MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction.
MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction.
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DOI：
10.18632/oncotarget.3897
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发表时间：
2015-06-20
期刊：
影响因子：
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通讯作者：
Abrams SI
中科院分区：
文献类型：
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作者：
Banik D;Netherby CS;Bogner PN;Abrams SI
干扰素调节因子-8(IRF8)最初被认为是一种白血病肿瘤抑制因子，在实体瘤中也能发挥抗肿瘤活性。我们以前发现，IRF8缺失促进了肿瘤的生长，同时伴随着肿瘤细胞对凋亡的敏感性降低。然而，IRF8的表达对肿瘤生长的影响不能仅仅通过它对凋亡反应的调节来解释。探索性基因表达谱进一步揭示了IRF8和MMP3表达之间的反向关系，暗示了IRF8调节肿瘤行为的其他内在机制。虽然MMP3的表达最初与肿瘤的发生有关，但MMP3在这一阶段之后的作用仍不清楚。因此，我们假设MMP3控制了疾病的后期，包括进展到转移，并通过一个新的IRF8-MMP3轴做到了这一点。总之，我们显示了IRF8和MMP3在肿瘤进展中的表达之间的反向机制关系。重要的是，在沉默MMP3表达后，由于IRF8缺失而产生的生长优势显著降低。此外，在原位乳腺癌小鼠模型中，MMP3缺失减少了自发性肺转移。MMP3在一定程度上以细胞固有的方式发挥作用，并作为IRF8的直接转录靶点。因此，我们确定了IRF8-MMP3轴在肿瘤进展中的新作用，这揭示了新的治疗机会。
Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung metastasis in an orthotopic mouse model of mammary carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in tumor progression, which unveils new therapeutic opportunities.