Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2020; 26(47): 7497-7512
Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7497
Blockage of ETS homologous factor inhibits the proliferation and invasion of gastric cancer cells through the c-Met pathway
Meng-Li Gu, Xin-Xin Zhou, Meng-Ting Ren, Ke-Da Shi, Mo-Sang Yu, Wen-Rui Jiao, Ya-Mei Wang, Wei-Xiang Zhong, Feng Ji
Meng-Li Gu, Xin-Xin Zhou, Meng-Ting Ren, Ke-Da Shi, Mo-Sang Yu, Wen-Rui Jiao, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Ya-Mei Wang, Department of Gastroenterology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, Zhejiang Province, China
Wei-Xiang Zhong, Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Author contributions: Gu ML and Zhou XX contributed equally to this work; Gu ML designed the research and wrote the manuscript; Gu ML, Zhou XX, Ren MT, and Jiao WR performed the experiments and acquired the data; Shi KD and Yu MS analyzed and interpreted the data; Wang YM performed some of the experiments; Zhong WX provided valuable suggestions for this study; Ji F contributed to study supervision; All authors have read and approved the final manuscript.
Supported by The Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province, No. 2017ZZ010; and Zhejiang Medical Science and Technology Program, No. 2018266817.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital, College of Medicine, Zhejiang University, Approval No. 2019-1218.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Feng Ji, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. jifeng@zju.edu.cn
Received: July 21, 2020
Peer-review started: July 21, 2020
First decision: September 30, 2020
Revised: October 13, 2020
Accepted: November 2, 2020
Article in press: November 2, 2020
Published online: December 21, 2020
Processing time: 151 Days and 6.3 Hours
Abstract
BACKGROUND

Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.

AIM

To investigate the role and mechanism of EHF in the occurrence and development of GC.

METHODS

The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.

RESULTS

The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).

CONCLUSION

These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.

Keywords: Gastric cancer; ETS homologous factor; c-Met; Antineoplastic target; Signaling pathway

Core Tip: The purpose of this study was to investigate the role and mechanism of ETS homologous factor (EHF) in the occurrence and development of gastric cancer (GC). The results showed that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and epithelial-to-mesenchymal transition. EHF may contribute to the tumorigenesis and progression of GC via the c-Met pathway. Therefore, EHF is a promising target for the diagnosis and treatment of GC.