFN-8）是由一个新的候选肿瘤抑制基因（IRF 8）编码的，其启动子在多种肿瘤中经常被甲基化。然而，IRF 8在乳腺癌中的启动子甲基化状态、功能和潜在机制仍不清楚。我们发现，与正常乳腺组织相比，IRF 8在乳腺癌细胞系和原发性肿瘤中下调，主要是因为异常的启动子甲基化。然而，其表达与病理特征无关。IRF 8表达的恢复抑制细胞增殖、集落形成、5-乙炔基-2 ′-脱氧尿苷掺入、细胞迁移和侵袭，并诱导细胞凋亡和细胞周期阻滞。IRF 8还抑制裸鼠体内异种移植物生长。IRF 8突变体（K79 E）与IRF 8功能的竞争增强了体外4 T1鼠细胞的细胞迁移和侵袭。重要的是，IRF 8作为IFN-γ/STAT 1信号传导的下游靶基因和调节剂，抑制经典β-catenin信号传导。这些发现将IRF 8鉴定为在乳腺癌中调节IFN-γ/STAT 1信号传导和β-连环蛋白信号传导的新型肿瘤抑制剂。
Interferon (IFN) regulatory factor 8 is encoded by a novel candidate tumor suppressor gene (IRF8), its promotor is frequently methylated in multiple cancers. However, the promoter methylation status, functions and underlying mechanisms of IRF8 in breast cancer remain unclear. We found that IRF8 was downregulated in breast cancer cell lines and primary tumors, compared with normal breast tissues, mainly because of aberrant promoter methylation. However, its expression was not associated with pathological characteristics. Restoration of IRF8 expression suppressed cell proliferation, colony formation, 5-ethynyl-2′-deoxyuridine incorporation, cell migration and invasion, and induced apoptosis and cell cycle arrest in vitro. IRF8 also inhibited xenograft growth in nude mice in vivo. Competition with IRF8 function by IRF8 mutant (K79E) enhanced cell migration and invasion in 4T1 murine cells in vitro. Importantly, IRF8, as both downstream target gene and regulator of IFN-γ/STAT1 signaling, inhibited canonical β-catenin signaling. These findings identify IRF8 as a novel tumor suppressor regulating IFN-γ/STAT1 signaling and β-catenin signaling in breast cancer.