Forkhead Box Q1 Is Critical to Angiogenesis and Macrophage Recruitment of Colorectal Cancer.

Hui Tang,Jin-Li Wang,Xuan Bai,Dan-Yang Li,Ji Zheng,Lin-Ping Wang,Qiang Guo,Jian-Hua Liang,Ke-Lin Yue

doi:10.3389/fonc.2020.564298

Abstract

Angiogenesis and the tumor microenvironment (TME) play important roles in tumorigenesis. Forkhead box Q1 (FOXQ1) is a well-established oncogene in multiple tumors, including colorectal cancer (CRC); however, whether FOXQ1 contributes to angiogenesis and TME modification in CRC remains largely uncharacterized. Here, we demonstrate an essential role of FOXQ1-induced angiogenesis and macrophage recruitment in CRC that is related to its ability to promote the migration of endothelial cells and macrophages through activation of the EGF/PDGF pathway and the Twist1/CCL2 axis. We also provide evidence showing that the clinical significance between FOXQ1, Twist1, CCL2, and macrophage infiltration is associated with reduced 8-year survival in CRC patients. Our findings suggest FOXQ1 plays critical roles in the malignancy and progression of CRC, Therefore, FOXQ1 may serve as a therapeutic target for inhibiting angiogenesis and reducing macrophage recruitment in CRC.

Highlights

Tumor initiation and malignancy are closely associated with angiogenesis [1], and pathological neovascularization initiates tumor tissue ischaemia, growth, and metastasis [2]
The results showed that mRNA expression of CCL2, CXCL12, IL6, IL8, and TNF, all of which are implicated in macrophage recruitment and inflammation, were dramatically downregulated in DLD1shFOXQ1 compared with control cells (Figure 1F; CCL2 and IL6, P
The results show that HCT116-Forkhead box Q1 (FOXQ1) cells elicited a strong angiogenic response and induced HUVECs to differentiate into microvessel structures; a similar angiogenic response was observed with HCT116-FOXQ1-Conditioned Medium (CM), though the effect was less obvious (Figure 3C)

Summary

Introduction

Tumor initiation and malignancy are closely associated with angiogenesis [1], and pathological neovascularization initiates tumor tissue ischaemia, growth, and metastasis [2]. Macrophages within the tumor microenvironment (TME) facilitate angiogenesis and extracellular-matrix breakdown, remodelling and promoting tumor cell migration, invasion, and metastasis [4]. Recent studies suggest that the tumorogenic function of FOXQ1 may be related to its ability to promote cell cycle progression [10, 16], tumor angiogenesis [10], cell proliferation [11, 21], stem cell-like properties [14], resistance to chemotherapy-induced apoptosis [14], modification of the TME [19], epithelial-mesenchymal transition (EMT) [22, 23], senescence-associated inflammation [24], and Wnt signaling activation [25]. FOXQ1 has been shown to be a regulator of cancer invasion and metastasis in CRC and a modulator of Twist expression [11]. The role of Twist1induced CCL2 in angiogenesis has been demonstrated [26], which raises the possibility that FOXQ1 may induce angiogenesis in CRC by inducing Twist; a role for FOXQ1 in inducing tumor angiogenesis and TME modification in CRC has not been evaluated

Methods

Results

Conclusion