Muscarinic acetylcholine receptor 3 mediates vagus nerve-induced gastric cancer

Linjun Wang,Zheng Li,Li Yang,Bowen Li,Weizhi Wang,Yiwen Xia,Zekuan Xu,Jianghao Xu,Hao Xu,Kai Yin

doi:10.1038/s41389-018-0099-6

Abstract

Increasing evidence shows that the vagus nerve plays an important role in tumourigenesis. However, the effects and underlying mechanisms of the vagus nerve on gastric cancer (GC) development have not been established. In this study, we performed a unilateral truncal vagotomy at the subdiaphragmatic level in a mouse xenograft GC model to study the effects of the vagus nerve on GC development. Gene microarray analysis was used to explore the mechanism underlying this process. Significantly altered genes and pathways were analysed by Kyoto Encyclopaedia of Genes and Genomes analysis tool. We also detected muscarinic acetylcholine receptor 3 (M3) mRNA and protein levels by quantitative real-time polymerase chain reaction and immunohistochemical staining in mouse stomach tissue. To further confirm the functional role of M3, an in vivo M3 selective antagonist (darifenacin) assay was applied. Finally, we determined the M3 protein levels in human GC tissues and paired non-cancerous gastric tissues by immunohistochemical staining. We found that the surgical vagotomy inhibited the development of GC in an orthotopic xenograft mouse model. Further analysis showed that multiple signalling pathways participated in this process and that M3 was a key factor in these pathways. We established that the M3 mRNA and protein levels decreased in the vagotomy group relative to the sham group. We also demonstrated that the M3 antagonist suppressed the development of GC. Finally, we revealed that M3 protein level was up-regulated in human GC tissues. In conclusions, we revealed the functional role of M3 on mediating the effects of the vagus nerve on GC. Our study contributes to understanding the mechanism underlying the interaction between GC and the vagus nerve and may help to identify new therapeutic targets for GC.

Highlights

Nerves are traditionally regarded as transmission structures for electrical and chemical signals
In this study, we found that the vagus nerve played an important role in the development of gastric cancer (GC)
Surgical vagotomy inhibited the development of GC in an orthotopic xenograft mouse model

Summary

Introduction

Nerves are traditionally regarded as transmission structures for electrical and chemical signals. Increasing evidence has shown that they play an important role in tissue repair, regeneration and tumourigenesis[1]. The interaction between nerves and cancer has been established in several tumour types. (approximately 80% of tumours) was higher than in the greater curvature[12,13,14]. The vagus nerve exerts a prominent role in the innervation of the stomach, and it is mainly distributed in the lesser curvature, suggesting that tumour prevalence correlates with the distribution of nerve fibres. Zhao et al showed that the densities of vagus nerve fibres and terminals correlate with tumour prevalence in the murine stomach, and surgical or pharmacological denervation inhibited gastric tumourigenesis in three independent mouse models of GC13. The effects and underlying mechanisms of the vagus nerve on the development of GC have not been established

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Results

Conclusion