Interleukin-1 receptor antagonist inhibits angiogenesis in gastric cancer

Zhenqiang Gong,Tiankang Guo,Xiaodan Zhao,Jianbo Du,Hui Cai,He Su,Jianbo Qi,Jiachi Ma,Quan Chen

doi:10.1007/s10147-018-1242-2

Abstract

BackgroundInterleukin-1 alpha (IL-1α) plays an important role in tumorigenesis and angiogenesis of gastric cancer. The interleukin-1 receptor antagonist (IL-1RA) inhibits IL-1 selectively and specifically through IL-1R type I (IL-1RI). However, the underlying mechanism by which IL-1RA modulates the interactions of tumor cells and their micro-environment is poorly understood. We have evaluated the role of IL-1RA in the metastatic process as well as the mutual or reciprocal actions between gastric cancer cells and stromal cells.Materials and methodsThe expressions of IL-1α, vascular endothelial growth factor (VEGF), and IL-1RI mRNA were determined by reverse transcriptase-PCR. The regulatory effect of IL-1RA on the secretion of VEGF in human gastric cancer cells and human umbilical vein endothelial cells (HUVECs) was detected by enzyme-linked immunosorbent assay. The effect of IL-1RA on metastatic potential was evaluated using proliferation, invasion, and angiogenesis assays, respectively, including in vitro co-culture system models consisting of tumor cells and stromal cells that were used to detect invasion and angiogenesis.ResultsInterleukin-1α mRNA was detected in the higher liver metastatic gastric cell line MKN45. IL-1α protein was expressed in MKN45 cells and in HUVECs. VEGF mRNA and protein were detected in the three gastric cancer cell lines (MKN4, NUGC-4, and AGS). Levels of VEGF secreted by gastric cancer cells and HUVECs appeared to be reduced through the action of IL-1RA via IL-1RI in a dose-dependent manner (P < 0.01). IL-1RA significantly inhibited the proliferation and migration of HUVECs (P < 0.01) and tube formation by HUVECs (P < 0.01), both in a dose-dependent manner. Compared with HUVECs grown without cancer cells (control) or with NUGC-4 cells, tube formation by HUVECs was significantly enhanced by co-culture with MKN45 cells (P < 0.01). The enhanced tube formation in the presence of MKN45 cells was inhibited by the addition of IL-1RA (P < 0.01).ConclusionsThe IL-1RA downregulated the metastatic potential of gastric cancer through blockage of the IL-1α/VEGF signaling pathways. IL-1RA has the potential to play a role in the treatment of gastric cancer.

Highlights

Interleukin-1 (IL-1) is a pro-inflammatory chemokine that interacts with specific membrane receptors on tumor cell surfaces and affects the proliferation and differentiation of tumor cell survival [1, 2]
We investigated whether IL-1α promotes vascular endothelial growth factor (VEGF) secretion by human gastric cancer cells and human umbilical vein endothelial cells (HUVECs) and, if so, whether and how interleukin-1 receptor antagonist (IL-1RA) affects the proliferation, invasion, and angiogenesis of HUVECs
The results of the reverse transcription (RT)-PCR analysis revealed that IL-1α mRNA was expressed only in the MKN45 cell line; no expression of IL-1α mRNA was detected in the NUGC-4 and AGS cell lines (Fig. 1a)

Summary

Introduction

Interleukin-1 (IL-1) is a pro-inflammatory chemokine that interacts with specific membrane receptors on tumor cell surfaces and affects the proliferation and differentiation of tumor cell survival [1, 2]. It regulates the expression of pro-metastatic genes, such as those of the matrix metalloproteinase family [5], CD44 [6], a multifunctional cell adhesion molecule, and c-MET, a tyrosine-protein kinase [7], and of activators of transcription factors, such as nuclear factor kappa B and activation protein-1 [8]. It promotes tumor growth and metastasis via enhanced process of angiogenesis through its regulation of the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) [9,10,11]. IL-1RA has the potential to play a role in the treatment of gastric cancer

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Conclusion