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ETV4 overexpression promotes progression of non–small cell lung cancer by upregulating PXN and MMP1 transcriptionally
Author(s) -
Wang Yan,
Ding Xiaosong,
Liu Bei,
Li Minglei,
Chang Ying,
Shen Haitao,
Xie Shelly M.,
Xing Lingxiao,
Li Yuehong
Publication year - 2020
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23130
Subject(s) - mmp1 , biology , cancer research , carcinogenesis , lung cancer , tumor progression , cell growth , microarray analysis techniques , metastasis , cancer , medicine , gene expression , gene , genetics
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.