An Essential NRP1-Mediated Role for Tagln2 in Gastric Cancer Angiogenesis.

Hongwei Jin,Jingjing Hou,Huiqin Zhuo,Huifang Peng,Wei Zheng

doi:10.3389/fonc.2021.653246

Abstract

Knowledge about the precise biological role and underlying mechanism of Tagln2 in tumor progression is relatively limited, especially in angiogenesis focused on tumor derived endothelial cells (ECs) has rarely been reported. Here, the function, molecular mechanism and potential clinical value of Tagln2 in gastric cancer (GC) angiogenesis were investigated. GC tissue microarrays were used to assess the expression of Tagln2 in ECs. The relationships between expression and clinicopathological features were analyzed to evaluate the clinical value of Tagln2. Gain- and loss-of-function approaches were performed in ECs to investigate the functions of Tagln2 in angiogenesis. A combination of angiogenesis antibody array, RNA-Seq analyses and a series of in vitro experiments were performed to reveal the proangiogenic mechanism mediated by NRP1. Immunohistochemistry performed on an independent tissue chip (n=75) revealed significant upregulation of Tagln2 in tumor-derived ECs which were specifically immunolabeled with CD34. Additionally, high Tagln2 levels correlated significantly with the presence of lymph node as well as distant metastases. Gain- and loss-of-function approaches highlighted the function of Tagln2 in promoting EC proliferation, motility, and capillary-like tube formation and in reducing apoptosis. Tagln2 upregulation led to significantly increased mRNA and protein levels of NRP1 and subsequently activated the NRP1/VEGFR2 and downstream MAPK signaling pathways. These data indicate the importance of Tagln2 in angiogenesis, as a potential therapeutic target, and as a candidate prognostic marker in GC.

Highlights

Gastric cancer (GC) is one of the most common malignant tumors worldwide
These findings demonstrated the essential function of Tagln2 in tumor angiogenesis for the first time, but the precise molecular mechanism involved in this process has not yet been reported
Tagln2 Protein Expression Was Aberrantly Increased in GC-Derived endothelial cells (ECs)

Summary

INTRODUCTION

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Its morbidity and mortality rate ranked fifth and fourth, respectively, in 2020 [1]. Our group found that Tagln expression was significantly higher in microvascular endothelial cells (ECs) from lung cancer tumor tissues than in their paired normal counterparts, which was associated with advanced clinical stage, increased tumor size, and histological neural invasion [16]. These findings demonstrated the essential function of Tagln in tumor angiogenesis for the first time, but the precise molecular mechanism involved in this process has not yet been reported. A combination of angiogenesis antibody array, RNA-Seq analyses and a series of cell-based functional experiments were performed to reveal the critical role of Neuropilin-1 (NRP1, the coreceptor with VEGFR2 for the VEGF165 isoform of VEGF-A) and downstream MAPK signaling pathways in the angiogenic activity of Tagln

MATERIALS AND METHODS

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT