Published online Feb 28, 2021. doi: 10.3748/wjg.v27.i8.692
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
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.
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.
This study aimed to investigate whether FoxM1 enhanced the angiogenesis of GBC via regulating VEGF-A.
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.
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.
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.
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.