Docking Proteins Upregulate IL-1β Expression in Lower Esophageal Sphincter Muscle in Esophageal Achalasia

TL;DR

This study finds that increased DOK1 and DOK2 proteins in the lower esophageal sphincter may lead to IL-1β expression, contributing to esophageal achalasia.

Contribution

The novel finding is the link between upregulated DOK1/DOK2 and IL-1β in achalasia pathogenesis.

Findings

DOK1 and DOK2 mRNA levels are significantly increased in the LES of achalasia patients.

IL-1β expression correlates with DOK1 and DOK2 levels in the LES muscle.

Reduced hsa-miR-377-3p and miR-376a-3p expression is observed in achalasia LES muscle.

Abstract

Background/Objectives: Esophageal achalasia is an archetypal esophageal motility disorder characterized by abnormal peristalsis of the esophageal body and impaired lower esophageal sphincter (LES) relaxation. Methods: In this study, the mRNA expression of docking proteins 1 and 2 (DOK1 and DOK2, respectively) were analyzed and the mechanisms underlying achalasia onset were investigated. Results: DOK1 and DOK2 mRNA levels significantly increased in the LES of patients with achalasia. Moreover, significant correlations were observed between IL-1β and DOK1, IL-1β and DOK2, ATG16L1 and DOK1, and HSV1-miR-H1-3p and DOK2 expression levels. However, a correlation between ATG16L1 and DOK2 or between HSV-miR-H1-3p and DOK1 expression was not observed. In addition, a positive correlation was observed between patient age and DOK1 expression. Microarray analysis revealed a significant decrease in the expression of hsa-miR-377-3p and miR-376a-3p in the LES muscle of patients with achalasia. Conclusions: These miRNAs possessed sequences targeting DOK. The upregulation of DOK1 and DOK2 expression induces IL-1β expression in the LES of achalasia patients, which may contribute to the development of esophageal motility disorder.

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