Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7497
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
Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, and 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.
Currently, surgical resection represents the best curative option for GC. On the other hand, advanced novel targets for GC diagnosis and treatment have resulted in decreased incidence and mortality rates in recent years. However, the 5-year overall survival rate of patients with advanced GC is less than 30% due to delayed diagnosis and recurrence. Therefore, revealing the oncogenic mechanisms of GC and further exploring the strategies for GC diagnosis and treatment are urgent.
To investigate the role and mechanism of EHF in the occurrence and development of GC.
The expression of EHF mRNA in GC tissues and cell lines was measured by qPCR. 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 checked by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNAs (siRNAs) against EHF were 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/PI and PI staining to determine apoptosis and the cell cycle, respectively. Cell migration and invasion were assessed by transwell assays.
The data indicated 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 cell proliferation in 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 the c-Met downregulation and further blocked Ras/c-Raf/Erk1/2. Additionally, PTEN was upregulated and GSK-3β was deactivated. Moreover, inactivation of STAT3 was detected following EHF inhibition, leading to the blockage of the epithelial-to-mesenchymal transition (EMT).
These results suggested that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway.
EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.