ETV4 overexpression promotes progression of non-small cell lung cancer by upregulating PXN and MMP1 transcriptionally
ETV4 overexpression promotes progression of non-small cell lung cancer by upregulating PXN and MMP1 transcriptionally
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ETV4过表达通过上调PXN和MMP1转录促进非小细胞肺癌进展
DOI：
10.1002/mc.23130
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发表时间：
2020-01-01
影响因子：
4.6
通讯作者：
Li, Yuehong
中科院分区：
文献类型：
--
作者：
Wang, Yan;Ding, Xiaosong;Li, Yuehong
ETS变体4（ETV 4）与ETV 1和ETV 5一起构成ETS转录因子的PEA 3亚家族，其涉及许多癌症的进展。然而，在肺癌中，尤其是在肺鳞状细胞癌中，ETV 4调控的临床病理学意义和分子事件仍然知之甚少。在这里，我们的目的是确定参与ETV 4驱动的肺肿瘤发生的功能靶标。微阵列分析和验证数据显示，ETV 4是PEA 3中最具优势的因子，与非小细胞肺癌（NSCLC）的晚期、淋巴结转移和预后不良显著相关;所有P < .001。ETV 4表达降低抑制体内和体外NSCLC的生长和转移。微阵列、功能获得或丧失和荧光素酶报告分析揭示了ETV 4对粘着斑基因PXN和基质金属蛋白酶1（MMP 1）表达的直接调节作用，并且PXN和/或MMP 1抑制部分地消除了ETV 4诱导的细胞增殖和迁移。Kaplan-Meier分析表明ETV 4和PXN或MMP 1共过表达与人NSCLC的不良预后相关。总之，ETV 4-PXN和ETV 4-MMP 1轴是NSCLC中肿瘤进展和更差结果的有用生物标志物。
ETS variant 4 (ETV4), together with ETV1 and ETV5, constitute the PEA3 subfamily of ETS transcription factors, which are implicated in the progression of many cancers. However, the clinicopathologic significance and molecular events regulated by ETV4 in lung cancer are still poorly understood, especially in squamous cell carcinoma of the lung. Here, we aimed to identify functional targets involved in ETV4-driven lung tumorigenesis. Microarray analysis and validation data revealed that ETV4 was the most preponderant PEA3 factor, which was significantly related to the advanced stage, lymph node metastasis, and poor prognosis of non-small cell lung cancers (NSCLCs; all P < .001). Reduced ETV4 expression suppressed the growth and metastasis of NSCLC both in vivo and in vitro. Microarray, gain, or loss of function and luciferase report assays revealed the direct regulatory effect of ETV4 on the expression of focal adhesion gene PXN and matrix metalloproteinase 1 (MMP1), and PXN and/or MMP1 inhibition partially abolished cell proliferation and migration induced by ETV4. Kaplan-Meier analysis indicated that ETV4 and PXN or MMP1 co-overexpression is associated with poor prognosis in human NSCLCs. In conclusion, the ETV4-PXN and ETV4-MMP1 axes are useful biomarkers of tumor progression and worse outcomes in NSCLCs.