ETV4 promotes the progression of gastric cancer through regulating KDM5D
Authors: M-Z Cai
Q-X Chen
S-Y Fang
M-J Lian
M-Q Lian
L-S Cai
Journal: European review for medical and pharmacological sciences (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: ETV4; Gastric cancer; KDM5D; Expression characteristics; Metastasis
Affiliations: Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China. .

Abstract:  Objective: This study was aimed to investigate the expression characteristics of ETS variant 4 (ETV4) in gastric cancer (GCa), and to further explore whether it promotes the development of GCa by regulating KDM5D. Patients and methods: Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to examine the expression of ETV4 in 35 pairs of tumor tissue and paracancerous tissue specimens collected from GCa patients, and the interplay between ETV4 expression and clinical indexes, as well as the prognosis of GCa patients, were analyzed. Meanwhile, the expression of ETV4 in GCa cell lines was verified using qRT-PCR assay. Furthermore, ETV4 knockdown model was constructed using lentivirus in GCa cell lines including AGS and BGC-823, and then, the transwell invasion and cell wound healing assays were applied to analyze the effect of ETV4 on the biological function of GCa cells. In addition, an in-depth study of the relationship between ETV4 and KDM5D was conducted. Results: The results of qRT-PCR showed that the expression level of ETV4 in GCa tissue samples was remarkably higher than that in adjacent tissues, and the difference was statistically significant. Compared with patients with low expression of ETV4, the patients with high ETV4 expression had a higher occurrence rate of lymph node or distant metastasis and a lower overall survival rate. Similarly, the metastasis ability of GCa cells in the ETV4 expression knockdown group (sh-ETV4) was remarkably decreased when compared with the sh-NC group. In addition, qRT-PCR results indicated that the protein expression of KDM5D was significantly increased after the knockdown of ETV4. Therefore, it was demonstrated that ETV4 might be able to regulate the malignant progression of GCa via modulating KDM5D expression. Finally, the results of the cell reverse experiment confirmed that the silence of ETV4 could reverse the malignant progression of GCa induced by the downregulation of KDM5D. Conclusions: ETV4 expression was found remarkably elevated in GCa tissues and was significantly associated with the occurrence of lymph node or distant metastasis and poor prognosis. In addition, ETV4 might promote GCa cell metastasis by modulating KDM5D. 

Retracted: No

PubPeer comments:
 Figure 1.  ETV4 is highly expressed in gastric cancer tissues and cell lines. A, qRT-PCR was used to detect the difference in the expression of ETV4 in gastric cancer tissues and adjacent tissues. B, qRT-PCR was used to detect the difference in the expression of ETV4 in tissue samples from patients with gastric cancer with distant metastasis. C, qRT-PCR was used to detect the expression level of ETV4 in gastric cancer cell lines. D, Based on the Kaplan-Meier survival curve of gastric cancer patients with ETV4 expression, the prognosis of patients with high expression was found significantly worse than that of the low expression group . Expression of ETV4 in tumor samples ranges between 8 and 17.5 in 1A, but between 3 and 17.5 when the samples are subgrouped by  distant metastasis . This makes no sense. ![file] 1D is Another manifestation of Hoya s Law for J.BUOn and ERMPS...  When 40 or 50 cases of any given cancer are dichotomised into half-groups of high- or low-expression of any given nc-RNA, survival rate for one half-group or both will drop to 0% at 75 months. Other examples, from left to right: - Fig 1 from [Zang et al (2020)] - Fig 1 from [Li et al (2020)] - Fig 1, and Fig 4D, from [Cui et al (2019)] - Fig 1D from [Gao et al (2019)] . ![file] *[left]* Figure 1C from [Wu et al (2020)] . *[right]* Figs 1D, 3E from [Wu et al (2019)] . ![file] , 
 Fig 3  B, qRT-PCR was used to detect the differential expression of KDM5D in gastric cancer tissues and adjacent tissues. C, The Kaplan-Meier survival curve of gastric cancer patients was shown based on KDM5D expression; the prognosis of patients with low expression was significantly worse than that of the high expression group. D, There was a significant negative correlation between the expression levels of ETV4 and KDM5D in gastric cancer tissues. #1 Fig 3D offers a **third** distribution for ETV4 expression in the cancers : between 2 and 13. Meanwhile the expression of KDM5D in the cancer samples ranges between 1.5 and 6 (in 3B) OR between 2 and 12 (in 3D). ![file] It appears that the overall survival of the patients was greater when they were split into high- and low-KDM5D groups (in 3C) than when split into high- and low-ETV4 groups (in 1D). It is not possible for 1D and 3C to have come from the same set of survival data, dichotomised by different criteria. ,