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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2021; 27(8): 692-707
Published online Feb 28, 2021. doi: 10.3748/wjg.v27.i8.692
Fork head box M1 regulates vascular endothelial growth factor-A expression to promote the angiogenesis and tumor cell growth of gallbladder cancer
Rui-Tao Wang, Run-Chen Miao, Xing Zhang, Gang-Hua Yang, Yi-Ping Mu, Zi-Yun Zhang, Kai Qu, Chang Liu
Rui-Tao Wang, Run-Chen Miao, Xing Zhang, Zi-Yun Zhang, Kai Qu, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Run-Chen Miao, Chang Liu, Department of SICU, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Gang-Hua Yang, Department of Geriatric Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Yi-Ping Mu, Department of Medical Information Management Office, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Author contributions: Wang RT, Miao RC and Zhang X contributed equally to this work; Wang RT and Liu C designed the research; Wang RT, Miao RC and Zhang X wrote the paper; Yang GH, Mu YP and Miao RC collected the patient’s clinical data; Yang GH, Zhang ZY and Qu K analyzed the data; Zhang X revised the paper; all authors read and approved the final manuscript.
Supported by Scientific and Technological Development Research Project Foundation of Shaanxi Province of China, No. 2020SF-069.
Institutional review board statement: The study was reviewed and approved by the First Affiliated Hospital of Xi’an Jiaotong University College of Medicine Institutional Review Board.
Institutional animal care and use committee statement: This study was reviewed and approved by the Ethics Committee of the Xi’an Jiaotong University.
Conflict-of-interest statement: The authors declared no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Chang Liu, MD, PhD, Chief Doctor, Professor, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 West Yanta Road, Xi’an 710061, Shaanxi Province, China. liuchangdoctor@163.com
Received: September 9, 2020
Peer-review started: September 9, 2020
First decision: December 4, 2020
Revised: December 16, 2020
Accepted: January 21, 2021
Article in press: January 21, 2021
Published online: February 28, 2021
ARTICLE HIGHLIGHTS
Research background
Gallbladder cancer (GBC), with low detectable diagnosis and high metastasis, has a short survival time and a low 5-yr survival rate. Fork head box M1 (FoxM1) is relevant to poor prognosis and malignant behaviors, including proliferation, invasion and metastasis. Vascular endothelial growth factor-A (VEGF-A) plays an important role in angiogenesis. In GBC, it is meaningful to investigate the functional correlation between FoxM1 and VEGF-A.
Research motivation
FoxM1 is relevant to poor prognosis and malignant behaviors including proliferation, invasion and metastasis. VEGF-A plays an important role in angiogenesis. However, it is unclear whether FoxM1 could regulate VEGF-A.
Research objectives
This study aimed to investigate whether FoxM1 enhanced the angiogenesis of GBC via regulating VEGF-A.
Research methods
Using immunohistochemistry, we investigated FoxM1 and VEGF-A expression in GBC tissues, paracarcinoma tissues and cholecystitis tissues. Soft agar, cell invasion, migration and apoptosis assays were used to analyze the malignant phenotype influenced by FoxM1 in GBC. Kaplan-Meier survival analysis was performed to evaluate the impact of FoxM1 and VEGF-A expression in GBC patients. We investigated the relationship between FoxM1 and VEGF-A by regulating the level of FoxM1. Next, we performed MTT assays and Transwell invasion assays by knocking out or overexpressing VEGF-A to evaluate its function in GBC cells. The luciferase assay was used to reveal the relationship between FoxM1 and VEGF-A. BALB/c nude mice were used to establish the xenograft tumor model.
Research results
FoxM1 expression was higher in GBC tissues than in paracarcinoma tissues. Furthermore, the high expression of FoxM1 in GBC was significantly correlated with the malignant phenotype and worse overall survival. Meanwhile, high expression of FoxM1 influenced angiogenesis. Attenuated FoxM1 significantly suppressed cell proliferation, transfer and invasion in vitro. Knockdown of FoxM1 in GBC cells reduced the expression of VEGF-A. The luciferase assay showed that FoxM1 was the transcription factor of VEGF-A. Knockdown VEGF-A in FoxM1 overexpressed cells could partly reverse the malignant phenotype of GBC cells. High expression of FoxM1 combined with high expression of VEGF-A was related to poor prognosis. In this study, we found that FoxM1 was involved in regulation of VEGF-A expression.
Research conclusions
FoxM1 and VEGF-A overexpression were associated with prognosis of GBC patients. FoxM1 upregulated VEGF-A expression, which played an important role in the progression of GBC.
Research perspectives
By comprehending the way FoxM1 induced angiogenesis through regulating VEGF-A in GBC, the present study showed a possible method for treatment strategy of GBC patients with metastasis and in late stage.
