FOXM 1 induces Vasculogenic mimicry in esophageal cancer through \u03b2-catenin /Tcf4 signaling

Lili Cheng,Dafang Zheng,Qiong Wu,Zhiwei Wang,Qi Wang,Zenong Cheng,Jia Ma,Hongfei Ci,Yanzi Qin,Yong Zhang,Yisheng Tao,Xiaoying Tao,Damin Chai,Danna Wang,Shiwu Wu,Dongbing Lu

doi:10.1186/s13000-020-00929-9

Lili Cheng, Dafang Zheng + Show 14 more

Open Access

https://doi.org/10.1186/s13000-020-00929-9

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Abstract

ObjectiveTo investigate the role of FOXM1, β-catenin and TCF4 in esophageal cancer (EC) and their relationship to VM (Vasculogenic Mimicry).MethodsCCK-8 were performed to examine EC cell proliferation in FOXM1 silenced cells. EC cell migration and invasion were investigated through wound healing and Transwell assays, respectively. The formation of pipe like structures were assessed in 3D cultures. The expression of Foxm1, β-catenin, Tcf4 and E-cadherin were investigated through western blot, RT-qPCR and immunohistochemistry (IHC) staining. The relationship between FOXM1 expression, clinic-pathological features, and overall survival (OS) were further analyzed.ResultsA loss of FOXM1 expression correlated with the OS of ESCC patients. FOXM1 silencing led to a loss of cell growth and suppressed cell migration and invasion in ESCC cells. VM structures were identified in ESCC tissues and human EC cell lines. Mechanistically, FOXM1 was found to promote tumorigenesis through the regulation of β-catenin, Tcf4, and E-cadherin in EC cells, leading to the formation of VM structures.ConclusionsThese findings highlight FoxM1 as a novel therapeutic target in ESCC.

Highlights

Esophageal Carcinoma (EC) is an invasive malignancy of the digestive system and the 6th leading cause of tumorrelated mortality
As for Vasculogenic mimicry (VM) (Fig. 2a), Forkhead box protein M1 (FOXM1)+ expression was confined to the nucleus, with higher positivity in esophageal squamous cell carcinoma (ESCC) samples (68.98%, 149/216) compared to adjacent normal tissues (15.28%, 33/216; P < 0.001; Fig. 2b)
The results showed that the expression FoxM1 and Tcf4 in FoxM1 silenced groups were significantly lower than blank- and negative control groups (P < 0.05, Fig. 4d-e)

Summary

Introduction

Esophageal Carcinoma (EC) is an invasive malignancy of the digestive system and the 6th leading cause of tumorrelated mortality. EC originates from the mucosa or glands of the esophagus [1, 2]. It is estimated that 17,290 patients in the United States (US) alone were diagnosed with esophageal cancer in 2018, from which 15,850 individuals died [3]. Two major histopathological subtypes of EC exist, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC is the predominant histological subtype in China, accounting for ~ 90% of cases

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