Basic Study
Copyright ©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
Processing time: 170 Days and 3 Hours
Abstract
BACKGROUND

Gallbladder cancer (GBC) is an aggressive type of biliary tract cancer that lacks effective therapeutic targets. Fork head box M1 (FoxM1) is an emerging molecular target associated with tumor progression in GBC, and accumulating evidence suggests that vascular endothelial growth factor (VEGF) promotes various tumors by inducing neoangiogenesis.

AIM

To investigate the role of FoxM1 and the angiogenesis effects of VEGF-A in primary GBC.

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.

RESULTS

FoxM1 expression was higher in GBC tissues than in paracarcinoma tissues. Furthermore, the high expression of Foxm1 in GBC was significantly correlated with a malignant phenotype and worse overall survival. Meanwhile, high expression of FoxM1 influenced angiogenesis; high expression of FoxM1 combined with high expression of VEGF-A was related to poor prognosis. Attenuated FoxM1 significantly suppressed cell proliferation, transfer and invasion in vitro. Knockdown of FoxM1 in GBC cells reduced the expression of VEGF-A. Luciferase assay showed that FoxM1 was the transcription factor of VEGF-A, and knockdown VEGF-A in FoxM1 overexpressed cells could partly reverse the malignancy phenotype of GBC cells. In this study, we found that FoxM1 was involved in regulation of VEGF-A expression.

CONCLUSION

FoxM1 and VEGF-A overexpression were associated with the prognosis of GBC patients. FoxM1 regulated VEGF-A expression, which played an important role in the progression of GBC.

Keywords: Gallbladder neoplasms; Fork head box M1; Vascular endothelial growth factor-A; Angiogenesis; Progression; Prognosis

Core Tip: Fork head box M1 (FoxM1) is an emerging molecular target associated with early metastasis, drug resistance and poor patient survival in gallbladder cancer. Accumulating evidence suggests that vascular endothelial growth factor (VEGF) plays important roles in many kinds of tumors by inducing neoangiogenesis. In the present study, we found that VEGF-A overexpression was correlated with proliferation, invasion and poor prognosis. The results of Kaplan-Meier analysis showed that both FoxM1 and VEGF-A were associated with survival in gallbladder cancer. VEGF-A expression was regulated by FoxM1, which was the mechanism of FoxM1 enhancing the angiogenesis of gallbladder cancer.