背景：转移是结直肠癌（CRC）患者高致死率的原因。不幸的是，CRC转移的分子机制仍然是一个谜。在这里，我们调查了E74-like factor 4（ELF4），一个ETS家族成员，在促进CRC进展方面的功能。 方法：通过定量实时PCR、免疫组织化学和免疫印迹确定ELF4在人类CRC样本和CRC细胞系中的表达。通过体外转移实验和体内转移模型评估CRC细胞的迁移和侵袭表型。利用RNA测序探索ELF4的下游靶基因。利用荧光素酶报告试验和染色质免疫共沉淀试验确定与ELF4相关的转录调控。 结果：我们发现，ELF4升高与远处转移、进展的AJCC阶段和CRC患者极差的预后呈正相关。ELF4表达还是差预后的独立预测因子。ELF4的过表达通过转录其下游靶基因——成纤维细胞生长因子受体4（FGFR4）和SRC非受体酪氨酸激酶——促进CRC转移。成纤维细胞生长因子19（FGF19）通过ERK1 / 2 / SP1轴上调ELF4表达。在临床上，ELF4表达与FGF19，FGFR4和SRC呈正相关，并且共表达FGF19 / ELF4，ELF4 / FGFR4或ELF4 / SRC的CRC患者显示最差的临床结果。此外，FGFR4抑制剂BLU-554和SRC抑制剂KX2-391的联合显著抑制了ELF4介导的CRC转移。 结论：我们证明了ELF4在CRC转移过程中的必要性，而针对ELF4相关正反馈回路可能代表一种新型治疗策略。©作者（s）。

Background: Metastasis accounts for the high lethality of colorectal cancer (CRC) patients. Unfortunately, the molecular mechanism manipulating metastasis in CRC is still elusive. Here, we investigated the function of E74-like factor 4 (ELF4), an ETS family member, in facilitating CRC progression. Methods: The expression of ELF4 in human CRC samples and CRC cell lines was determined by quantitative real-time PCR, immunohistochemistry and immunoblotting. The migratory and invasive phenotypes of CRC cells were evaluated by in vitro transwell assays and in vivo metastatic models. The RNA sequencing was used to explore the downstream targets of ELF4. The luciferase reporter assays and chromatin immunoprecipitation assays were used to ascertain the transcriptional regulation related to ELF4. Results: We found elevated ELF4 was positively correlated with distant metastasis, advanced AJCC stages, and dismal outcomes in CRC patients. ELF4 expression was also an independent predictor of poor prognosis. Overexpression of ELF4 boosted CRC metastasis via transactivating its downstream target genes, fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, non-receptor tyrosine kinase, SRC. Fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis. Clinically, ELF4 expression had a positive correlation with FGF19, FGFR4 and SRC, and CRC patients who positively coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC exhibited the worst clinical outcomes. Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. Conclusions: We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.© The author(s).