Early Growth Response 1-Dependent Downregulation of Matrix Metalloproteinase 9 and Mouse Double Minute 2 Attenuates Head and Neck Squamous Cell Carcinoma Metastasis
Early Growth Response 1-Dependent Downregulation of Matrix Metalloproteinase 9 and Mouse Double Minute 2 Attenuates Head and Neck Squamous Cell Carcinoma Metastasis
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DOI：
10.1159/000494867
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Hong, Su-Hyung
中科院分区：
文献类型：
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作者：
Kim, Jinkyung;Kang, Sung-Min;Hong, Su-Hyung
背景/目的：早期生长反应-1(Egr1)与肿瘤侵袭的功能相关性仍存在争议。Egr1对HNSCC侵袭过程中起重要作用的MMP9表达的影响仍存在争议。以前没有数据显示EGR1对小鼠双分钟2(MDM2)的影响，MDM2是一种基质金属蛋白酶9(MMP9)的表达增强剂。我们的目的是阐明Egr1表达与头颈部鳞状细胞癌(HNSCC)转移的负相关性。方法：采用肿瘤基因组图谱(TCGA)数据集分析和免疫组织化学(IHC)方法，比较正常组织和HNSCC组织中EGR1mRNA和蛋白的表达。采用Matrigel侵袭实验检测细胞体外侵袭能力。通过启动子-荧光素酶活性测定和染色质免疫沉淀(ChIP)检测Egr1对MDM2转录的抑制作用。结果：TCGA结果显示，正常口腔组织中Egr1的表达水平显著高于HNSCC肿瘤组织(校正后P=1.64×10(-16))。此外，非转移性喉癌组织中EGR1mRNA的表达水平显著高于转移性喉癌组织(调整后P=0.023)。免疫组化分析显示，原发肿瘤组织的核Egr1表达水平显著高于配对的转移淋巴结组织(P<；0.05)。Egr1过表达下调MMP9和MDM2蛋白表达。与这些观察结果一致的是，TCGA数据分析发现，在Egr1表达较高而MMP9和/或MDM2较低的人群中，转移患者显著减少。结论：Egr1通过下调MMP9和MDM2的表达来预防HNSCC的转移。Egr1可能是抑制HNSCC转移的潜在候选基因。
Background/Aims: The functional relevance of early growth response-1 (EGR1) on cancer invasion remains controversial. The effect of EGR1 on the expression of MMP9, which is important for HNSCC invasion, is still disputed. There is no previous data showing the effect of EGR1 on mouse double minute 2 (MDM2), an enhancer of matrix metalloproteinase 9 (MMP9) expression. Our aim is to clarify the negative correlation between EGR1 expression and head and neck squamous cell carcinoma (HNSCC) metastasis. Methods: EGR1 mRNA and protein expressions were compared in normal and HNSCC tissues using The Cancer Genome Atlas (TCGA) dataset analysis or immunohistochemistry (IHC), respectively. In vitro cell invasion was evaluated Matrigel invasion assay. EGR1-dependent inhibition of MDM2 transcription was assessed by promoter-luciferase assay and chromatin immunoprecipitation (ChIP). Results: TCGA data showed that EGR1 mRNA levels are significantly higher in normal oral tissues as compared with HNSCC tumor tissues (adjusted P = 1.64x10(-16)). In addition, nonmetastatic HNSCC tissues showed significantly higher EGR1 mRNA levels as compared with metastatic tissues (adjusted P = 0.023). IHC analysis showed that primary tumor tissues expressed significantly higher levels of nuclear EGR1 compared with paired metastatic lymph node tissues (P < 0.05). EGR1 overexpression downregulated MMP9 and MDM2 protein expression. Consistent with these observations, TCGA data analysis found significantly fewer metastatic patients among a subgroup of population presenting higher EGR1 expressions with lower MMP9 and/or MDM2. Conclusion: Our data suggests that EGR1 prevents HNSCC metastasis through downregulation of MMP9 and MDM2. EGR1 might be a potential candidate to attenuate HNSCC metastasis.